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Sample records for adenosine induces persistence

  1. Adenosine prevents isoprenaline-induced cardiac contractile and electrophysiological dysfunction.

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    Shao, Yangzhen; Redfors, Björn; Mattson-Hultén, Lillemor; Scharing Täng, Margareta; Daryoni, Elma; Said, Mohammed; Omerovic, Elmir

    2013-10-15

    Excessive levels of catecholamines are believed to contribute to cardiac dysfunction in a variety of disease states, including myocardial infarction and heart failure, and are particularly implicated in stress-induced cardiomyopathy, an increasingly recognized cardiomyopathy associated with significant morbidity and mortality. We have previously shown that a high dose of isoprenaline induces reversible regional dysfunction of the left ventricle in mice. We now hypothesize that adenosine can prevent cardiac dysfunction in this mouse model of stress-induced cardiomyopathy. Hundred male C57BL/6 mice were injected with 400mg/kg isoprenaline and then randomized to either 400mg/kg adenosine or saline. Cardiac function was evaluated by echocardiography at baseline and 2, 24, 48, 72, 96 and 120 min post isoprenaline. Myocardial fibrosis was quantified after 10 days. Intracellular lipid accumulation was quantified after 2 and 24h. Electrophysiological parameters and degree of lipid accumulation were evaluated in cultured HL1 cardiomyocytes. Two hours post isoprenaline treatment, echocardiographic parameters of global and posterior wall regional function were significantly better in adenosine-treated mice (P<0.05). This difference persisted at 24h, but saline-treated mice gradually recovered over the next 96 h. Intracellular lipid accumulation was also significantly lower in adenosine mice. We found no sign of fibrosis in the adenosine mice, whereas the extent of fibrosis in isoprenaline mice was 1.3% (P<0.05). Furthermore, adenosine-treated HL1 cells showed preserved electrophysiological function and displayed less severe intracellular lipid accumulation in response to isoprenaline. In conclusion, adenosine attenuates isoprenaline-induced cardiac dysfunction in mice and cells. © 2013 Elsevier B.V. All rights reserved.

  2. Isolation of the posterior left atrium for patients with persistent atrial fibrillation: routine adenosine challenge for dormant posterior left atrial conduction improves long-term outcome.

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    McLellan, Alex J A; Prabhu, Sandeep; Voskoboinik, Alex; Wong, Michael C G; Walters, Tomos E; Pathik, Bhupesh; Morris, Gwilym M; Nisbet, Ashley; Lee, Geoffrey; Morton, Joseph B; Kalman, Jonathan M; Kistler, Peter M

    2017-12-01

    Catheter ablation to achieve posterior left atrial wall (PW) isolation may be performed as an adjunct to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF). We aimed to determine whether routine adenosine challenge for dormant posterior wall conduction improved long-term outcome. A total of 161 patients with persistent AF (mean age 59 ± 9 years, AF duration 6 ± 5 years) underwent catheter ablation involving circumferential PVI followed by PW isolation. Posterior left atrial wall isolation was performed with a roof and inferior wall line with the endpoint of bidirectional block. In 54 patients, adenosine 15 mg was sequentially administered to assess reconnection of the pulmonary veins and PW. Sites of transient reconnection were ablated and adenosine was repeated until no further reconnection was present. Holter monitoring was performed at 6 and 12 months to assess for arrhythmia recurrence. Posterior left atrial wall isolation was successfully achieved in 91% of 161 patients (procedure duration 191 ± 49 min, mean RF time 40 ± 19 min). Adenosine-induced reconnection of the PW was demonstrated in 17%. The single procedure freedom from recurrent atrial arrhythmia was superior in the adenosine challenge group (65%) vs. no adenosine challenge (40%, P conduction was associated with an improvement in the success of catheter ablation for persistent AF.

  3. Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity

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    Sun, Kaiqi; Zhang, Yujin; Bogdanov, Mikhail V.; Wu, Hongyu; Song, Anren; Li, Jessica; Dowhan, William; Idowu, Modupe; Juneja, Harinder S.; Molina, Jose G.; Blackburn, Michael R.; Kellems, Rodney E.

    2015-01-01

    Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown. Here we report that adenosine induces SphK1 activity in human and mouse sickle and normal erythrocytes in vitro. Next, using 4 adenosine receptor-deficient mice and pharmacological approaches, we determined that the A2B adenosine receptor (ADORA2B) is essential for adenosine-induced SphK1 activity in human and mouse normal and sickle erythrocytes in vitro. Subsequently, we provide in vivo genetic evidence that adenosine deaminase (ADA) deficiency leads to excess plasma adenosine and elevated erythrocyte SphK1 activity. Lowering adenosine by ADA enzyme therapy or genetic deletion of ADORA2B significantly reduced excess adenosine-induced erythrocyte SphK1 activity in ADA-deficient mice. Finally, we revealed that protein kinase A-mediated extracellular signal-regulated kinase 1/2 activation functioning downstream of ADORA2B underlies adenosine-induced erythrocyte SphK1 activity. Overall, our findings reveal a novel signaling network regulating erythrocyte SphK1 and highlight innovative mechanisms regulating SphK1 activity in normal and SCD. PMID:25587035

  4. Regadenoson induces comparable left ventricular perfusion defects as adenosine: a quantitative analysis from the ADVANCE MPI 2 trial.

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    Mahmarian, John J; Cerqueira, Manuel D; Iskandrian, Ami E; Bateman, Timothy M; Thomas, Gregory S; Hendel, Robert C; Moye, Lemuel A; Olmsted, Ann W

    2009-08-01

    This study sought to determine whether regadenoson induces left ventricular perfusion defects of similar size and severity as seen with adenosine stress. Total and ischemic left ventricular perfusion defect size predict patient outcome. Therefore, it is important to show that newer stressor agents induce similar perfusion abnormalities as observed with currently available ones. The ADVANCE MPI 2 (Adenosine versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging) study was a prospective, double-blind, randomized trial comparing image results in patients undergoing standard gated adenosine single-photon emission computed tomography (SPECT) myocardial perfusion imaging who were then randomized in a 2:1 ratio to either regadenoson (N = 495) or a second adenosine SPECT (N = 260). Quantitative SPECT analysis was used to determine total left ventricular perfusion defect size and the extent of ischemia. Quantification was performed by a single observer who was blinded to randomization and image sequence. Baseline gated perfusion results were similar in patients randomized to adenosine or regadenoson. No significant differences in total (11.5 +/- 15.7 vs. 11.4 +/- 15.8, p = 0.88) or ischemic (4.8 +/- 9.2 vs. 4.6 +/- 8.9, p = 0.43) perfusion defect sizes were observed between the regadenoson and adenosine groups, respectively. Linear regression showed a close correlation between adenosine and regadenoson for total (r = 0.97, p regadenoson versus adenosine, respectively. The good correlation between serial adenosine and regadenoson studies regarding total (0.41 +/- 5.43 vs. 0.21 +/- 5.23, p = 0.76) and ischemic (0.17 +/- 5.31 vs. 0.23 +/- 6.08, p = 0.94) perfusion defects persisted in the subgroup of 308 patients with an abnormal baseline SPECT. Applying quantitative analysis, regadenoson induces virtually identical scintigraphic results as adenosine regarding the size and severity of left ventricular perfusion defects and the extent of scintigraphic

  5. Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats.

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    Tofovic, S P; Zacharia, L; Carcillo, J A; Jackson, E K

    2001-09-01

    The purpose of this study was to investigate in vivo the effects of modulating the adenosine system on endotoxin-induced release of cytokines and changes in heart performance and neurohumoral status in early, profound endotoxemia in rats. Time/pressure variables of heart performance and blood pressure were recorded continuously, and plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 1-beta (IL-1beta), plasma renin activity (PRA), and catecholamines were determined before and 90 min after administration of endotoxin (30 mg/kg of lipopolysaccharide, i.v.). Erythro-9[2-hydroxyl-3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects on measured time-pressure variables of heart performance under baseline conditions and during endotoxemia, yet significantly attenuated endotoxin-induced release of cytokines and PRA. Pretreatment with the non-selective adenosine receptor antagonist DPSPX not only prevented the effects of EHNA but also increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP/dtmax, heart rate x ventricular pressure product (HR x VPSP) and +dP/dtmax normalized by pressure (+dP/dtmax/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on heart performance and neurohumoral activation during the early phase of endotoxemia. 6N-cyclopentyladenosine (CPA; selective A1 adenosine receptor agonist) induced bradicardia and negative inotropic effects, reduced work load (i.e., decreased HR, VPSP, +dP/dtmax, +dP/dtmax/VPSP and HR x VPSP) and inhibited endotoxin-induced tachycardia and renin release. CGS 21680 (selective A2A adenosine receptor agonist) decreased blood pressure under basal condition but did not potentiate decreases in blood pressure

  6. Adenosine-induced neuroprotection : involvement of glia cells and cytokines

    NARCIS (Netherlands)

    Wittendorp, Maria Catharina

    2004-01-01

    Adenosine is released during pathological conditions and has significant neuroprotective effects mainly by stimulating adenosine A1 receptors in neurons. These neuroprotective effects are increased following upregulation of adenosine A1 receptors. Much research has been performed to enhance the

  7. Adenosine A(3) receptor-induced CCL2 synthesis in cultured mouse astrocytes

    NARCIS (Netherlands)

    Wittendorp, MC; Boddeke, HWGM; Biber, K

    During neuropathological conditions, high concentrations of adenosine are released, stimulating adenosine receptors in neurons and glial cells. It has recently been shown that stimulation of adenosine receptors in glial cells induces the release of neuroprotective substances such as NGF, S-100beta,

  8. Mechanisms and clinical significance of adenosine-induced dormant accessory pathway conduction after catheter ablation.

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    Spotnitz, Michelle D; Markowitz, Steven M; Liu, Christopher F; Thomas, George; Ip, James E; Liez, Joshua; Lerman, Bruce B; Cheung, Jim W

    2014-12-01

    Adenosine can unmask dormant pulmonary vein conduction after isolation. The role of adenosine in uncovering dormant accessory pathway (AP) conduction after AP ablation is unknown. We evaluated 109 consecutive patients (age, 41 ± 28 years; 62 [57%] men) who were administered adenosine after successful AP ablation. Dormant AP conduction was defined as adenosine-induced recurrent AP conduction, as demonstrated by recurrent preexcitation or change in retrograde ventriculoatrial activation patterns. Dormant AP conduction was identified in 13 (12%) patients. Adenosine led to transient retrograde AP conduction in 6 patients and transient anterograde AP conduction in 8 patients. In all these cases, adenosine-induced AP conduction occurred during the bradycardia phase of adenosine effect and resulted in dormant AP conduction times shorter than atrioventricular nodal conduction times before adenosine administration. On the basis of analysis of timing of occurrence of dormant AP conduction, the mechanism of adenosine-induced AP conduction was determined to be caused by AP excitability recovery in ≥ 12 (92%) cases. The presence of dormant AP conduction was a significant predictor of chronic recurrent AP conduction requiring repeat ablation (odds ratio, 8.54; 95% confidence interval, 1.09-66.9; P=0.041). Adenosine can unmask dormant AP conduction after catheter ablation. Direct effects of adenosine on the AP, possibly via AP membrane potential hyperpolarization, are the dominant mechanism of adenosine-induced AP conduction after ablation. Dormant AP conduction is associated with higher rates of recurrent AP conduction requiring repeat ablation. © 2014 American Heart Association, Inc.

  9. Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia.

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    Huang, Aji; Wu, Hongyu; Iriyama, Takayuki; Zhang, Yujin; Sun, Kaiqi; Song, Anren; Liu, Hong; Peng, Zhangzhe; Tang, Lili; Lee, Minjung; Huang, Yun; Ni, Xin; Kellems, Rodney E; Xia, Yang

    2017-07-01

    Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality. Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient mice. Genetic deletion of CD73 (an ectonucleotidase that converts AMP to adenosine) prevented the elevation of placental adenosine in the autoantibody-induced preeclampsia mouse model and ameliorated preeclampsia features and placental DNA hypomethylation. Immunohistochemical studies revealed that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts and that this effect is independent of A2B adenosine receptor activation in both preeclampsia models. Extending our mouse findings to humans, we used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without A2B adenosine receptor activation. Altogether, both mouse and human studies reveal novel mechanisms underlying placental DNA hypomethylation and potential therapeutic approaches for preeclampsia. © 2017 American Heart Association, Inc.

  10. Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease.

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    Poth, Jens M; Brodsky, Kelley; Ehrentraut, Heidi; Grenz, Almut; Eltzschig, Holger K

    2013-02-01

    Inflammatory lesions, ischemic tissues, or solid tumors are characterized by the occurrence of severe tissue hypoxia within the diseased tissue. Subsequent stabilization of hypoxia-inducible transcription factors-particularly of hypoxia-inducible factor 1α (HIF1A)--results in significant alterations of gene expression of resident cells or inflammatory cells that have been recruited into such lesions. Interestingly, studies of hypoxia-induced changes of gene expression identified a transcriptional program that promotes extracellular adenosine signaling. Adenosine is a signaling molecule that functions through the activation of four distinct adenosine receptors--the ADORA1, ADORA2A, ADORA2B, and ADORA3 receptors. Extracellular adenosine is predominantly derived from the phosphohydrolysis of precursor nucleotides, such as adenosine triphosphate or adenosine monophosphate. HIF1A-elicited alterations in gene expression enhance the enzymatic capacity within inflamed tissues to produce extracellular adenosine. Moreover, hypoxia-elicited induction of adenosine receptors--particularly of ADORA2B--results in increased signal transduction. Functional studies in genetic models for HIF1A or adenosine receptors implicate this pathway in an endogenous feedback loop that dampens excessive inflammation and promotes injury resolution, while at the same time enhancing ischemia tolerance. Therefore, pharmacological strategies to enhance HIF-elicited adenosine production or to promote adenosine signaling through adenosine receptors are being investigated for the treatment of acute inflammatory or ischemic diseases characterized by tissue hypoxia.

  11. Does coronary vasodilation after adenosine override endothelin-1-induced coronary vasoconstriction?

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    Loghin, Catalin; Sdringola, Stefano; Gould, K Lance

    2007-01-01

    Endothelin-1 is a powerful coronary vasoconstrictor that is overexpressed in coronary artery disease. Adenosine is a powerful coronary vasodilator used for myocardial perfusion imaging to identify flow-limiting coronary artery stenosis. Therefore, in an animal model we tested the hypothesis that intracoronary endothelin-1 may cause myocardial perfusion abnormalities by positron emission tomography (PET) at resting conditions that may persist or only partially improve after intravenous adenosine stress in the absence of myocardial scar and flow-limiting stenosis. Fourteen dogs underwent serial PET perfusion imaging with rubidium-82 before and after subselective intracoronary infusion of endothelin-1, followed by intravenous and then intracoronary adenosine. Small physiological doses of endothelin-1 infused into the mid-left circumflex coronary artery caused quantitatively significant resting perfusion abnormalities that normalized after intracoronary adenosine but not consistently after intravenous adenosine used for diagnostic imaging. After effects of adenosine abated, resting perfusion defects returned, lasting up to 5 h in some animals. Cumulative doses of endothelin-1 caused perfusion defects that did not normalize after intravenous adenosine. In an animal model without myocardial scar or flow-limiting stenosis, intracoronary endothelin-1 causes visually apparent, quantitatively significant, long-lasting myocardial perfusion defects at resting conditions that may persist or only partially improve after intravenous adenosine used for diagnostic imaging. These results may potentially explain resting perfusion abnormalities or heterogeneity by clinical PET that may persist or only partially improve after adenosine stress perfusion imaging in the absence of myocardial scar and flow-limiting stenosis.

  12. Teriparatide Induced Delayed Persistent Hypercalcemia

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    Nirosshan Thiruchelvam

    2014-01-01

    Full Text Available Teriparatide, a recombinant PTH, is an anabolic treatment for osteoporosis that increases bone density. Transient hypercalcemia is a reported side effect of teriparatide that is seen few hours following administration of teriparatide and resolves usually within 16 hours of drug administration. Persistent hypercalcemia, although not observed in clinical trials, is rarely reported. The current case describes a rare complication of teriparatide induced delayed persistent hypercalcemia.

  13. Mechanisms of adenosine-induced renal vasodilatation in hypertensive patients.

    NARCIS (Netherlands)

    Wierema, T.K.; Houben, A.J.H.M.; Kroon, A.A.; Postma, C.T.; Koster, D.; Engelshoven, J.M. van; Smits, P.; Leeuw, P.W. de

    2005-01-01

    BACKGROUND: Adenosine is an endogenous nucleoside with potent vasodilatory capacities, released under ischaemic conditions in particular. Its mechanisms of action, however, remain elusive. OBJECTIVE: To evaluate the role of adenosine, using a non-selective purinergic receptor antagonist, and the

  14. Adenosine induced ventricular arrhythmias in the emergency room

    NARCIS (Netherlands)

    Tan, H. L.; Spekhorst, H. H.; Peters, R. J.; Wilde, A. A.

    2001-01-01

    While adenosine effectively terminates most supraventricular tachycardias (SVT), rare case reports have demonstrated its proarrhythmic potential, including induction of ventricular tachycardia (VT). The aim of this study was to define the proarrhythmic effects of adenosine in a large, unselected

  15. Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction.

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    Ma, Yunfang; Zhang, Jun; Zhang, Qi; Chen, Ping; Song, Junyao; Yu, Shunji; Liu, Hui; Liu, Fuchen; Song, Chunhua; Yang, Dongqin; Liu, Jie

    2014-05-23

    Mitochondria are the most important sensor for apoptosis. Extracellular adenosine is well reported to induce apoptosis of tumor cells. Here we found that extracellular adenosine suppresses the cell growth by induction of apoptosis in BEL-7404 liver cancer cells, and identified a novel mechanism that extracellular adenosine triggers apoptosis by increasing Reactive Oxygen Species (ROS) production and mitochondrial membrane dysfunction in the cells. We observed that adenosine increases ROS production, activates c-Caspase-8 and -9 and Caspase effectors, c-Caspase-3 and c-PARP, induces accumulation of apoptosis regulator Bak, decreases Bcl-xL and Mcl-1, and causes the mitochondrial membrane dysfunction and the release of DIABLO, Cytochrome C, and AIF from mitochondria to cytoplasm in the cells; ROS inhibitor, NAC significantly reduces adenosine-induced ROS production; it also shows the same degree of blocking adenosine-induced loss of mitochondrial membrane potential (MMP) and apoptosis. Our study first observed that adenosine increases ROS production in tumor cells and identified the positive feedback loop for ROS-mediated mitochondrial membrane dysfunction which amplifies the death signals in the cells. Our findings indicated ROS production and mitochondrial dysfunction play a key role in adenosine-induced apoptosis of 7404 cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis

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    Alsharif, Khalaf F.; Thomas, Mark R.; Judge, Heather M.; Khan, Haroon; Prince, Lynne R.; Sabroe, Ian; Ridger, Victoria C.; Storey, Robert F.

    2015-01-01

    In the PLATO study, ticagrelor was associated with fewer pulmonary infections and subsequent deaths than clopidogrel. Neutrophils are a first-line defence against bacterial lung infection; ticagrelor inhibits cellular uptake of adenosine, a known regulator of neutrophil chemotaxis and phagocytosis. We assessed whether the inhibition of adenosine uptake by ticagrelor influences neutrophil chemotaxis and phagocytosis. Neutrophils and erythrocytes were isolated from healthy volunteers. Concentration-dependent effects of adenosine on IL-8-induced neutrophil chemotaxis were investigated and the involved receptors identified using adenosine receptor antagonists. The modulatory effects of ticagrelor on adenosine-mediated changes in neutrophil chemotaxis and phagocytosis of Streptococcus pneumoniae were determined in the presence of erythrocytes to replicate physiological conditions of cellular adenosine uptake. Low-concentration adenosine (10− 8 M) significantly increased IL-8-induced neutrophil chemotaxis (% neutrophil chemotaxis: adenosine 28.7% ± 4.4 vs. control 22.6% ± 2.4; p ticagrelor and dipyridamole (another inhibitor of adenosine uptake) but not by control or by cangrelor. Similarly, in the presence of erythrocytes, a low concentration of adenosine (10− 8 M) significantly increased neutrophil phagocytic index compared to control when ticagrelor was present (37.6 ± 6.6 vs. 28.0 ± 6.6; p = 0.028) but had no effect in the absence of ticagrelor. We therefore conclude that the inhibition of cellular adenosine reuptake by ticagrelor potentiates the effects of a nanomolar concentration of adenosine on neutrophil chemotaxis and phagocytosis. This represents a potential mechanism by which ticagrelor could influence host defence against bacterial lung infection. PMID:25869515

  17. Adenosine induces growth-cone turning of sensory neurons.

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    Grau, Benjamin; Eilert, John-Christian; Munck, Sebastian; Harz, Hartmann

    2008-12-01

    The formation of appropriate connections between neurons and their specific targets is an essential step during development and repair of the nervous system. Growth cones are located at the leading edges of the growing neurites and respond to environmental cues in order to be guided to their final targets. Directional information can be coded by concentration gradients of substrate-bound or diffusible-guidance molecules. Here we show that concentration gradients of adenosine stimulate growth cones of sensory neurons (dorsal root ganglia) from chicken embryos to turn towards the adenosine source. This response is mediated by adenosine receptors. The subsequent signal transduction process involves cAMP. It may be speculated that the in vivo function of this response is concerned with the formation or the repair and regeneration of the peripheral nervous system.

  18. Role of Adenosine Signaling on Pentylenetetrazole-Induced Seizures in Zebrafish

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    Siebel, Anna Maria; Menezes, Fabiano Peres; Capiotti, Katiucia Marques; Kist, Luiza Wilges; Schaefer, Isabel da Costa; Frantz, Juliana Zanetti; Bogo, Maurício Reis; Da Silva, Rosane Souza

    2015-01-01

    Abstract Adenosine is a well-known endogenous modulator of neuronal excitability with anticonvulsant properties. Thus, the modulation exerted by adenosine might be an effective tool to control seizures. In this study, we investigated the effects of drugs that are able to modulate adenosinergic signaling on pentylenetetrazole (PTZ)-induced seizures in adult zebrafish. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) decreased the latency to the onset of the tonic-clonic seizure stage. The adenosine A1 receptor agonist cyclopentyladenosine (CPA) increased the latency to reach the tonic-clonic seizure stage. Both the adenosine A2A receptor agonist and antagonist, CGS 21680 and ZM 241385, respectively, did not promote changes in seizure parameters. Pretreatment with the ecto-5′nucleotidase inhibitor adenosine 5′-(α,β-methylene) diphosphate (AMPCP) decreased the latency to the onset of the tonic-clonic seizure stage. However, when pretreated with the adenosine deaminase (ADA) inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), or with the nucleoside transporter (NT) inhibitors, dipyridamole and S-(4-Nitrobenzyl)-6-thioinosine (NBTI), animals showed longer latency to reach the tonic-clonic seizure status. Finally, our molecular analysis of the c-fos gene expression corroborates these behavioral results. Our findings indicate that the activation of adenosine A1 receptors is an important mechanism to control the development of seizures in zebrafish. Furthermore, the actions of ecto-5′-nucleotidase, ADA, and NTs are directly involved in the control of extracellular adenosine levels and have an important role in the development of seizure episodes in zebrafish. PMID:25560904

  19. Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury

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    Gorshkov, Boris; Varn, Matthew N.; Zemskova, Marina A.; Zemskov, Evgeny A.; Sridhar, Supriya; Lucas, Rudolf; Verin, Alexander D.

    2014-01-01

    Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) affect 200,000 people a year in the USA. Pulmonary vascular and specifically endothelial cell (EC) barrier compromise is a hallmark of these diseases. We have recently shown that extracellular adenosine enhances human pulmonary (EC) barrier via activation of adenosine receptors (ARs) in cell cultures. On the basis of these data, we hypothesized that activation of ARs might exert barrier-protective effects in a model of ALI/ARDS in mice. To test this hypothesis, we examined the effects of pre- and posttreatment of adenosine and 5′-N-ethylcarboxamidoadenosine (NECA), a nonselective stable AR agonist, on LPS-induced lung injury. Mice were given vehicle or LPS intratracheally followed by adenosine, NECA, or vehicle instilled via the internal jugular vein. Postexperiment cell counts, Evans Blue Dye albumin (EBDA) extravasation, levels of proteins, and inflammatory cytokines were analyzed. Harvested lungs were used for histology and myeloperoxidase studies. Mice challenged with LPS alone demonstrated an inflammatory response typical of ALI. Cell counts, EBDA extravasation, as well as levels of proteins and inflammatory cytokines were decreased in adenosine-treated mice. Histology displayed reduced infiltration of neutrophils. NECA had a similar effect on LPS-induced vascular barrier compromise. Importantly, posttreatment with adenosine or NECA recovers lung vascular barrier and reduces inflammation induced by LPS challenge. Furthermore, adenosine significantly attenuated protein degradation of A2A and A3 receptors induced by LPS. Collectively, our results demonstrate that activation of ARs protects and restores vascular barrier functions and reduces inflammation in LPS-induced ALI. PMID:24414256

  20. Bradykinin and adenosine receptors mediate desflurane induced postconditioning in human myocardium: role of reactive oxygen species

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    Gérard Jean-Louis

    2010-07-01

    Full Text Available Abstract Background Desflurane during early reperfusion has been shown to postcondition human myocardium, in vitro. We investigated the role of adenosine and bradykinin receptors, and generation of radical oxygen species in desflurane-induced postconditioning in human myocardium. Methods We recorded isometric contraction of human right atrial trabeculae hanged in an oxygenated Tyrode's solution (34 degrees Celsius, stimulation frequency 1 Hz. After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of N-mercaptopropionylglycine, a reactive oxygen species scavenger, 8-(p-Sulfophenyltheophylline, an adenosine receptor antagonist, HOE140, a selective B2 bradykinin receptor antagonist. In separate groups, adenosine and bradykinin were administered during the first minutes of reoxygenation alone or in presence of N-mercaptopropionylglycine. The force of contraction of trabeculae was recorded continuously. Developed force at the end of a 60-min reoxygenation period was compared (mean ± standard deviation between the groups by a variance analysis and post hoc test. Results Desflurane 6% (84 ± 6% of baseline enhanced the recovery of force after 60-min of reoxygenation as compared to control group (51 ± 8% of baseline, P N-mercaptopropionylglycine (54 ± 3% of baseline, 8-(p-Sulfophenyltheophylline (62 ± 9% of baseline, HOE140 (58 ± 6% of baseline abolished desflurane-induced postconditioning. Adenosine (80 ± 9% of baseline and bradykinin (83 ± 4% of baseline induced postconditioning (P vs control, N-mercaptopropionylglycine abolished the beneficial effects of adenosine and bradykinin (54 ± 8 and 58 ± 5% of baseline, respectively. Conclusions In vitro, desflurane-induced postconditioning depends on reactive oxygen species production, activation of adenosine and bradykinin B2 receptors. And, the cardioprotective effect of adenosine and bradykinin

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

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    Pizzino, Gabriele; Irrera, Natasha; Galfo, Federica; Oteri, Giacomo; Atteritano, Marco; Pallio, Giovanni; Mannino, Federica; D'Amore, Angelica; Pellegrino, Enrica; Aliquò, Federica; Anastasi, Giuseppe P; Cutroneo, Giuseppina; Squadrito, Francesco; Altavilla, Domenica; Bitto, Alessandra

    2017-01-01

    Glucocorticoid-induced osteoporosis (GIO) is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP) for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN), an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A 2 antagonist), or vehicle (0.9% NaCl). Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days) PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist), or zoledronate (as control for gold standard treatment), or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

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

    Directory of Open Access Journals (Sweden)

    Gabriele Pizzino

    2017-09-01

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

  3. Caffeine's Attenuation of Cocaine-Induced Dopamine Release by Inhibition of Adenosine.

    Science.gov (United States)

    Malave, Lauren B; Broderick, Patricia A

    2014-06-01

    Background: It is well known that the reinforcing properties of cocaine addiction are caused by the sharp increase of dopamine (DA) in the reward areas of the brain. However, other mechanisms have been speculated to contribute to the increase. Adenosine is one system that is associated with the sleep-wake cycle and is most important in regulating neuronal activity. Thus, more and more evidence is pointing to its involvement in regulating DA release. The current study set out to examine the role of adenosine in cocaine-induced DA release. Methods: Increasing doses of cocaine, caffeine, and their combination, as well as, 8-cyclopentyltheophylline (CPT), an adenosine A1 antagonist (alone and in combination with cocaine) were used to denote a response curve. A novel biosensor, the BRODERICK PROBE(®) was implanted in the nucleus accumbens to image the drug-induced surge of DA release in vivo, in the freely moving animal in real time. Results: Combinations of cocaine and caffeine were observed to block the increased release of DA moderately after administration of the low dose (2.5 mg/kg cocaine and 12.5 mg/kg caffeine) and dramatically after administration of the high dose (10 mg/kg cocaine and 50 mg/kg caffeine), suggesting neuroprotection. Similarly, CPT and cocaine showed a decreased DA surge when administered in combination. Thus, the low and high dose of a nonselective adenosine antagonist, caffeine, and a moderate dose of a selective adenosine antagonist, CPT, protected against the cocaine-induced DA release. Conclusions: These results show a significant interaction between adenosine and DA release and suggest therapeutic options for cocaine addiction and disorders associated with DA dysfunction.

  4. Adenosine kinase inhibition protects against cranial radiation-induced cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Munjal M Acharya

    2016-06-01

    Full Text Available Clinical radiation therapy for the treatment of CNS cancers leads to unintended and debilitating impairments in cognition. Radiation-induced cognitive dysfunction is long lasting, however, the underlying molecular and cellular mechanisms are still not well established. Since ionizing radiation causes microglial and astroglial activation, we hypothesized that maladaptive changes in astrocyte function might be implicated in radiation-induced cognitive dysfunction. Among other gliotransmitters, astrocytes control the availability of adenosine, an endogenous neuroprotectant and modulator of cognition, via metabolic clearance through adenosine kinase (ADK. Adult rats exposed to cranial irradiation (10 Gy showed significant declines in performance of hippocampal-dependent cognitive function tasks (novel place recognition, novel object recognition, and contextual fear conditioning 1 month after exposure to ionizing radiation using a clinically relevant regimen. Irradiated rats spent less time exploring a novel place or object. Cranial irradiation also led to reduction in freezing behavior compared to controls in the fear conditioning task. Importantly, immunohistochemical analyses of irradiated brains showed significant elevation of ADK immunoreactivity in the hippocampus that was related to astrogliosis and increased expression of glial fibrillary acidic protein (GFAP. Conversely, rats treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 3.1 mg/kg, i.p., for 6 days prior to cranial irradiation showed significantly improved behavioral performance in all cognitive tasks 1 month post exposure. Treatment with 5-ITU attenuated radiation-induced astrogliosis and elevated ADK immunoreactivity in the hippocampus. These results confirm an astrocyte-mediated mechanism where preservation of extracellular adenosine can exert neuroprotection also against radiation-induced pathology. These innovative findings link radiation-induced changes in cognition and CNS

  5. Adenosine Stress Induced Left Bundle Branch Block During Technetium-99m Tetrofosmin Myocardial Perfusion Imaging.

    Science.gov (United States)

    Jayanthi, Mohan Roop; Sasikumar, Arun; Gorla, Arun Kumar Reddy; Sood, Ashwani; Bhattacharya, Anish; Mittal, Bhagwant Rai

    2017-01-01

    The occurrence of left bundle branch block (LBBB) in electrocardiogram during exercise testing is a relatively rare finding. The incidence of LBBB during exercise testing ranges from 0.5% to 1.1%. The mechanism of exercise-induced LBBB (EI-LBBB) is poorly understood, but ischemia is a proposed etiology. Stress myocardial perfusion imaging (MPI) can be useful in patients with EI-LBBB to rule out coronary artery disease. Adenosine vasodilator stress is the preferred mode of stress in patients with LBBB for performing stress-MPI. Here we present an interesting case of adenosine-induced LBBB during stress-MPI in a 67-year-old female patient with normal coronary angiography.

  6. Acute, persistent quinine-induced blindness

    African Journals Online (AJOL)

    1991-05-04

    May 4, 1991 ... auinine-induced blindness arising during empirical treatment for malaria in a young man is reported. The condition was noteworthy because it was total and permanent, which is at varia.nce with other published reports. The condition usually disappears within minutes to weeks, but persistent deficits.

  7. Adenosine induces vasoconstriction through Gi-dependent activation of phospholipase C in isolated perfused afferent arterioles of mice

    DEFF Research Database (Denmark)

    Hansen, Pernille B; Castrop, Hayo; Briggs, Josie

    2003-01-01

    Adenosine induces vasoconstriction of renal afferent arterioles through activation of A1 adenosine receptors (A1AR). A1AR are directly coupled to Gi/Go, resulting in inhibition of adenylate cyclase, but the contribution of this signaling pathway to smooth muscle cell activation is unclear....... In perfused afferent arterioles from mouse kidney, adenosine and the A1 agonist N(6)-cyclohexyladenosine, when added to the bath, caused constriction in the concentration range of 10(-9) to 10(-6) M (mean diameter: control, 8.8 +/- 0.3 micro m; adenosine at 10(-6) M, 2.8 +/- 0.5 micro m). Adenosine......-induced vasoconstriction was stable for up to 30 min and was most pronounced in the most distal part of the afferent arterioles. Adenosine did not cause vasoconstriction in arterioles from A1AR-/- mice. Pretreatment with pertussis toxin (PTX) (400 ng/ml) for 2 h blocked the vasoconstricting action of adenosine or N(6...

  8. Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney

    Directory of Open Access Journals (Sweden)

    Ayodele Jacob Akinyemi

    2017-04-01

    Full Text Available In this study, the effect of enzymes involved in degradation of renal adenosine and l-arginine was investigated in rats exposed to cadmium (Cd and treated with curcumin, the principal active phytochemical in turmeric rhizome. Animals were divided into six groups (n = 6: saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. The results of this study revealed that the activities of renal adenosine deaminase and arginase were significantly increased in Cd-treated rats when compared with the control (p < 0.05. However, co-treatment with curcumin inhibits the activities of these enzymes compared with Cd-treated rats. Furthermore, Cd intoxication increased the levels of some renal biomarkers (serum urea, creatinine, and electrolytes and malondialdehyde level with a concomitant decrease in functional sulfhydryl group and nitric oxide (NO. However, co-treatment with curcumin at 12.5 mg/kg and 25 mg/kg, respectively, increases the nonenzymatic antioxidant status and NO in the kidney, with a concomitant decrease in the levels of malondialdehyde and renal biomarkers. Therefore, our results reinforce the importance of adenosine deaminase and arginase activities in Cd poisoning conditions and suggest some possible mechanisms of action by which curcumin prevent Cd-induced renal toxicity in rats.

  9. Comparison of adenosine-induced myocardial ischemia and atherosclerosis measured by coronary calcium tomography

    Energy Technology Data Exchange (ETDEWEB)

    Cho, I. H.; Chun, K. A.; Won, K. C.; Lee, H. W.; Hong, K. L.; Park, J. S.; Shin, D. K.; Kim, Y. C.; Sim, B. S. [Yeungnam University Medical Center, Daegu (Korea, Republic of)

    2005-07-01

    Coronary artery calcium shows a anatomic information and coronary atherosclerotic burde, but myocardial perfusion SPECT shows a physiologic significance of coronary stenosis and stress induced ischemia. Both are valuable in the noninvasive assessment of patients with suspected coronary artery disease. There has been little evaluation regarding the relationship between CAC and adenosine-induced ischemia and how to integrate CAC with myocardial perfusion SPECT. We assessed the relationship between adenosine-induced myocardial ischemia on myocardial perfusion single-photon emission computed tomography (MPS) and magnitude of coronary calcification (CAC) by MDCT in patients undergoing both tests. A total of 111 patients underwent adenosine-induced MPS and CAC within 2days. Coronary angiography was done in 55 patients. The frequency of ischemia by MPS was compared to the magnitude of CAC. Among 56 patients with ischemic MPS, the CAC scores were >0 in 87.5%, >100 in 76.8%, and > 400 in 50.0%. Of 25 normal MPS, the CAC scores were >0 in 70.9%. >100 in 34.5%, and > 400 in 14.5%, respectively. Of 38 patient with coronary artery stenosis proved by coronary angiography, the CAC scores were >0 in 92.1%, >100 in 78.9%, and > 400 in 50.0 %, respectively. Of 12 patient without coronary artery stenosis, the CAC scores were >100 in 66.7%, and > 400 in 41.7%. Ischemic MPS is associated with a high likelihood of subclinical atherosclerosis by CAC, but it can be also seen for CAC scores <100. The patient without significant coronary artery stenosis, however, may have extensive atherosclerosis by CAC criteria. Although, low CAC scores appear to obviate the need for subsequent testing, but MPS is still needed to diagnosis the myocardial ischemia.

  10. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors.

    Science.gov (United States)

    Gonca, Ersöz; Darıcı, Faruk

    2015-01-01

    Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid with anti-inflammatory activity mediated by enhancing adenosine signaling. As the adenosine A1 receptor activation confers protection against ischemia/reperfusion (I/R)-induced ventricular arrhythmias, we hypothesized that CBD may have antiarrhythmic effect through the activation of adenosine A1 receptor. Cannabidiol has recently been shown to suppress ischemia-induced ventricular arrhythmias. We aimed to research the effect of CBD on the incidence and the duration of I/R-induced ventricular arrhythmias and to investigate the role of adenosine A1 receptor activation in the possible antiarrhythmic effect of CBD. Myocardial ischemia and reperfusion was induced in anesthetized male rats by ligating the left anterior descending coronary artery for 6 minutes and by loosening the bond at the coronary artery, respectively. Cannabidiol alone was given in a dose of 50 µg/kg, 10 minutes prior to coronary artery occlusion and coadministrated with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in a dose of 100 µg/kg, 15 minutes prior to coronary artery occlusion to investigate whether the antiarrhythmic effect of CBD is modified by the activation of adenosine A1 receptors. The experimental groups were as follows: (1) vehicle control (n = 10), (2) CBD (n = 9), (3) DPCPX (n = 7), and (4) CBD + DPCPX group (n = 7). Cannabidiol treatment significantly decreased the incidence and the duration of ventricular tachycardia, total length of arrhythmias, and the arrhythmia scores compared to control during the reperfusion period. The DPCPX treatment alone did not affect the incidence and the duration of any type of arrhythmias. However, DPCPX aborted the antiarrhythmic effect of CBD when it was combined with it. The present results demonstrated that CBD has an antiarrhythmic effect against I/R-induced arrhythmias, and the antiarrhythmic effect of CBD may be mediated through the activation of adenosine

  11. A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Stefania Merighi

    2005-10-01

    Full Text Available Hypoxia-inducible factor-1 (HIF-1 is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% 02, adenosine upregulates HIF-1α protein expression in a dose-dependent and timedependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2 protein accumulation through the induction of HIF-1α. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1a and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells.

  12. Adenosine-induced stress myocardial perfusion imaging using dual-source cardiac computed tomography.

    Science.gov (United States)

    Blankstein, Ron; Shturman, Leon D; Rogers, Ian S; Rocha-Filho, Jose A; Okada, David R; Sarwar, Ammar; Soni, Anand V; Bezerra, Hiram; Ghoshhajra, Brian B; Petranovic, Milena; Loureiro, Ricardo; Feuchtner, Gudrun; Gewirtz, Henry; Hoffmann, Udo; Mamuya, Wilfred S; Brady, Thomas J; Cury, Ricardo C

    2009-09-15

    This study sought to determine the feasibility of performing a comprehensive cardiac computed tomographic (CT) examination incorporating stress and rest myocardial perfusion imaging together with coronary computed tomography angiography (CTA). Although cardiac CT can identify coronary stenosis, very little data exist on the ability to detect stress-induced myocardial perfusion defects in humans. Thirty-four patients who had a nuclear stress test and invasive angiography were included in the study. Dual-source computed tomography (DSCT) was performed as follows: 1) stress CT: contrast-enhanced scan during adenosine infusion; 2) rest CT: contrast-enhanced scan using prospective triggering; and 3) delayed scan: acquired 7 min after rest CT. Images for CTA, computed tomography perfusion (CTP), and single-photon emission computed tomography (SPECT) were each read by 2 independent blinded readers. The DSCT protocol was successfully completed for 33 of 34 subjects (average age 61.4 +/- 10.7 years; 82% male; body mass index 30.4 +/- 5 kg/m(2)) with an average radiation dose of 12.7 mSv. On a per-vessel basis, CTP alone had a sensitivity of 79% and a specificity of 80% for the detection of stenosis > or =50%, whereas SPECT myocardial perfusion imaging had a sensitivity of 67% and a specificity of 83%. For the detection of vessels with > or =50% stenosis with a corresponding SPECT perfusion abnormality, CTP had a sensitivity of 93% and a specificity of 74%. The CTA during adenosine infusion had a per-vessel sensitivity of 96%, specificity of 73%, and negative predictive value of 98% for the detection of stenosis > or =70%. Adenosine stress CT can identify stress-induced myocardial perfusion defects with diagnostic accuracy comparable to SPECT, with similar radiation dose and with the advantage of providing information on coronary stenosis.

  13. Prostaglandins induce vasodilatation of the microvasculature during muscle contraction and induce vasodilatation independent of adenosine.

    Science.gov (United States)

    Murrant, Coral L; Dodd, Jason D; Foster, Andrew J; Inch, Kristin A; Muckle, Fiona R; Ruiz, Della A; Simpson, Jeremy A; Scholl, Jordan H P

    2014-03-15

    Blood flow data from contracting muscle in humans indicates that adenosine (ADO) stimulates the production of nitric oxide (NO) and vasodilating prostaglandins (PG) to produce arteriolar vasodilatation in a redundant fashion such that when one is inhibited the other can compensate. We sought to determine whether these redundant mechanisms are employed at the microvascular level. First, we determined whether PGs were involved in active hyperaemia at the microvascular level. We stimulated four to five skeletal muscle fibres in the anaesthetized hamster cremaster preparation in situ and measured the change in diameter of 2A arterioles (maximum diameter 40 μm, third arteriolar level up from the capillaries) at a site of overlap with the stimulated muscle fibres before and after 2 min of contraction [stimulus frequencies: 4, 20 and 60 Hz at 15 contractions per minute (CPM) or contraction frequencies of 6, 15 or 60 CPM at 20 Hz; 250 ms train duration]. Muscle fibres were stimulated in the absence and presence of the phospholipase A2 inhibitor quinacrine. Further, we applied a range of concentrations of ADO (10(-7)-10(-5) M) extraluminally, (to mimic muscle contraction) in the absence and presence of L-NAME (NO synthase inhibitor), indomethacin (INDO, cyclooxygenase inhibitor) and L-NAME + INDO and observed the response of 2A arterioles. We repeated the latter experiment on a different level of the cremaster microvasculature (1A arterioles) and on the microvasculature of a different skeletal muscle (gluteus maximus, 2A arterioles). We observed that quinacrine inhibited vasodilatation during muscle contraction at intermediate and high contraction frequencies (15 and 60 CPM). L-NAME, INDO and L-NAME + INDO were not effective at inhibiting vasodilatation induced by any concentration of ADO tested in 2A and 1A arterioles in the cremaster muscle or 2A arterioles in the gluteus maximus muscle. Our data show that PGs are involved in the vasodilatation of the microvasculature in

  14. Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Kazuhiro; Yoshida, Katsuya [Chiba Univ. (Japan). School of Medicine; Tadokoro, Hiroyuki [and others

    2000-12-01

    The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg{center_dot}kg{sup -1}{center_dot}min{sup -1}) in 8 WHHL rabbits (13.8{+-}0.5 months) with {sup 13}N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml{center_dot}min{sup -1}{center_dot}g{sup -1}) did not differ significantly between control and WHHL groups both at baseline (3.67{+-}0.72 vs 4.26{+-}1.12 ml{center_dot}min{sup -1}{center_dot}g{sup -1}, p=NS) and with adenosine (7.92{+-}2.00 vs 9.27{+-}2.91 ml{center_dot}min{sup -1}{center_dot}g{sup -1}, p=NS), nor did coronary flow reserve (2.16{+-}0.37 vs 2.18{+-}0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model. (author)

  15. Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia.

    Directory of Open Access Journals (Sweden)

    Mei Cui

    Full Text Available Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC or 6 days (E6d HPC. Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC. Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1. An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.

  16. A3 Adenosine Receptor Allosteric Modulator Induces an Anti-Inflammatory Effect: In Vivo Studies and Molecular Mechanism of Action

    Directory of Open Access Journals (Sweden)

    Shira Cohen

    2014-01-01

    Full Text Available The A3 adenosine receptor (A3AR is overexpressed in inflammatory cells and in the peripheral blood mononuclear cells of individuals with inflammatory conditions. Agonists to the A3AR are known to induce specific anti-inflammatory effects upon chronic treatment. LUF6000 is an allosteric compound known to modulate the A3AR and render the endogenous ligand adenosine to bind to the receptor with higher affinity. The advantage of allosteric modulators is their capability to target specifically areas where adenosine levels are increased such as inflammatory and tumor sites, whereas normal body cells and tissues are refractory to the allosteric modulators due to low adenosine levels. LUF6000 administration induced anti-inflammatory effect in 3 experimental animal models of rat adjuvant induced arthritis, monoiodoacetate induced osteoarthritis, and concanavalin A induced liver inflammation in mice. The molecular mechanism of action points to deregulation of signaling proteins including PI3K, IKK, IκB, Jak-2, and STAT-1, resulting in decreased levels of NF-κB, known to mediate inflammatory effects. Moreover, LUF6000 induced a slight stimulatory effect on the number of normal white blood cells and neutrophils. The anti-inflammatory effect of LUF6000, mechanism of action, and the differential effects on inflammatory and normal cells position this allosteric modulator as an attractive and unique drug candidate.

  17. Contraction induced secretion of VEGF from skeletal muscle cells is mediated by adenosine

    DEFF Research Database (Denmark)

    Høier, Birgitte; Olsen, Karina; Nyberg, Michael Permin

    2010-01-01

    The role of adenosine and contraction for secretion of VEGF in skeletal muscle was investigated in human subjects and rat primary skeletal muscle cells. Microdialysis probes were inserted into the thigh muscle of seven male subjects and dialysate was collected at rest, during infusion of adenosine...... and during knee extensor exercise. The dialysate was analyzed for content of VEGF protein and adenosine. The mechanism of VEGF secretion from muscle cells in culture was examined in resting and electro stimulated cells, and in response to the adenosine analogue NECA, and the adenosine A(2A) receptor specific...... infusion enhanced (Pmuscle cells, NECA...

  18. Neuronal transporter and astrocytic ATP exocytosis underlie activity-dependent adenosine release in the hippocampus

    Science.gov (United States)

    Wall, Mark J; Dale, Nicholas

    2013-01-01

    The neuromodulator adenosine plays an important role in many physiological and pathological processes within the mammalian CNS. However, the precise mechanisms of how the concentration of extracellular adenosine increases following neural activity remain contentious. Here we have used microelectrode biosensors to directly measure adenosine release induced by focal stimulation in stratum radiatum of area CA1 in mouse hippocampal slices. Adenosine release was both action potential and Ca2+ dependent and could be evoked with low stimulation frequencies and small numbers of stimuli. Adenosine release required the activation of ionotropic glutamate receptors and could be evoked by local application of glutamate receptor agonists. Approximately 40% of stimulated-adenosine release occurred by translocation of adenosine via equilibrative nucleoside transporters (ENTs). This component of release persisted in the presence of the gliotoxin fluoroacetate and thus results from the direct release of adenosine from neurons. A reduction of adenosine release in the presence of NTPDase blockers, in slices from CD73−/− and dn-SNARE mice, provides evidence that a component of adenosine release arises from the extracellular metabolism of ATP released from astrocytes. This component of release appeared to have slower kinetics than the direct ENT-mediated release of adenosine. These data suggest that activity-dependent adenosine release is surprisingly complex and, in the hippocampus, arises from at least two distinct mechanisms with different cellular sources. PMID:23713028

  19. Utilization of adenosine triphosphate in rat mast cells during histamine release induced by the ionophore A23187

    DEFF Research Database (Denmark)

    Johansen, Torben

    1979-01-01

    The role of endogenous adenosine triphosphate (ATP) in histamine release from rat mast cells induced by the ionophore A23187 in vitro has been studied. 2 The amount of histamine released by calcium from rat mast cells primed with the ionophore A23187 was dependent on the ATP content of the mast...

  20. Cardiac displacement during13N-Ammonia myocardial perfusion PET/CT: comparison between adenosine and regadenoson induced stress.

    Science.gov (United States)

    Vleeming, Elise; Lazarenko, Sergiy; van der Zant, Friso; Pan, Xiao-Bo; Declerck, Jerome; Wondergem, Maurits; Knol, Remco

    2017-12-22

    In this study, differences are investigated in cardiac displacement during adenosine stress versus regadenoson stress in 13 N-Ammonia( 13 NH 3 ) MP PET/CT scans. A total of 61 MP PET/CTs were acquired using either adenosine (n=30) or regadenoson (n=31) as a stressor. For both groups, cardiac displacement during rest and stress was measured three-dimensionally, relative to either a fixed reference frame or the previous frame, in each 1-minute frame of a list-mode PET acquisition of 25 minutes. All stress scans were additionally evaluated for the presence of motion artifacts. Also, patient tolerability and occurrence of various side effects were compared between groups. Significantly larger cardiac displacement during stress was detected in the adenosine group as compared to the regadenoson group, reflected by both maximal cardiac displacement (p=0.022) and mean cardiac displacement (p=0.001). The duration of the movement was typically shorter in the regadenoson group. Frames with cardiac displacement ≥5 mm were observed nearly twice as frequent when using adenosine instead of regadenoson. The displacement during regadenoson stress is of lower amplitude and lasts shorter, and may therefore contribute to the lower incidence of motion artifacts on regadenoson compared to adenosine induced stress PET/CT scans. Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  1. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Directory of Open Access Journals (Sweden)

    Gabriela Hurtado-Alvarado

    Full Text Available Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261 in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1, adherens junction protein (E-cadherin, A2A adenosine receptor, adenosine-synthesizing enzyme (CD73, and neuroinflammatory markers (Iba-1 and GFAP in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent

  2. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  3. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  4. Involvement of a cyclic adenosine monophosphate-dependent signal in the diet-induced canalicular trafficking of adenosine triphosphate-binding cassette transporter g5/g8.

    Science.gov (United States)

    Yamazaki, Yasuhiro; Yasui, Kenta; Hashizume, Takahiro; Suto, Arisa; Mori, Ayaka; Murata, Yuzuki; Yamaguchi, Masahiko; Ikari, Akira; Sugatani, Junko

    2015-10-01

    The adenosine triphosphate-binding cassette (ABC) half-transporters Abcg5 and Abcg8 promote the secretion of neutral sterol into bile. Studies have demonstrated the diet-induced gene expression of these transporters, but the regulation of their trafficking when the nutritional status changes in the liver remains to be elucidated. Here, we generated a novel in vivo kinetic analysis that can monitor the intracellular trafficking of Abcg5/Abcg8 in living mouse liver by in vivo transfection of the genes of fluorescent protein-tagged transporters and investigated how hypernutrition affects the canalicular trafficking of these transporters. The kinetic analysis showed that lithogenic diet consumption accelerated the translocation of newly synthesized fluorescent-tagged transporters to intracellular pools in an endosomal compartment and enhanced the recruitment of these pooled gene products into the bile canalicular membrane in mouse liver. Because some ABC transporters are reported to be recruited from intracellular pools to the bile canaliculi by cyclic adenosine monophosphate (cAMP) signaling, we next evaluated the involvement of this machinery in a diet-induced event. Administration of a protein kinase A inhibitor, N-(2-{[3-(4-bromophenyl)-2-propenyl]amino}ethyl)-5-isoquinolinesulfonamide, decreased the canalicular expression of native Abcg5/Abcg8 in lithogenic diet-fed mice, and injection of a cAMP analog, dibutyryl cAMP, transiently increased their levels in standard diet-fed mice, indicating the involvement of cAMP signaling. Indeed, canalicular trafficking of the fluorescent-tagged Abcg5/Abcg8 was enhanced by dibutyryl cAMP administration. These observations suggest that diet-induced lipid loading into liver accelerates the trafficking of Abcg5/Abcg8 to the bile canalicular membrane through cAMP signaling machinery. © 2015 by the American Association for the Study of Liver Diseases.

  5. Preconditioning induces sustained neuroprotection by downregulation of adenosine 5'-monophosphate-activated protein kinase.

    Science.gov (United States)

    Venna, V R; Li, J; Benashski, S E; Tarabishy, S; McCullough, L D

    2012-01-10

    Ischemic preconditioning (IPC) induces endogenous neuroprotection from a subsequent ischemic injury. IPC involves downregulation of metabolic pathways. As adenosine 5'-monophosphate-activated protein kinase (AMPK) is a critical sensor of energy balance and plays a major role in cellular metabolism, its role in IPC was investigated. A brief 3-min middle cerebral artery occlusion (MCAO) was employed to induce IPC in male mice 72 h before 90-min MCAO. Levels of AMPK and phosphorylated AMPK (pAMPK), the active form of the kinase, were assessed after IPC. A pharmacological activator or inhibitor of AMPK was used to determine the dependence of IPC on AMPK signaling. Additionally, AMPK-α2 null mice were subjected to IPC, and subsequent infarct damage was assessed. IPC induced neuroprotection, enhanced heat shock protein-70 (HSP-70), and improved behavioral outcomes. These beneficial effects occurred in parallel with a significant inhibition of pAMPK protein expression. Although both pharmacological inhibition of AMPK or IPC led to neuroprotection, IPC offered no additional protective effects when co-administered with an AMPK inhibitor. Moreover, pharmacological activation of AMPK with metformin abolished the neuroprotective effects of IPC. AMPK-α2 null mice that lack the catalytic isoform of AMPK failed to demonstrate a preconditioning response. Regulation of AMPK plays an important role in IPC-mediated neuroprotection. AMPK may be a potential therapeutic target for the treatment of cerebral ischemia. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Spreading depolarization-induced adenosine accumulation reflects metabolic status in vitro and in vivo

    Science.gov (United States)

    Lindquist, Britta E; Shuttleworth, C William

    2014-01-01

    Spreading depolarization (SD), a pathologic feature of migraine, stroke and traumatic brain injury, is a propagating depolarization of neurons and glia causing profound metabolic demand. Adenosine, the low-energy metabolite of ATP, has been shown to be elevated after SD in brain slices and under conditions likely to trigger SD in vivo. The relationship between metabolic status and adenosine accumulation after SD was tested here, in brain slices and in vivo. In brain slices, metabolic impairment (assessed by nicotinamide adenine dinucleotide (phosphate) autofluorescence and O2 availability) was associated with prolonged extracellular direct current (DC) shifts indicating delayed repolarization, and increased adenosine accumulation. In vivo, adenosine accumulation was observed after SD even in otherwise healthy mice. As in brain slices, in vivo adenosine accumulation correlated with DC shift duration and increased when DC shifts were prolonged by metabolic impairment (i.e., hypoglycemia or middle cerebral artery occlusion). A striking pattern of adenosine dynamics was observed during focal ischemic stroke, with nearly all the observed adenosine signals in the periinfarct region occurring in association with SDs. These findings suggest that adenosine accumulation could serve as a biomarker of SD incidence and severity, in a range of clinical conditions. PMID:25160669

  7. ATP induced vasodilatation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins and adenosine

    DEFF Research Database (Denmark)

    Mortensen, Stefan P; Gonzalez-Alonso, Jose; Bune, Laurids

    2009-01-01

    Plasma adenosine-5'-triphosphate (ATP) is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study...... investigated: 1) the role of nitric oxide (NO), prostaglandins and adenosine as mediators of ATP induced limb vasodilation and 2) the expression and distribution of purinergic P2 receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra.......05) and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O2 extraction. Infusion of theophylline did not alter the ATP induced leg hyperemia or systemic variables. Real time PCR analysis of the mRNA content from the vastus lateralus muscle of 8...

  8. Adenosine A2a receptor induces GDNF expression by the Stat3 signal in vitro.

    Science.gov (United States)

    Ke, Rong-Hu; Xiong, Ji; Liu, Ying

    2012-11-14

    Adenosine A2a receptor (A2aR) is believed to play a role in a number of physiological responses and pathological conditions. Our group has shown previously that A2aR-activated astrocytes occurred following oxygen-glucose deprivation. However, the relationship between A2aR and neurotrophins is poorly understood. Here, we investigate the effect of A2aR on glial cell line-derived neurotrophic factor (GDNF) expression in rat brain astrocyte-2 (RBA-2) cells by quantitative PCR and western blot. We established a stable A2aR-overexpressing cell line and found that A2aR induced GDNF expression both at mRNA and protein levels. A2aR-selective antagonist Sch58261 decreased GDNF expression in a dose-dependent manner with increased activation of Stat3. The Stat3 inhibitor reversed the effect of Sch58261 on GDNF expression. Therefore, these data indicate that A2aR induces GDNF expression by the Stat3 pathway, which provides a new insight into the function of A2aR in cerebral ischemia and neuroprotection.

  9. Butterbur, a herbal remedy, attenuates adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis.

    Science.gov (United States)

    Lee, D K C; Carstairs, I J; Haggart, K; Jackson, C M; Currie, G P; Lipworth, B J

    2003-07-01

    Butterbur (BB) or Petasites hybridus, a herbal remedy, exhibits in vitro inhibition of cysteinyl leukotriene biosynthesis. However, no placebo-controlled studies have been performed to evaluate the effectiveness of BB on objective outcomes such as nasal provocation testing in seasonal allergic rhinitis (SAR). Twenty patients with grass-pollen-sensitized SAR were randomized in a double-blind, cross-over manner to receive for 2 weeks either BB 50 mg twice daily or placebo (PL) twice daily during the grass pollen season. Nasal adenosine monophosphate (AMP) challenge (the primary outcome) was administered as a single 400 mg/mL dose after each randomized treatment. Spontaneous recovery following AMP challenge (area under the response time profile curve as % x min+/-SEM) was significantly attenuated (P=0.028) with BB (584+/-289) compared to PL (1438+/-240); mean difference: 854 (95% CI 95-1614), and the maximum % peak nasal inspiratory flow reduction from baseline following AMP challenge was significantly blunted (P=0.036) with BB (30+/-4) compared to PL (43+/-5); mean difference: 13 (95% CI 1-25). BB exhibited protection against AMP-induced nasal responsiveness during the grass pollen season in sensitized patients. This is turn may explain its potential clinical efficacy in patients with SAR.

  10. Effects of adenosine 5’monophosphate-activated protein kinase on europrotection induced by ischemic preconditioning

    Directory of Open Access Journals (Sweden)

    Yuan-ru-hua TIAN

    2015-06-01

    Full Text Available Objective To investigate the effects of adenosine 5'-monophosphate-activated protein kinase (AMPK and phosphated AMPK (pAMPK signals in ischemic preconditioning (IPC, and the effect of pharmacological intervention of AMPK on infarct size of the brain. Methods A brief (3min middle cerebral artery occlusion (MCAO was employed to induce IPC in male rat, and another 90-min MCAO was performed 4 or 72h later. The levels of AMPK and pAMPK were assessed after IPC. A pharmacological activator metformin, or inhibitor compound C of AMPK, was used to analyze the correlation of IPC to AMPK signaling in MCAO rats. Results The infarct size of total cerebral hemisphere and cortex was significantly decreased in MCAO animals by IPC for 72h (P0.05, n=6. The AMPK activator metformin can significantly reverse the protective effect of IPC (P<0.05, n=6. Conclusions The signals of AMPK and pAMPK play an important role in neuroprotective effect of IPC on cerebral ischemic injury. The neuroprotective effect of IPC may be associated with the down-regulation of pAMPK. DOI: 10.11855/j.issn.0577-7402.2015.05.07

  11. Leptin suppresses adenosine triphosphate-induced impairment of spinal cord astrocytes.

    Science.gov (United States)

    Li, Baoman; Qi, Shuang; Sun, Guangfeng; Yang, Li; Han, Jidong; Zhu, Yue; Xia, Maosheng

    2016-10-01

    Spinal cord injury (SCI) causes long-term disability and has no clinically effective treatment. After SCI, adenosine triphosphate (ATP) may be released from neuronal cells and astrocytes in large amounts. Our previous studies have shown that the extracellular release of ATP increases the phosphorylation of cytosolic phospholipase A2 (cPLA2 ) and triggers the rapid release of arachidonic acid (AA) and prostaglandin E2 (PGE2) via the stimulation of epidermal growth factor receptor (EGFR) and the downstream phosphorylation of extracellular-regulated protein kinases 1 and 2. Leptin, a glycoprotein, induces the activation of the Janus kinase (JAK2)/signal transducers and activators of transcription-3 (Stat3) pathway via the leptin receptor. In this study, we found that 1) prolonged leptin treatment suppressed the ATP-stimulated release of AA and PGE2 from cultured spinal cord astrocytes; 2) leptin elevated the expression of caveolin-1 (Cav-1) via the JAK2/Stat3 signaling pathway; 3) Cav-1 blocked the interaction between Src and EGFR, thereby inhibiting the phosphorylation of EGFR and cPLA2 and attenuating the release of AA or PGE2; 4) pretreatment with leptin decreased ;he level of apoptosis and the release of interleukin-6 from cocultured neurons and astrocytes; and 5) leptin improved the recovery of locomotion in mice after SCI. Our results highlight leptin as a promising therapeutic agent for SCI. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. ALLERGEN-INDUCED CHANGES IN ADENOSINE 5'-MONOPHOSPHATE BRONCHIAL RESPONSIVENESS - EFFECT OF NEDOCROMIL SODIUM

    NARCIS (Netherlands)

    AALBERS, R; KAUFMAN, HF; GROEN, H; KOETER, GH; DEMONCHY, JGR

    1992-01-01

    Bronchial hyperresponsiveness to adenosine 5'-monophosphate (AMP) was studied after allergen challenge in allergic asthmatic patients. Measurements were made with and without nedocromil sodium pretreatment. Nedocromil sodium inhibited both the early and late asthmatic reactions (P <.01). After

  13. Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain.

    Science.gov (United States)

    Kim, Youngsoo; Elmenhorst, David; Weisshaupt, Angela; Wedekind, Franziska; Kroll, Tina; McCarley, Robert W; Strecker, Robert E; Bauer, Andreas

    2015-10-01

    Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26-31% from SR1 to R1). A decrease in β-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction. © 2015 European Sleep Research Society.

  14. Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain

    Science.gov (United States)

    WEISSHAUPT, ANGELA; WEDEKIND, FRANZISKA; KROLL, TINA; MCCARLEY, ROBERT W.

    2015-01-01

    SUMMARY Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day–1 for 5 consecutive days (SR1–SR5), followed by 3 unrestricted recovery sleep days (R1–R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep restriction reduced adenosine A2a receptor density significantly in one of the three brain areas analysed (olfactory tubercle which declined 26–31% from SR1 to R1). A decrease in b-adrenergic receptors density was seen in substantia innominata and ventral pallidum which remained reduced on R3, but no changes were found in the anterior cingulate cortex. These data suggest that chronic sleep restriction can induce long-term changes in the brain adenosine and noradrenaline receptors, which may underlie the long-lasting neurocognitive impairments observed in chronic sleep restriction. PMID:25900125

  15. Acute, persistent quinine-induced blindness

    African Journals Online (AJOL)

    1991-05-04

    min, blood pressure of ... (60 mg/d) were administered. On the second hospital day the visual acuity appeared to be 6 and 7,5 in the ... Severe, virtually total, visual impairment of vision has persisted. Discussion. This' case ...

  16. [Proteomics analysis of adenosine A1 receptor agonist-induced delayed myocardial protection in rabbits].

    Science.gov (United States)

    Zhou, Jianmei; Zou, Dingquan; Ran, Ke; Chang, Yetian

    2011-10-01

    To investigate the changes of myocardial protein expression profiles in 2-chloro-N6-cyclopentyladenosine (CCPA), an adenosine A1 receptor agonist-induced delayed myocardial protection in New Zealand rabbits . A total of 8 rabbits were randomly divided into a CCPA group (CCPA group) and a normal saline group (NS group). CCPA and NS were infused into rabbits in the CCPA group and the NS group respectively. Twenty-four hours later, the rabbits were subjected to 30 min left anterior descending coronary artery occlusion and were reperfused for 2 hours, then the ischemic zone tissues of left ventricle were sampled for proteomic analysis.A total of 12 other New Zeland rabbits were divided into a sham group (Sham group), a normal saline group (NS group) and a CCPA group (CCPA group). The expression of αB-crystalline, one of the differential proteins, was confirmed by Western blot. Analysis of two dimensional gel electrophoresis showed that the expression of 55 protein spots were different between the two groups, 17 protein spots were preliminarily identified with the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and Mascot and Expasy bioinformatics software. These proteins included stress proteins, metabolism-associated proteins, signal transduction pathway-related proteins, ionophorous proteins, immunity-associated proteins, and so on. Western blot showed that the expression of αB-crystalline was significantly up-regulated in the CCPA group. The myocardial protein expression profiles are changed markedly in the preconditioning late phase of CCPA .The differential proteins might be involved in the delayed cardioprotection induced by CCPA.

  17. Impaired cerebral microcirculation induced by ammonium chloride in rats is due to cortical adenosine release

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Bjerrum, Esben Jannik; Larsen, Fin Stolze

    2018-01-01

    chloride applied on the brain surface and compared to control groups exposed to artificial cerebrospinal fluid or ammonium + an adenosine receptor antagonist. A flow preservation curve was obtained by analysis of flow responses to a haemorrhagic hypotensive challenge and during stepwise exsanguination....... The periarteriolar adenosine concentration was measured with enzymatic biosensors inserted in cortex. RESULTS: After ammonium exposure the arteriolar flow velocity increased by 21.7 (23.4)% vs. controls 7.2 (10.2)% (median (IQR), N=10 and 6, respectively p... rise in the periarteriolar adenosine concentration was observed. During the hypotensive challenge the flow decreased by 27.8 (14.9)% vs. 9.2 (14.9)% (p

  18. Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement.

    Science.gov (United States)

    Zhou, Zhichao; Sorop, Oana; de Beer, Vincent J; Heinonen, Ilkka; Cheng, Caroline; Jan Danser, A H; Duncker, Dirk J; Merkus, Daphne

    2017-05-24

    We previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of P1 receptors after myocardial infarction. In view of the deleterious effect of metabolic derangement on vascular function, we hypothesized that the coronary vasodilator response to Up4A is impaired in metabolic derangement, and that the involvement of purinergic receptor subtypes and endothelium-derived vasoactive factors (EDVFs) is altered. Coronary small arteries, dissected from the apex of healthy swine and swine 6 months after induction of diabetes with streptozotocin and fed a high-fat diet, were mounted on wire myographs. Up4A (10(-9)-10(-5) M)-induced coronary relaxation was maintained in swine with metabolic derangement compared to normal swine, despite impaired endothelium-dependent relaxation to bradykinin and despite blunted P2X7 receptor and NO-mediated vasodilator influences of Up4A. Moreover, a thromboxane-mediated vasoconstrictor influence was unmasked. In contrast, an increased Up4A-mediated vasodilator influence via P2Y1 receptors was observed, while, in response to Up4A, cytochrome P450 2C9 switched from producing vasoconstrictor to vasodilator metabolites in swine with metabolic derangement. Coronary vascular expression of A2A and P2X7 receptors as well as eNOS, as assessed with real-time PCR, was reduced in swine with metabolic derangement. In conclusion, although the overall coronary vasodilator response to Up4A was maintained in swine with metabolic derangement, the involvement of purinergic receptor subtypes and EDVF was markedly altered, revealing compensatory mechanisms among signaling pathways in Up4A-mediated coronary vasomotor influence in the early phase of metabolic derangement. Future studies are warranted to investigate the effects of severe

  19. Effects of caffeine intake prior to stress cardiac magnetic resonance perfusion imaging on regadenoson- versus adenosine-induced hyperemia as measured by T1 mapping.

    Science.gov (United States)

    van Dijk, R; Kuijpers, D; Kaandorp, T A M; van Dijkman, P R M; Vliegenthart, R; van der Harst, P; Oudkerk, M

    2017-11-01

    The antagonistic effects of caffeine on adenosine receptors are a possible cause of false-negative stress perfusion imaging. The purpose of this study was to determine the effects of coffee intake regadenoson- versus adenosine-induced hyperemia as measured with T1-mapping. 98 consecutive patients with suspected coronary artery disease referred for either adenosine or regadenoson perfusion CMR were included in this analysis. Twenty-four patients reported coffee consumption regadenoson); 74 patients reported no coffee intake (50 patients with adenosine, and 24 patients with regadenoson). T1 mapping was performed using a modified look-locker inversion recovery sequence. T1 reactivity was determined by subtracting T1 rest from T1 stress . T1 rest , T1 stress , and T1 reactivity in patients referred for regadenoson perfusion CMR were not significantly different when comparing patients with regadenoson perfusion CMR (p regadenoson perfusion CMR has no effect on stress-induced hyperemia as measured with T1 mapping.

  20. Adenosine A

    National Research Council Canada - National Science Library

    Vallon, Volker; Schroth, Jana; Satriano, Joseph; Blantz, Roland C; Thomson, Scott C; Rieg, Timo

    2009-01-01

    ...'). Here, experiments were performed in adenosine A receptor knockout mice (A R-/-), which lack an immediate TGF response, to determine whether A Rs are essential for early diabetic hyperfiltration and the salt paradox. Methods...

  1. Extracellular Adenosine: A Safety Signal That Dampens Hypoxia-Induced Inflammation During Ischemia

    Science.gov (United States)

    Grenz, Almut; Homann, Dirk

    2011-01-01

    Abstract Traditionally, the single most unique feature of the immune system has been attributed to its capability to discriminate between self (e.g., host proteins) and nonself (e.g., pathogens). More recently, an emerging immunologic concept involves the notion that the immune system responds via a complex system for sensing signals of danger, such as pathogens or host-derived signals of cellular distress (e.g., ischemia), while remaining unresponsive to nondangerous motifs. Experimental studies have provided strong evidence that the production and signaling effects of extracellular adenosine are dramatically enhanced during conditions of limited oxygen availability as occurs during ischemia. As such, adenosine would fit the bill of signaling molecules that are enhanced during situations of cellular distress. In contrast to a danger signal, we propose here that extracellular adenosine operates as a countermeasure, in fact as a safety signal, to both restrain potentially harmful immune responses and to maintain and promote general tissue integrity during conditions of limited oxygen availability. Antioxid. Redox Signal. 15, 2221–2234. PMID:21126189

  2. Acute, persistent quinine-induced blindness - A case report ...

    African Journals Online (AJOL)

    Quinine-induced blindness arising during empirical treatment for malaria in a young man is reported. The condition was noteworthy because it was total and permanent, which is at variance with other published reports. The condition usually disappears within minutes to weeks, but persistent deficits tend to be mild and are ...

  3. Astrocytic Lrp4 (Low-Density Lipoprotein Receptor-Related Protein 4) Contributes to Ischemia-Induced Brain Injury by Regulating ATP Release and Adenosine-A2AR (Adenosine A2A Receptor) Signaling.

    Science.gov (United States)

    Ye, Xin-Chun; Hu, Jin-Xia; Li, Lei; Li, Qiang; Tang, Fu-Lei; Lin, Sen; Sun, Dong; Sun, Xiang-Dong; Cui, Gui-Yun; Mei, Lin; Xiong, Wen-Cheng

    2018-01-01

    Lrp4 (low-density lipoprotein receptor-related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4's function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. The brain-specific Lrp4 conditional knockout mice (Lrp4 GFAP-Cre ), astrocytic-specific Lrp4 conditional knockout mice (Lrp4 GFAP-creER ), and their control mice (Lrp4 f/f ) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A 2A R (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4 GFAP-Cre and Lrp4 GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P 2 X 7 R or adenosine-A 2A R signaling diminished Lrp4 GFAP-creER 's protective effect. The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A 2A R signaling. © 2017 American Heart

  4. Adolescent nicotine induces persisting changes in development of neural connectivity.

    Science.gov (United States)

    Smith, Robert F; McDonald, Craig G; Bergstrom, Hadley C; Ehlinger, Daniel G; Brielmaier, Jennifer M

    2015-08-01

    Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part

  5. Case report of rabies-induced persistent mental symptoms

    OpenAIRE

    Wang, Xiaoqing; Yu, Xiaowen; Guan, Yangtai

    2015-01-01

    Summary Rabies is a viral infection with a high case fatality rate. Typical symptoms of rabies include hydrophobia, pharynx muscle spasms, and progressive paralysis. Rabies-induced persistent mental disturbances are rare. Here we report a 22-year-old male who was infected with rabies after being attacked by a dog. He did not receive rabies vaccine immediately after the incident and was only provided with non-standard treatment at a local clinic. A week later he became disorientated, paranoid,...

  6. Increased Na+/K(+)-pump activity and adenosine triphosphate utilization after compound 48/80-induced histamine secretion from rat mast cells

    DEFF Research Database (Denmark)

    Johansen, Torben; Praetorius, Birger Hans

    1994-01-01

    The Na+/K(+)-pump activity and the utilization of adenosine triphosphate (ATP) were studied in rat peritoneal mast cells after histamine secretion induced by compound 48/80. We measured the ouabain-sensitive K(+)-uptake by a radioactive technique (86Rb+). The ATP content and the glycolytic ATP...

  7. Ethanol-induced alterations in sup 14 C-glucose utilization: Modulation by brain adenosine in mice

    Energy Technology Data Exchange (ETDEWEB)

    Anwer, J.; Dar, M.S. (East Carolina Univ., Greenville, NC (United States))

    1992-02-26

    The possible role of brain adenosine (Ado) in acute ethanol-induced alteration in glucose utilization in the cerebellum and brain stem was investigated. The slices were incubated for 100 min in a glucose medium in Warburg flasks using {sup 14}C-glucose as a tracer. Trapped {sup 14}CO{sub 2} was counted to estimate glucose utilization. Ethanol markedly increased the glucose utilization in both areas of brain. Theophylline, an Ado antagonist, significantly reduced ethanol-induced increase in glucose utilization in both brain areas. Ado agonist CHA significantly accentuated ethanol-induced increase in glucose utilization in both motor areas. Ado agonist CHA significantly accentuated ethanol-induced increase in glucose utilization in both motor areas. Ethanol was still able to produce a smaller but significant increase in glucose utilization in both brain areas when theophylline and CHA were given together, suggesting an additional mechanism. Collectively, the data indicate that ethanol-induced glucose utilization in the cerebellum and brain stem is modulated by brain Ado receptor and by non-adenosinergic mechanism.

  8. Gravity loading induces adenosine triphosphate release and phosphorylation of extracellular signal-regulated kinases in human periodontal ligament cells.

    Science.gov (United States)

    Ito, Mai; Arakawa, Toshiya; Okayama, Miki; Shitara, Akiko; Mizoguchi, Itaru; Takuma, Taishin

    2014-11-01

    The periodontal ligament (PDL) receives mechanical stress (MS) from dental occlusion or orthodontic tooth movement. Mechanical stress is thought to be a trigger for remodeling of the PDL and alveolar bone, although its signaling mechanism is still unclear. So we investigated the effect of MS on adenosine triphosphate (ATP) release and extracellular signal-regulated kinases (ERK) phosphorylation in PDL cells. Mechanical stress was applied to human PDL cells as centrifugation-mediated gravity loading. Apyrase, Ca(2+)-free medium and purinergic receptor agonists and antagonists were utilized to analyze the contribution of purinergic receptors to ERK phosphorylation. Gravity loading and ATP increased ERK phosphorylation by 5 and 2.5 times, respectively. Gravity loading induced ATP release from PDL cells by tenfold. Apyrase and suramin diminished ERK phosphorylation induced by both gravity loading and ATP. Under Ca(2+)-free conditions the phosphorylation by gravity loading was partially decreased, whereas ATP-induced phosphorylation was unaffected. Receptors P2Y4 and P2Y6 were prominently expressed in the PDL cells. Gravity loading induced ATP release and ERK phosphorylation in PDL fibroblasts, and ATP signaling via P2Y receptors was partially involved in this phosphorylation, which in turn would enhance gene expression for the remodeling of PDL tissue during orthodontic tooth movement. © 2013 Wiley Publishing Asia Pty Ltd.

  9. Methylene blue induces macroautophagy through 5′ adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation

    Science.gov (United States)

    Xie, Luokun; Li, Wenjun; Winters, Ali; Yuan, Fang; Jin, Kunlin; Yang, Shaohua

    2013-01-01

    Methylene blue has been shown to be neuroprotective in multiple experimental neurodegenerative disease models. However, the mechanisms underlying the neuroprotective effects have not been fully elucidated. Previous studies have shown that macroautophagy has multiple beneficial roles for maintaining normal cellular homeostasis and that induction of macroautophagy after myocardial ischemia is protective. In the present study we demonstrated that methylene blue could protect HT22 hippocampal cell death induced by serum deprivation, companied by induction of macroautophagy. We also found that methylene blue-mediated neuroprotection was abolished by macroautophagy inhibition. Interestingly, 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling, but not inhibition of mammalian target of rapamycin signaling, was activated at 12 and 24 h after methylene blue treatment in a dose-dependent manner. Methylene blue-induced macroautophagy was blocked by AMPK inhibitor. Consistent with in vitro data, macroautophagy was induced in the cortex and hippocampus of mouse brains treated with methylene blue. Our findings suggest that methylene blue-induced neuroprotection is mediated, at least in part, by macroautophagy though activation of AMPK signaling. PMID:23653592

  10. Methylene blue induces macroautophagy through 5' adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation.

    Science.gov (United States)

    Xie, Luokun; Li, Wenjun; Winters, Ali; Yuan, Fang; Jin, Kunlin; Yang, Shaohua

    2013-01-01

    Methylene blue has been shown to be neuroprotective in multiple experimental neurodegenerative disease models. However, the mechanisms underlying the neuroprotective effects have not been fully elucidated. Previous studies have shown that macroautophagy has multiple beneficial roles for maintaining normal cellular homeostasis and that induction of macroautophagy after myocardial ischemia is protective. In the present study we demonstrated that methylene blue could protect HT22 hippocampal cell death induced by serum deprivation, companied by induction of macroautophagy. We also found that methylene blue-mediated neuroprotection was abolished by macroautophagy inhibition. Interestingly, 5' adenosine monophosphate-activated protein kinase (AMPK) signaling, but not inhibition of mammalian target of rapamycin signaling, was activated at 12 and 24 h after methylene blue treatment in a dose-dependent manner. Methylene blue-induced macroautophagy was blocked by AMPK inhibitor. Consistent with in vitro data, macroautophagy was induced in the cortex and hippocampus of mouse brains treated with methylene blue. Our findings suggest that methylene blue-induced neuroprotection is mediated, at least in part, by macroautophagy though activation of AMPK signaling.

  11. Selective attenuation of norepinephrine release and stress-induced heart rate increase by partial adenosine A1 agonism.

    Directory of Open Access Journals (Sweden)

    Lorenz Bott-Flügel

    Full Text Available The release of the neurotransmitter norepinephrine (NE is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR, NE release was induced by electrical stimulation under control conditions (S1, and with capadenoson 6 · 10(-8 M (30 µg/l, 6 · 10(-7 M (300 µg/l or 2-chloro-N(6-cyclopentyladenosine (CCPA 10(-6 M (S2. Under control conditions (S1, NE release was significantly higher in SHR hearts compared to Wistar (766+/-87 pmol/g vs. 173+/-18 pmol/g, p<0.01. Capadenoson led to a concentration-dependent decrease of the stimulation-induced NE release in SHR (S2/S1  =  0.90 ± 0.08 with capadenoson 6 · 10(-8 M, 0.54 ± 0.02 with 6 · 10(-7 M, but not in Wistar hearts (S2/S1  =  1.05 ± 0.12 with 6 · 10(-8 M, 1.03 ± 0.09 with 6 · 10(-7 M. CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [(35S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/-2% A(1-receptor stimulation. These results suggest that partial adenosine A(1-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release.

  12. Case report of rabies-induced persistent mental symptoms.

    Science.gov (United States)

    Wang, Xiaoqing; Yu, Xiaowen; Guan, Yangtai

    2015-02-25

    Rabies is a viral infection with a high case fatality rate. Typical symptoms of rabies include hydrophobia, pharynx muscle spasms, and progressive paralysis. Rabies-induced persistent mental disturbances are rare. Here we report a 22-year-old male who was infected with rabies after being attacked by a dog. He did not receive rabies vaccine immediately after the incident and was only provided with non-standard treatment at a local clinic. A week later he became disorientated, paranoid, and aggressive. One month after the attack, rabies antibody was found in his cerebrospinal fluid and a Magnetic Resonance Imaging (MRI) examination of his head revealed abnormal signals in the putamina, caudate nucleus, and insula. His mental symptoms persisted for six years and his daily functioning was severely impaired, but his vital signs were stable without signs of brain stem damage. Six years after the incident, a repeat MRI showed brain atrophy.

  13. Salidroside attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2a receptor related mitochondria-dependent apoptosis pathway.

    Science.gov (United States)

    Huang, Xiaoying; Zou, Lizhen; Yu, Xiaoming; Chen, Mayun; Guo, Rui; Cai, Hui; Yao, Dan; Xu, Xiaomei; Chen, Yanfan; Ding, Cheng; Cai, Xueding; Wang, Liangxing

    2015-05-01

    Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16 mg/kg, 32 mg/kg, and 64 mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway. Copyright © 2015. Published by Elsevier Ltd.

  14. Effect of an inhaled adenosine A(2A) agonist on the allergen-induced late asthmatic response

    NARCIS (Netherlands)

    Luijk, B.; van den Berge, M.; Kerstjens, H. A. M.; Postma, D. S.; Cass, L.; Sabin, A.; Lammers, J. -W. J.

    Background: Adenosine receptor activation is suggested to play a role in asthmatic airway inflammation. Inhibition of adenosine receptors may have an effect on the late asthmatic response (LAR) after allergen inhalation and this mechanism could offer a potential new treatment in asthma. Methods: We

  15. Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans

    DEFF Research Database (Denmark)

    Calbet, J A L; Boushel, Robert Christopher; Robach, P

    2014-01-01

    AIMS: To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. METHODS: The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the f...

  16. Exercise-induced increase in interstitial bradykinin and adenosine concentrations in skeletal muscle and peritendinous tissue in humans

    DEFF Research Database (Denmark)

    Langberg, H; Bjørn, C; Boushel, Robert Christopher

    2002-01-01

    Bradykinin is known to cause vasodilatation in resistance vessels and may, together with adenosine, be an important regulator of tissue blood flow during exercise. Whether tissue concentrations of bradykinin change with exercise in skeletal muscle and tendon-related connective tissue has not yet......, range 22-33 years). Interstitial bradykinin and adenosine concentrations were determined using an internal reference to determine relative recovery ([2,3,prolyl-3,4-(3)H(N)]-bradykinin and [2-(3)H]-adenosine). Bradykinin and adenosine recovery were closely related and in the range of 30......-50 %. The interstitial concentration of bradykinin rose in response to exercise both in skeletal muscle (from 23.1 +/- 4.9 nmol l(-1) to 110.5 +/- 37.9 nmol l(-1); P adenosine concentration...

  17. Diosmin prevents left ventricular hypertrophy, adenosine triphosphatases dysfunction and electrolyte imbalance in experimentally induced myocardial infarcted rats.

    Science.gov (United States)

    Sabarimuthu, Sharmila Queenthy; Ponnian, Stanely Mainzen Prince; John, Babu

    2017-11-05

    Currently, there has been an increased interest globally to identify natural compounds that are pharmacologically potent and have low or no adverse effects for use in preventive medicine. Myocardial infarction is a vital pathological feature resulting in high levels of mortality and morbidity. Left ventricular hypertrophy (LVH), adenosine triphosphatases (ATPases) dysfunction and electrolyte imbalance play a vital role in the pathogenesis of myocardial infarction. This study aims to evaluate the preventive effects of diosmin on LVH, ATPases dysfunction and electrolyte imbalance in isoproterenol induced myocardial infarcted rats. Male albino Wistar rats were pretreated orally with diosmin (10mg/kg body weight) daily for a period of 10 days. After pretreatment, isoproterenol (100mg/kg body weight) was injected subcutaneously into the rats twice at an interval of 24h to induce myocardial infarction. Isoproterenol induced myocardial infarcted rats showed increased LVH, altered levels/ concentrations of serum cardiac troponin-T, heart ATPases, heart sodium ion, calcium ion and potassium ion, and increased myocardial infarct size. Pretreatment with diosmin revealed preventive effects on LVH, and all the above mentioned biochemical parameters evaluated in isoproterenol induced myocardial infarcted rats. The 2, 3, 5-triphenyl tetrazolium chloride staining on myocardial infarct size confirmed the prevention of myocardial infarction. Further, the 1, 1 diphenyl-2- picryl-hydrazyl (DPPH) radical in vitro study revealed a potent DPPH free radical scavenging action of diosmin. Thus, the observed effects of diosmin are due to its antihypertrophic and free radical scavenging activities in isoproterenol induced myocardial infarcted rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Exposure of Human Lung Cancer Cells to 8-Chloro-Adenosine Induces G2/M Arrest and Mitotic Catastrophe

    Directory of Open Access Journals (Sweden)

    Hong-Yu Zhang

    2004-11-01

    Full Text Available 8-Chloro-adenosine (8-CI-Ado is a potent chemotherapeutic agent whose cytotoxicity in a variety of tumor cell lines has been widely investigated. However, the molecular mechanisms are uncertain. In this study, we found that exposure of human lung cancer cell lines A549 (p53-wt and H1299 (p53-depleted to 8-CI-Ado induced cell arrest in the G2/M phase, which was accompanied by accumulation of binucleated and polymorphonucleated cells resulting from aberrant mitosis and failed cytokinesis. Western blotting showed the loss of phosphorylated forms of Cdc2 and Cdc25C that allowed progression into mitosis. Furthermore, the increase in Ser10-phosphorylated histone H3-positive cells revealed by fluorescence-activated cell sorting suggested that the agent-targeted cells were able to exit the G2 phase and enter the M phase. Immunocytochemistry showed that microtubule and microfilament arrays were changed in exposed cells, indicating that the dynamic instability of microtubules and microfilaments was lost, which may correlate with mitotic dividing failure. Aberrant mitosis resulted in mitotic catastrophe followed by varying degrees of apoptosis, depending on the cell lines. Thus, 8-CI-Ado appears to exert its cytotoxicity toward cells in culture by inducing mitotic catastrophe.

  19. Pulling habits out of rats: adenosine 2A receptor antagonism in dorsomedial striatum rescues meth-amphetamine-induced deficits in goal-directed action.

    Science.gov (United States)

    Furlong, Teri M; Supit, Alva S A; Corbit, Laura H; Killcross, Simon; Balleine, Bernard W

    2017-01-01

    Addiction is characterized by a persistent loss of behavioral control resulting in insensitivity to negative feedback and abnormal decision-making. Here, we investigated the influence of methamphetamine (METH)-paired contextual cues on decision-making in rats. Choice between goal-directed actions was sensitive to outcome devaluation in a saline-paired context but was impaired in the METH-paired context, a deficit that was also found when negative feedback was provided. Reductions in c-Fos-related immunoreactivity were found in dorsomedial striatum (DMS) but not dorsolateral striatum after exposure to the METH context suggesting this effect reflected a loss specifically in goal-directed control in the METH context. This reduction in c-Fos was localized to non-enkephalin-expressing neurons in the DMS, likely dopamine D1-expressing direct pathway neurons, suggesting a relative change in control by the D1-direct versus D2-indirect pathways originating in the DMS may have been induced by METH-context exposure. To test this suggestion, we infused the adenosine 2A receptor antagonist ZM241385 into the DMS prior to test to reduce activity in D2 neurons relative to D1 neurons in the hope of reducing the inhibitory output from this region of the striatum. We found that this treatment fully restored sensitivity to negative feedback in a test conducted in the METH-paired context. These results suggest that drug exposure alters decision-making by downregulation of the circuitry mediating goal-directed action, an effect that can be ameliorated by acute A2A receptor inhibition in this circuit. © 2015 Society for the Study of Addiction.

  20. Impact of targeting adenosine-induced transient venous reconnection in patients undergoing pulmonary vein isolation for atrial fibrillation: a meta-analysis of 3524 patients.

    Science.gov (United States)

    Blandino, Alessandro; Biondi-Zoccai, Giuseppe; Battaglia, Alberto; Grossi, Stefano; Bianchi, Francesca; Conte, Maria Rosa; Rametta, Francesco; Gaita, Fiorenzo

    2017-07-01

    Atrial fibrillation recurrences after pulmonary vein isolation (PVI) are not uncommon and are frequently related to pulmonary vein reconnection. Adenosine/ATP can reveal dormant pulmonary vein conduction after PVI. Previous studies revealed that adenosine-guided Additional ablation could improve arrhythmia-free survival. We performed a meta-analysis to assess the impact of additional ablation to eliminate adenosine-induced transient pulmonary vein reconnection in terms of atrial fibrillation recurrence at follow-up. MEDLINE/PubMed, Cochrane Library and references reporting atrial fibrillation ablation and adenosine/ATP-following PVI were screened, and studies were included if they matched inclusion and exclusion criteria. A total of 3524 patients were enrolled with a median follow-up of 13 (6-20) months. Overall, 70% (60-85) of patients in ATP-guided ablation vs. 63% (48-79) in no ATP-guided ablation were free of atrial fibrillation at follow-up. Pooled results revealed that ATP-guided ablation reduced the risk of atrial fibrillation recurrence of 42% [odds ratio (OR) 0.58, 0.41-0.81], but this result was primary because of the contribution of retrospective over-randomized studies [OR 0.48 (0.35-0.65) vs. 0.76 (0.42-1.40), respectively]. 3.2% of patients experienced an adverse event. ATP-guided ablation is related to a nonsignificant increase in fluoroscopy time (OR 1.71, 0.98-2.96) and to a significant increase in procedure time (OR 2.84, 1.32-6.09). Additional ablation aiming to eliminate adenosine-induced transient pulmonary vein reconnection failed to reduce the risk of atrial fibrillation recurrence at follow-up. Moreover, although adenosine-guided PVI is not affected by an augmented risk of adverse events, it is associated with a NS increased fluoroscopy exposure and significantly longer procedure duration. Further studies are required to identify the actual role of adenosine in PVI.

  1. Release of Periplasmic Nucleotidase Induced by Human Antimicrobial Peptide in E. coli Causes Accumulation of the Immunomodulator Adenosine.

    Directory of Open Access Journals (Sweden)

    Andreia Bergamo Estrela

    Full Text Available Previous work by our group described that human β-defensin-2 induces accumulation of extracellular adenosine (Ado in E. coli cultures through a non-lytic mechanism causing severe plasmolysis. Here, we investigate the presence of AMP as a direct precursor and the involvement of a bacterial enzyme in the generation of extracellular Ado by treated bacteria. Following hBD-2 treatment, metabolites were quantified in the supernatants using targeted HPLC-MS/MS analysis. Microbial growth was monitored by optical density and cell viability was determined by colony forming units counts. Phosphatase activity was measured using chromogenic substrate pNPP. The results demonstrate that defensin-treated E. coli strain W releases AMP in the extracellular space, where it is converted to Ado by a bacterial soluble factor. An increase in phosphatase activity in the supernatant was observed after peptide treatment, similar to the effect of sucrose-induced osmotic stress, suggesting that the periplasmic 5'nucleotidase (5'-NT is released following the plasmolysis event triggered by the peptide. Ado accumulation was enhanced in the presence of Co2+ ion and inhibited by EDTA, further supporting the involvement of a metallo-phosphatase such as 5'-NT in extracellular AMP conversion into Ado. The comparative analysis of hBD-induced Ado accumulation in different E. coli strains and in Pseudomonas aeruginosa revealed that the response is not correlated to the peptide's effect on cell viability, but indicates it might be dependent on the subcellular distribution of the nucleotidase. Taken together, these data shed light on a yet undescribed mechanism of host-microbial interaction: a human antimicrobial peptide inducing selective release of a bacterial enzyme (E. coli 5'-NT, leading to the formation of a potent immunomodulator metabolite (Ado.

  2. Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a Gαs Protein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

    Science.gov (United States)

    Pont, Frédéric; Bétous, Delphine; Ravet, Emmanuel; Ligat, Laetitia; Lopez, Frédéric; Poupot, Mary; Poirot, Marc; Pérouzel, Éric; Tiraby, Gérard; Verhoeyen, Els

    2014-01-01

    Cyclic dinucleotides are important messengers for bacteria and protozoa and are well-characterized immunity alarmins for infected mammalian cells through intracellular binding to STING receptors. We sought to investigate their unknown extracellular effects by adding cyclic dinucleotides to the culture medium of freshly isolated human blood cells in vitro. Here we report that adenosine-containing cyclic dinucleotides induce the selective apoptosis of monocytes through a novel apoptotic pathway. We demonstrate that these compounds are inverse agonist ligands of A2a, a Gαs-coupled adenosine receptor selectively expressed by monocytes. Inhibition of monocyte A2a by these ligands induces apoptosis through a mechanism independent of that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits protein kinase A (PKA) activity, thereby recruiting cytosolic p53, which opens the mitochondrial permeability transition pore and impairs mitochondrial respiration, resulting in apoptosis. A2a antagonists and inverse agonist ligands induce apoptosis of human monocytes, while A2a agonists are antiapoptotic. In vivo, we used a mock developing human hematopoietic system through NSG mice transplanted with human CD34+ cells. Treatment with cyclic di-AMP selectively depleted A2a-expressing monocytes and their precursors via apoptosis. Thus, monocyte recognition of cyclic dinucleotides unravels a novel proapoptotic pathway: the A2a Gαs protein-coupled receptor (GPCR)-driven tonic inhibitory signaling of mitochondrion-induced cell death. PMID:25384972

  3. Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: a novel perspective for seizure control

    OpenAIRE

    Ren, Gaoying; Li, Tianfu; Lan, Jiang Quan; Wilz, Andrew; Simon, Roger P.; Boison, Detlev

    2007-01-01

    Cell therapies based on focal delivery of the inhibitory neuromodulator adenosine were previously shown to provide potent seizure suppression in animal models of epilepsy. However, hitherto used therapeutic cells were derived from rodents and thus not suitable for clinical applications. Autologous patient-derived adenosine-releasing cell implants would constitute a major therapeutic advance to avoid both xenotransplantation and immunosuppression. Here we describe a novel approach based on len...

  4. Characterization of the EBV-Induced Persistent DNA Damage Response

    Directory of Open Access Journals (Sweden)

    Amy Y. Hafez

    2017-12-01

    Full Text Available Epstein-Barr virus (EBV is an oncogenic herpesvirus that is ubiquitous in the human population. Early after EBV infection in vitro, primary human B cells undergo a transient period of hyper-proliferation, which results in replicative stress and DNA damage, activation of the DNA damage response (DDR pathway and, ultimately, senescence. In this study, we investigated DDR-mediated senescence in early arrested EBV-infected B cells and characterized the establishment of persistent DNA damage foci. We found that arrested EBV-infected B cells exhibited an increase in promyelocytic leukemia nuclear bodies (PML NBs, which predominantly localized to markers of DNA damage, as well as telomeric DNA. Furthermore, arrested EBV-infected B cells exhibited an increase in the presence of telomere dysfunction-induced foci. Importantly, we found that increasing human telomerase reverse transcriptase (hTERT expression with danazol, a drug used to treat telomere diseases, permitted early EBV-infected B cells to overcome cellular senescence and enhanced transformation. Finally, we report that EBV-infected B cells undergoing hyper-proliferation are more sensitive than lymphoblastoid cell lines (LCLs to inhibition of Bloom syndrome-associated helicase, which facilitates telomere replication. Together, our results describe the composition of persistent DNA damage foci in the early stages of EBV infection and define key regulators of this barrier to long-term outgrowth.

  5. Irregular persistent activity induced by synaptic excitatory feedback

    Directory of Open Access Journals (Sweden)

    Francesca Barbieri

    2007-11-01

    Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

  6. Persistent optically induced magnetism in oxygen-deficient strontium titanate.

    Science.gov (United States)

    Rice, W D; Ambwani, P; Bombeck, M; Thompson, J D; Haugstad, G; Leighton, C; Crooker, S A

    2014-05-01

    Strontium titanate (SrTiO3) is a foundational material in the emerging field of complex oxide electronics. Although its bulk electronic and optical properties are rich and have been studied for decades, SrTiO3 has recently become a renewed focus of materials research catalysed in part by the discovery of superconductivity and magnetism at interfaces between SrTiO3 and other non-magnetic oxides. Here we illustrate a new aspect to the phenomenology of magnetism in SrTiO3 by reporting the observation of an optically induced and persistent magnetization in slightly oxygen-deficient bulk SrTiO3-δ crystals using magnetic circular dichroism (MCD) spectroscopy and SQUID magnetometry. This zero-field magnetization appears below ~18 K, persists for hours below 10 K, and is tunable by means of the polarization and wavelength of sub-bandgap (400-500 nm) light. These effects occur only in crystals containing oxygen vacancies, revealing a detailed interplay between magnetism, lattice defects, and light in an archetypal complex oxide material.

  7. Traumatic brain injury and obesity induce persistent central insulin resistance.

    Science.gov (United States)

    Karelina, Kate; Sarac, Benjamin; Freeman, Lindsey M; Gaier, Kristopher R; Weil, Zachary M

    2016-04-01

    Traumatic brain injury (TBI)-induced impairments in cerebral energy metabolism impede tissue repair and contribute to delayed functional recovery. Moreover, the transient alteration in brain glucose utilization corresponds to a period of increased vulnerability to the negative effects of a subsequent TBI. In order to better understand the factors contributing to TBI-induced central metabolic dysfunction, we examined the effect of single and repeated TBIs on brain insulin signalling. Here we show that TBI induced acute brain insulin resistance, which resolved within 7 days following a single injury but persisted until 28 days following repeated injuries. Obesity, which causes brain insulin resistance and neuroinflammation, exacerbated the consequences of TBI. Obese mice that underwent a TBI exhibited a prolonged reduction of Akt (also known as protein kinase B) signalling, exacerbated neuroinflammation (microglial activation), learning and memory deficits, and anxiety-like behaviours. Taken together, the transient changes in brain insulin sensitivity following TBI suggest a reduced capacity of the injured brain to respond to the neuroprotective and anti-inflammatory actions of insulin and Akt signalling, and thus may be a contributing factor for the damaging neuroinflammation and long-lasting deficits that occur following TBI. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  8. Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver.

    Science.gov (United States)

    Duarte, Filipe V; Amorim, João A; Varela, Ana T; Teodoro, João S; Gomes, Ana P; Cunha, Rodrigo A; Palmeira, Carlos M; Rolo, Anabela P

    2017-06-01

    Although adenosine A1 receptors (A1R) have been associated to ischemic preconditioning (IPC), direct evidence for their ability to preserve mitochondrial function upon hepatic preconditioning is still missing and could represent a novel strategy to boost the quality of liver transplants. We tested if the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prevented IPC in the liver and if the A1R agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) might afford a pharmacological preconditioning. Livers underwent a 120 min of 70% warm ischemia and 16 h of reperfusion (I/R), and the IPC group underwent a 5-min ischemic episode followed by a 10-min period of reperfusion before I/R. DPCPX or CCPA was administered intraperitoneally 2 h before IPC or I/R. The control of mitochondrial function emerged as the central element affected by IPC and controlled by endogenous A1R activation. Thus, livers from IPC- or CCPA-treated rats displayed an improved oxidative phosphorylation with higher state 3 respiratory rate, higher respiratory control ratio, increased ATP content, and decreased lag phase. IPC and CCPA also prevented the I/R-induced susceptibility to calcium-induced mitochondrial permeability transition, the rate of reactive oxygen species (ROS) generation, and the decreased mitochondrial content of phospho-Ser(9) GSK-3β. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3β activity by Akt-mediated Ser(9)-GSK-3β phosphorylation preserving the efficiency of oxidative phosphorylation and ROS-mediated cell death in the ability of A1R activation to mimic IPC in the liver. In conclusion, the parallel between IPC and A1R-mediated preconditioning also paves the way to consider a putative therapeutic use of the later in liver transplants.

  9. The inhibitory activity of ginsenoside Rp4 in adenosine diphosphate-induced platelet aggregation

    Directory of Open Access Journals (Sweden)

    Young-Min Son

    2017-01-01

    Conclusion: G-Rp4 significantly inhibited ADP-induced platelet aggregation and this is mediated via modulating the intracellular signaling molecules. These results indicate that G-Rp4 could be a potential candidate as a therapeutic agent against platelet-related cardiovascular diseases.

  10. The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology

    Science.gov (United States)

    2016-09-01

    of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE (DD...reactivation and seizure will continue.14 Because current inhibitory- and oxime-based strategies are unable to control seizure activity when treatment...neuroprotective mechanism, Joosen et al. correlated sarin’s cholinergic symptoms with CPA-induced bradycardia and hypotension .39 Because a peripherally acting A1

  11. Comparison of the clinical outcome after pulmonary vein isolation based on the appearance of adenosine-induced dormant pulmonary vein conduction.

    Science.gov (United States)

    Matsuo, Seiichiro; Yamane, Teiichi; Date, Taro; Hioki, Mika; Ito, Keiichi; Narui, Ryohsuke; Tanigawa, Shin-ichi; Nakane, Tokiko; Hama, Yoshiyuki; Tokuda, Michifumi; Yamashita, Seigo; Aramaki, Yasuko; Inada, Keiichi; Shibayama, Kenri; Miyanaga, Satoru; Yoshida, Hiroshi; Miyazaki, Hidekazu; Abe, Kunihiko; Sugimoto, Ken-ichi; Taniguchi, Ikuo; Yoshimura, Michihiro

    2010-08-01

    The elimination of transient pulmonary vein (PV) reconduction (dormant PV conduction) revealed by adenosine in addition to PV isolation reduced the atrial fibrillation (AF) recurrence after catheter ablation. The dormant PV conduction is induced in approximately half of the AF patients that undergo PV isolation. The present study compared the clinical outcome of AF ablation in patients whose dormant PV conduction was eliminated by additional radiofrequency applications with the outcome in patients without dormant conduction. A total of 233 consecutive patients (206 male, 54.2 +/- 10.1 years) that underwent AF ablation were included in the present study. Dormant PV conduction was induced by the administration of adenosine triphosphate after PV isolation and was eliminated by supplemental radiofrequency application. All patients were followed up for >12 months (mean 903 days) after the first ablation. Following PV isolation, dormant PV conduction was induced in 139 (59.7%) of 233 patients and was successfully eliminated in 98% (223/228) of those in the first ablation procedure. After the first procedure, 63.9% (149/233) of patients were free from AF recurrence events. The success rates of a single or final AF ablation in patients with the appearance of the dormant PV conduction were similar to those of patients without dormant conduction (P = .69 and P = .69, respectively). Dormant PV conduction was induced in over half of the patients with AF. After the elimination of adenosine triphosphate-induced reconnection, the clinical outcome of patients with the dormant PV conduction was equivalent to that of patients without conduction. Copyright 2010 Mosby, Inc. All rights reserved.

  12. Extracellular Adenosine Generation in the Regulation of Pro-Inflammatory Responses and Pathogen Colonization

    Directory of Open Access Journals (Sweden)

    M. Samiul Alam

    2015-05-01

    Full Text Available Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase and CD73 (ecto-5'-nucleotidase by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine’s control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis. Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen. The role of adenosine in dampening inflammation has been an area of active research, but the relevance of the CD39/CD73-axis and adenosine receptor signaling in host defense against infection has received less attention. Here, we review our recent knowledge regarding CD73 expression during murine Salmonellosis and Helicobacter-induced gastric infection and its role in disease pathogenesis and bacterial persistence. We also explored a possible role for the CD73/adenosine pathway in regulating innate host defense function during infection.

  13. Adenosine and its Related Nucleotides may Modulate Gastric Acid ...

    African Journals Online (AJOL)

    Studies on lumen-perfused rat isolated stomachs showed that adenosine, adenosine monophosphate (AMP) and reduced nicotinamide adenine dinucleotide (NADH) inhibited histamine-induced gastric acid secretion. The inhibitions and the calcium levels of the serosal solution exhibited inverse relationship. Adenosine ...

  14. Persistent Skin Reactions and Aluminium Hypersensitivity Induced by Childhood Vaccines

    DEFF Research Database (Denmark)

    Salik, Elaha; Løvik, Ida; Andersen, Klaus E

    2016-01-01

    There is increasing awareness of reactions to vaccination that include persistent skin reactions. We present here a retrospective investigation of long-lasting skin reactions and aluminium hypersensitivity in children, based on medical records and questionnaires sent to the parents. In the 10-year...... period 2003 to 2013 we identified 47 children with persistent skin reactions caused by childhood vaccinations. Most patients had a typical presentation of persisting pruritic subcutaneous nodules. Five children had a complex diagnostic process involving paediatricians, orthopaedics and plastic surgeons...... treated with potent topical corticosteroids and disappeared slowly. Although we advised families to continue vaccination of their children, one-third of parents omitted or postponed further vaccinations....

  15. Persistent Skin Reactions and Aluminium Hypersensitivity Induced by Childhood Vaccines.

    Science.gov (United States)

    Salik, Elaha; Løvik, Ida; Andersen, Klaus E; Bygum, Anette

    2016-11-02

    There is increasing awareness of reactions to vaccination that include persistent skin reactions. We present here a retrospective investigation of long-lasting skin reactions and aluminium hypersensitivity in children, based on medical records and questionnaires sent to the parents. In the 10-year period 2003 to 2013 we identified 47 children with persistent skin reactions caused by childhood vaccinations. Most patients had a typical presentation of persisting pruritic subcutaneous nodules. Five children had a complex diagnostic process involving paediatricians, orthopaedics and plastic surgeons. Two patients had skin biopsies performed from their skin lesions, and 2 patients had the nodules surgically removed. Forty-two children had a patch-test performed with 2% aluminium chloride hexahydrate in petrolatum and 39 of them (92%) had a positive reaction. The persistent skin reactions were treated with potent topical corticosteroids and disappeared slowly. Although we advised families to continue vaccination of their children, one-third of parents omitted or postponed further vaccinations.

  16. Affinity labeling of a human platelet membrane protein with 5'-p-fluorosulfonylbenzoyl adenosine. Concomitant inhibition of ADP-induced platelet aggregation and fibrinogen receptor exposure.

    Science.gov (United States)

    Figures, W R; Niewiarowski, S; Morinelli, T A; Colman, R F; Colman, R W

    1981-08-10

    Incubation of washed human blood platelets with 5'-p-fluorosulfonylbenzoyl [3H]adenosine (FSBA) covalently labels a single polypeptide of Mr = 100,000. Protection by ADP has suggested that an ADP receptor on the platelet surface membrane was modified. The modified cells, unlike native platelets, failed to aggregate in response to ADP (100 microM) and fibrinogen (1 mg/ml). The extent of binding of 125I-fibrinogen and aggregation was inhibited to a degree related to the incorporation of 5'-p-sulfonylbenzoyl adenosine (SBA) into platelets, indicating FSBA could inhibit the exposure of fibrinogen receptors by ADP necessary for aggregation. Incubation of SBA platelets with alpha-chymotrypsin cleaved the covalently labeled polypeptide and concomitantly reversed the inhibition of aggregation and fibrinogen binding. Platelets proteolytically digested by chymotrypsin prior to exposure to FSBA did not require ADP for aggregation and fibrinogen binding. Moreover, subsequent exposure to FSBA did not inhibit aggregation or fibrinogen binding. The affinity reagent FSBA can displace fibrinogen bound to platelets in the presence of ADP, as well as promote the rapid disaggregation of the platelets. The apparent initial pseudo-first order rate constant of dissociation of fibrinogen was linearly proportional to FSBA concentrations. These studies suggest that a single polypeptide can be altered either by ADP-induced conformational changes or proteolysis by chymotrypsin to reveal latent fibrinogen receptors and promote aggregation of platelets after fibrinogen binding.

  17. Adenosine dysfunction in epilepsy

    Science.gov (United States)

    Boison, Detlev

    2011-01-01

    Extracellular levels of the brain’s endogenous anticonvulsant and neuroprotectant adenosine largely depend on an astrocyte-based adenosine cycle, comprised of ATP release, rapid degradation of ATP into adenosine, and metabolic reuptake of adenosine through equilibrative nucleoside transporters and phosphorylation by adenosine kinase (ADK). Changes in ADK expression and activity therefore rapidly translate into changes of extracellular adenosine, which exerts its potent anticonvulsive and neuroprotective effects by activation of pre- and postsynaptic adenosine A1 receptors. Increases in ADK increase neuronal excitability, whereas decreases in ADK render the brain resistant to seizures and injury. Importantly, ADK was found to be overexpressed and associated with astrogliosis and spontaneous seizures in rodent models of epilepsy, as well as in human specimen resected from patients with hippocampal sclerosis and temporal lobe epilepsy. Several lines of evidence indicate that overexpression of astroglial ADK and adenosine deficiency are pathological hallmarks of the epileptic brain. Consequently, adenosine augmentation therapies constitute a powerful approach for seizure prevention, which is effective in models of epilepsy that are resistant to conventional antiepileptic drugs. The adenosine kinase hypothesis of epileptogenesis suggests that adenosine dysfunction in epilepsy undergoes a biphasic response: An acute surge of adenosine that can be triggered by any type of injury might contribute to the development of astrogliosis via adenosine receptor –dependent and –independent mechanisms. Astrogliosis in turn is associated with overexpression of ADK, which was shown to be sufficient to trigger spontaneous recurrent electrographic seizures. Thus, ADK emerges as a promising target for the prediction and prevention of epilepsy. PMID:22700220

  18. Dynamically Induced Displacements of a Persistent Cold-Air Pool

    Science.gov (United States)

    Lareau, Neil P.; Horel, John D.

    2015-02-01

    We examine the influence of a passing weather system on a persistent cold-air pool (CAP) during the Persistent Cold-Air Pool Study in the Salt Lake Valley, Utah, USA. The CAP experiences a sequence of along-valley displacements that temporarily and partially remove the cold air in response to increasing along-valley winds aloft. The displacements are due to the formation of a mountain wave over the upstream topography as well as adjustments to the regional horizontal pressure gradient and wind-stress divergence acting on the CAP. These processes appear to help establish a balance wherein the depth of the CAP increases to the north. When that balance is disrupted, the CAP tilt collapses, which sends a gravity current of cold air travelling upstream and thereby restores CAP conditions throughout the valley. Intra-valley mixing of momentum, heat, and pollution within the CAP by Kelvin-Helmholtz waves and seiching is also examined.

  19. A Multimode Responsive Aptasensor for Adenosine Detection

    Directory of Open Access Journals (Sweden)

    Na Zhao

    2014-01-01

    Full Text Available We report a novel multimode detection aptasensor with three signal responses (i.e., fluorescence recovery, enhanced Raman signal, and color change. The presence of adenosine induces the conformational switch of the adenosine aptamer (Apt, forming adenosine-aptamer complex and releasing quantum dots (QDs from AuNPs, resulting in the recovered fluorescence, the enhanced Raman signal, and color change of the solution. The multimode signal recognition is potentially advantageous in improving the precision and reliability of the detection in complex environments compared to the conventional single-mode sensing system. The multimode detection strategy opens up a new possibility in sensing and quantifying more other target molecules.

  20. Pressure-induced referred pain is expanded by persistent soreness.

    Science.gov (United States)

    Doménech-García, V; Palsson, T S; Herrero, P; Graven-Nielsen, T

    2016-05-01

    Several chronic pain conditions are accompanied with enlarged referred pain areas. This study investigated a novel method for assessing referred pain. In 20 healthy subjects, pressure pain thresholds (PPTs) were recorded and pressure stimuli (120% PPT) were applied bilaterally for 5 and 60 seconds at the infraspinatus muscle to induce local and referred pain. Moreover, PPTs were measured bilaterally at the shoulder, neck, and leg before, during, and after hypertonic saline-induced referred pain in the dominant infraspinatus muscle. The pressure and saline-induced pain areas were assessed on drawings. Subsequently, delayed onset muscle soreness was induced using eccentric exercise of the dominant infraspinatus muscle. The day-1 assessments were repeated the following day (day 2). Suprathreshold pressure stimulations and saline injections into the infraspinatus muscle caused referred pain to the frontal aspect of the shoulder/arm in all subjects. The 60-second pressure stimulation caused larger referred pain areas compared with the 5-second stimulation (P induced referred pain area was larger (P induced pain, the PPTs at the infraspinatus and supraspinatus muscles were reduced (P induced referred pain area was larger than baseline. Pressure pain thresholds at the infraspinatus and supraspinatus muscles were reduced at day 2 in the delayed onset muscle soreness side (P induced referred pain areas were observed on day 2 (P pain to the shoulder/arm was consistently induced and enlarged after 1 day of muscle soreness, indicating that the referred pain area may be a sensitive biomarker for sensitization of the pain system.

  1. Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: a possible role for plasticity in adenosine receptors

    Science.gov (United States)

    Clark, Peter J.; Ghasem, Parsa R.; Mika, Agnieszka; Day, Heidi E.; Herrera, Jonathan J.; Greenwood, Benjamin N.; Fleshner, Monika

    2014-01-01

    Emerging evidence indicates that adenosine is a major regulator of striatum activity, in part, through the antagonistic modulation of dopaminergic function. Exercise can influence adenosine and dopamine activity, which may subsequently promote plasticity in striatum adenosine and dopamine systems. Such changes could alter activity of medium spiny neurons and impact striatum function. The purpose of this study was two-fold. The first was to characterize the effect of long-term wheel running on adenosine 1 (A1R), adenosine 2A (A2AR), dopamine 1 (D1R), and dopamine 2 (D2R) receptor mRNA expression in adult rat dorsal and ventral striatum structures using in situ hybridization. The second was to determine if changes to adenosine and dopamine receptor mRNA from running are associated with altered cfos mRNA induction in dynorphin- (direct pathway) and enkephalin- (indirect pathway) expressing neurons of the dorsal striatum following stress exposure. We report that chronic running, as well as acute uncontrollable stress, reduced A1R and A2AR mRNA levels in the dorsal and ventral striatum. Running also modestly elevated D2R mRNA levels in striatum regions. Finally, stress-induced cfos was potentiated in dynorphin and attenuated in enkephalin expressing neurons of running rats. These data suggest striatum adenosine and dopamine systems are targets for neuroplasticity from exercise, which may contribute to changes in direct and indirect pathway activity. These findings may have implications for striatum mediated motor and cognitive processes, as well as exercise facilitated stress-resistance. PMID:25017571

  2. Genetic deletion of the adenosine A(2A) receptor prevents nicotine-induced upregulation of alpha 7, but not alpha 4 beta 2*nicotinic acetylcholine receptor binding in the brain

    NARCIS (Netherlands)

    Metaxas, A.; Al-Hasani, R.; Farshim, P.; Tubby, K.; Berwick, A.; Ledent, C.; Hourani, S.; Kitchen, I.; Bailey, A.

    2013-01-01

    Considerable evidence indicates that adenosine A2Areceptors (A2ARs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A2Aand nAChRs, we examined if

  3. Chronic Sleep Restriction Disrupts Sleep Homeostasis and Behavioral Sensitivity to Alcohol by Reducing the Extracellular Accumulation of Adenosine

    Science.gov (United States)

    Clasadonte, Jerome; McIver, Sally R.; Schmitt, Luke I.; Halassa, Michael M.

    2014-01-01

    Sleep impairments are comorbid with a variety of neurological and psychiatric disorders including depression, epilepsy, and alcohol abuse. Despite the prevalence of these disorders, the cellular mechanisms underlying the interaction between sleep disruption and behavior remain poorly understood. In this study, the impact of chronic sleep loss on sleep homeostasis was examined in C57BL/6J mice following 3 d of sleep restriction. The electroencephalographic power of slow-wave activity (SWA; 0.5–4 Hz) in nonrapid eye movement (NREM) sleep and adenosine tone were measured during and after sleep restriction, and following subsequent acute sleep deprivation. During the first day of sleep restriction, SWA and adenosine tone increased, indicating a homeostatic response to sleep loss. On subsequent days, SWA declined, and this was accompanied by a corresponding reduction in adenosine tone caused by a loss of one source of extracellular adenosine. Furthermore, the response to acute sleep deprivation (6 h) was significantly attenuated in sleep-restricted mice. These effects were long-lasting with reduced SWA and adenosine tone persisting for at least 2 weeks. To investigate the behavioral consequences of chronic sleep restriction, sensitivity to the motor-impairing effects of alcohol was also examined. Sleep-restricted mice were significantly less sensitive to alcohol when tested 24 h after sleep restriction, an effect that persisted for 4 weeks. Intracerebroventricular infusion of an adenosine A1 receptor antagonist produced a similar decrease in sensitivity to alcohol. These results suggest that chronic sleep restriction induces a sustained impairment in adenosine-regulated sleep homeostasis and consequentially impacts the response to alcohol. PMID:24478367

  4. One-step synthesis, self-assembly and bioimaging applications of adenosine triphosphate containing amphiphilies with aggregation-induced emission feature.

    Science.gov (United States)

    Long, Zi; Liu, Meiying; Mao, Liucheng; Zeng, Guangjian; Huang, Qiang; Huang, Hongye; Deng, Fengjie; Wan, Yiqun; Zhang, Xiaoyong; Wei, Yen

    2017-04-01

    Amphiphilic molecules with aggregation-induced emission (AIE) characteristics have attracted intensive interest for biological imaging applications for their self-assembly into nanostructures and obvious enhanced fluorescence intensity in aqueous solution. Although many AIE-active fluorescent organic nanoparticles (FONs) have been fabricated recently, the direct linkage of hydrophilic small molecules and hydrophobic AIE dyes has rarely been reported. In this work, we reported a one-pot strategy for preparation of adenosine triphosphate (ATP) containing molecules that conjugated the amino group of ATP and aldehyde-terminated AIE dye (PhCHO) based on mercaptoacetic acid locking imine (MALI) reaction. These AIE-active ATP-PhCHO showed amphiphilic properties and could self-assemble into micelles, which displayed high water dispersibility, strong yellow fluorescence, good biocompatibility and biological imaging capability. These advantages make ATP-PhCHO FONs promising for biomedical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Bordetella pertussis-induced Alteration of the Normal Hyperglycemic Response of Mice to 3′,5′-Adenosine Phosphate

    Science.gov (United States)

    Cronholm, Lois S.; Fishel, Charles W.

    1968-01-01

    Blockade of the adrenergic receptors or the injection of Bordetella pertussis vaccine prevented the normal hyperglycemic response of CFW mice to exogenous cyclic 3′,5′-adenosine phosphate (3′,5′-AMP). The cyclic nucleotide was also ineffective in offsetting the histamine hypersensitivity of the β-adrenergically blocked and the pertussis-sensitized groups. These observations suggest that the autonomic malfunction occurs at a point(s) subsequent to release of 3′,5′-AMP. Neither the hyperglycemic effect of epinephrine or 3′,5′-AMP, or both, nor the histamine sensitivity of pertussis-pretreated animals was influenced by the subcutaneous administration of theophylline. PMID:4299372

  6. Left ventricular dilatation and pulmonary thallium uptake after single-photon emission computer tomography using thallium-201 during adenosine-induced coronary hyperemia

    Energy Technology Data Exchange (ETDEWEB)

    Iskandrian, A.S.; Heo, J.; Nguyen, T.; Lyons, E.; Paugh, E. (Philadelphia Heart Institute, PA (USA))

    1990-10-01

    This study examined the implications of left ventricular (LV) dilatation and increased pulmonary thallium uptake during adenosine-induced coronary hyperemia. The lung-to-heart thallium ratio in the initial images was significantly higher in patients with coronary artery disease (CAD) than normal subjects; 0.48 +/- 0.16 in 3-vessel disease (n = 16), 0.43 +/- 0.10 in 2-vessel disease (n = 20), 0.43 +/- 0.08 in 1-vessel disease (n = 16) and 0.36 +/- 0.05 in normal subjects (n = 7) (p less than 0.001, 0.09 and 0.06, respectively). There was a significant correlation between the severity and the extent of the perfusion abnormality (determined from the polar maps) and the lung-to-heart thallium ratio (r = 0.51 and 0.52, respectively, p less than 0.0002). There was also a significant correlation between lung thallium washout and lung-to-heart thallium ratio (r = 0.42, p = 0.0009) and peak heart rate (r = -0.49, p less than 0.0001). The LV dilatation was mostly due to an increase in cavity dimension (30% increase) and to a lesser extent (6% increase) due to increase in LV size. (The cavity dimensions were measured from the short-axis slices at the midventricular level in the initial and delayed images). The dilation was seen in patients with CAD but not in the normal subjects. These changes correlated with the extent and severity of the thallium perfusion abnormality. Thus, adenosine-induced coronary hyperemia may cause LV dilation and increased lung thallium uptake on the basis of subendocardial ischemia.

  7. Chondroitin sulfate attenuates formalin-induced persistent tactile allodynia

    Directory of Open Access Journals (Sweden)

    Wataru Nemoto

    2016-08-01

    Full Text Available We examined the effect of chondroitin sulfate (CS, a compound used in the treatment of osteoarthritis and joint pain, on the formalin-induced tactile allodynia in mice. A repeated oral administration of CS (300 mg/kg, b.i.d. significantly ameliorated the formalin-induced tactile allodynia from day 10 after formalin injection. On day 14, the phosphorylation of spinal p38 MAPK and subsequent increase in c-Fos-immunoreactive dorsal lumbar neurons were attenuated by the repeated administration of CS. These findings suggest that CS attenuates formalin-induced tactile allodynia through the inhibition of p38 MAPK phosphorylation and subsequent up-regulation of c-Fos expression in the dorsal lumbar spinal cord.

  8. Adenosine and dialysis hypotension

    NARCIS (Netherlands)

    Franssen, CMF

    In this issue, Imai et al. report the results of a double-blind placebo-controlled study on the effect of an adenosine A1 receptor antagonist, FK352, on the incidence of dialysis hypotension in hypotension-prone patients. This Commentary discusses the use of selective adenosine A1 receptor

  9. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients

    OpenAIRE

    Bernardino Clavo; Norberto Santana-Rodriguez; Pedro Llontop; Dominga Gutierrez; Daniel Ceballos; Charlin Méndez; Gloria Rovira; Gerardo Suarez; Dolores Rey-Baltar; Laura Garcia-Cabrera; Gregorio Martínez-Sánchez; Dolores Fiuza

    2015-01-01

    Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n = 12) previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil...

  10. LSD-induced Hallucinogen Persisting Perception Disorder treated with clonazepam: two case reports.

    Science.gov (United States)

    Lerner, A G; Skladman, I; Kodesh, A; Sigal, M; Shufman, E

    2001-01-01

    Benzodiazepines are recommended for the treatment of Hallucinogen Persisting Perception Disorder (HPPD), although it is unclear which may be more helpful. Two out-patients with LSD-induced HPPD were successfully treated with clonazepam. They had not responded to low potency benzodiazepines or low doses of classic antipsychotics. After clonazepam discontinuation they reported a marked improvement and only mild symptomatology which persisted during a six month follow-up period. High potency benzodiazepines like clonazepam, which has serotonergic properties, may be superior to low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

  11. Effect of adenosine and adenosine analogs on ( sup 14 C)aminopyrine accumulation by rabbit parietal cells

    Energy Technology Data Exchange (ETDEWEB)

    Ota, S.; Hiraishi, H.; Terano, A.; Mutoh, H.; Kurachi, Y.; Shimada, T.; Ivey, K.J.; Sugimoto, T. (Univ. of Tokyo (Japan))

    1989-12-01

    Adenosine receptors that modulate adenylate cyclase activity have been identified recently in a number of tissues. Adenosine A2 receptor is stimulatory to adenylate cyclase, whereas adenosine A1 receptor is inhibitory to adenylate cyclase. We investigated the effect of adenosine and its analogs on (14C)aminopyrine accumulation by rabbit parietal cells. Rabbit gastric mucosal cells were isolated by enzyme digestion. Parietal cells were enriched by nonlinear percoll gradients. (14C)Aminopyrine accumulation was used as an indicator of acid secretion. The effect of 2-chloroadenosine on histamine-stimulated (14C)aminopyrine accumulation was studied. The effects of N-ethylcarboxamideadenosine, 2-chloroadenosine, stable analogs of adenosine, and adenosine on (14C)aminopyrine accumulation were assessed. Cyclic AMP content of parietal cells was determined by radioimmunoassay. Histamine and carbachol, known secretagogues, stimulated (14C)aminopyrine accumulation. 2-Chloroadenosine did not suppress histamine-stimulated (14C)aminopyrine accumulation. 2-Chloroadenosine, N-ethylcarboxamideadenosine, and adenosine dose dependently increased (14C)aminopyrine accumulation. The order of potency was N-ethylcarboxamideadenosine greater than 2-chloroadenosine greater than adenosine. 8-Phenyltheophylline and theophylline, adenosine-receptor antagonists, or cimetidine did not have significant effects on the increase of AP uptake induced by 2-chloroadenosine. Coadministration of dipyridamole, and adenosine uptake inhibitor, augmented the effect of adenosine on (14C)aminopyrine accumulation. 2-Chloroadenosine, N-ethylcarboxamideadenosine, and adenosine each induced a significant increase in cellular cyclic AMP. We conclude that there may be adenosine A2 receptors on rabbit parietal cells which modulate gastric acid secretion.

  12. A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.

    Science.gov (United States)

    Janes, Kali; Esposito, Emanuela; Doyle, Timothy; Cuzzocrea, Salvatore; Tosh, Dillip K; Jacobson, Kenneth A; Salvemini, Daniela

    2014-12-01

    Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. Copyright © 2014

  13. Attenuation of pentylenetrazole-induced acute status epilepticus in rats by adenosine involves inhibition of the mammalian target of rapamycin pathway.

    Science.gov (United States)

    Wang, Yuliang; Liu, Xuewu; Wang, Yuan; Chen, Jinbo; Han, Tao; Su, Lei; Zang, Kejun

    2017-10-18

    Adenosine (ADO) has been characterized as an endogenous anticonvulsant and alternative therapeutic drug, but its mechanism is not entirely clear. This study aimed to examine the relationship of ADO with the mammalian target of rapamycin (mTOR) in a Wistar rat model of pentylenetetrazole (PTZ)-induced acute status epilepticus. ADO (200 mg/kg) was administered intraperitoneally 30 min before PTZ (55-65 mg/kg) treatment, and Western blot assays and immunohistochemistry were performed 3 h after the onset of acute status epilepticus to detect phospho-TOR and the downstream target of mTOR, phospho-S6. The expression of these phosphoproteins in the hippocampus was significantly increased in PTZ-treated rats, but this increase was attenuated by the addition of ADO. To further verify a role for ADO in attenuating mTOR activity, we also evaluated its ability to suppress mTOR activity in normal rats that were not treated with PTZ. Our results suggest that ADO suppresses mTOR and S6 phosphorylation in normal rats and that this suppression can be reversed by the application of Compound C, an inhibitor of AMP-activated protein kinase, which functions as an upstream suppressor of the mTOR pathway. Thus, our results provide a novel antiepileptic mechanism for ADO in suppressing mTOR pathway activation upon PTZ-induced acute status epilepticus.

  14. Persistent wind-induced enhancement of diffusive CO2 transport in a mountain forest snowpack

    Science.gov (United States)

    D. R. Bowling; W. J. Massman

    2011-01-01

    Diffusion dominates the transport of trace gases between soil and the atmosphere. Pressure gradients induced by atmospheric flow and wind interacting with topographical features cause a small but persistent bulk flow of air within soil or snow. This forcing, called pressure pumping or wind pumping, leads to a poorly quantified enhancement of gas transport beyond the...

  15. Intracellular ATP concentration contributes to the cytotoxic and cytoprotective effects of adenosine.

    Directory of Open Access Journals (Sweden)

    Shujue Li

    Full Text Available Extracellular adenosine (ADE interacts with cells by two pathways: by activating cell surface receptors at nanomolar/micromolar concentrations; and by interfering with the homeostasis of the intracellular nucleotide pool at millimolar concentrations. Ade shows both cytotoxic and cytoprotective effects; however, the underlying mechanisms remain unclear. In the present study, the effects of adenosine-mediated ATP on cell viability were investigated. Adenosine treatment was found to be cytoprotective in the low intracellular ATP state, but cytotoxic under the normal ATP state. Adenosine-mediated cytotoxicity and cytoprotection rely on adenosine-derived ATP formation, but not via the adenosine receptor pathway. Ade enhanced proteasome inhibition-induced cell death mediated by ATP generation. These data provide a new pathway by which adenosine exerts dual biological effects on cell viability, suggesting an important role for adenosine as an ATP precursor besides the adenosine receptor pathway.

  16. Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway

    Directory of Open Access Journals (Sweden)

    Simões Ana

    2012-08-01

    Full Text Available Abstract Background and purpose Blockade of adenosine A2A receptors (A2AR affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL-1β. We investigated whether A2AR controls the signaling of IL-1β and its deleterious effects in cultured hippocampal neurons. Methods Hippocampal neuronal cultures were treated with IL-1β and/or glutamate in the presence or absence of the selective A2AR antagonist, SCH58261 (50 nmol/l. The effect of SCH58261 on the IL-1β-induced phosphorylation of the mitogen-activated protein kinases (MAPKs c-Jun N-terminal kinase (JNK and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1β was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A2AR blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1β, was studied using single-cell calcium imaging. Results IL-1β (10 to 100 ng/ml enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 μg/ml, in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1β failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 μmol/l glutamate for 25 minutes (evaluated after 24 hours. It is likely that this resulted from the ability of IL-1β to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1β alone. The selective A2AR antagonist, SCH58261 (50 nmol

  17. Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP.

    Science.gov (United States)

    Chiodi, Valentina; Mallozzi, Cinzia; Ferrante, Antonella; Chen, Jiang F; Lombroso, Paul J; Di Stasi, Anna Maria Michela; Popoli, Patrizia; Domenici, Maria Rosaria

    2014-02-01

    The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.

  18. Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide.

    Science.gov (United States)

    Betz, A J; Vontell, R; Valenta, J; Worden, L; Sink, K S; Font, L; Correa, M; Sager, T N; Salamone, J D

    2009-09-29

    Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.

  19. Garlic capsule and selenium-vitamins ACE combination therapy modulate key antioxidant proteins and cellular adenosine triphosphate in lisinopril-induced lung damage in rats.

    Science.gov (United States)

    Akintunde, Jacob K; Bolarin, Olakunle Enock; Akintunde, Daniel G

    2016-03-01

    Garlic capsule (GAR) and/or selenium- vitamin A, C, E (S-VACE) might be useful in the treatment of lung diseases. The present study evaluated the toxicity of lisinopril (LIS) in the lungs of male rats and the reversal effect of GAR and/or selenium-vitamins A, C, and E (S-VACE). Group I served as the control, whereas animals in groups II, III, IV, and V received 28 mg of LIS/kg body weight by gavage. Group III was co-treated with GAR at a therapeutic dosage of 250 mg/kg body weight per day. Group IV was co-treated with S-VACE at dosage of 500 mg/kg body weight per day. Lastly, group V was co-treated with GAR and S-VACE at dosages of 250 and 500 mg/kg body weight per day, respectively. The experiment lasted for 8 days (sub-acute exposure). Administration of therapeutic dose of LIS to male rats depleted enzymatic antioxidants (superoxide dismutase and catalase) and cellular adenosine triphosphate content with concomitant increase in lipid peroxidation. Histopathology examination showed damage to the epithelial cells of the airways. These effects were prevented by both single and combination treatment of GAR and S-VACE in male rats with LIS-induced lung toxicity. We therefore concluded that the combination of GAR and S-VACE can be a novel therapy for the management of lung diseases in humans.

  20. [Synesthesias in the context of hallucinogen-induced persistent perception disorder following the use of lsd].

    Science.gov (United States)

    Neven, A; Blom, J D

    2014-01-01

    The hallucinogen-induced persistent perception disorder (hppd) is a disturbing complication resulting from the use of hallucinogens. We report on a case-study in which an artist suffering from visual, auditory and olfactory hallucinations also experienced chromatic-phonemic synesthesias that had persisted for two years after he had stopped using lysergic acid diethylamide (lsd). The case described demonstrates that individuals suffering from hppd can also experience synesthesias that may in fact differ phenomenologically from 'coloured hearing', which is a symptom known to occur in the context of substance abuse.

  1. Induced hypothermia is protective in a rat model of pneumococcal pneumonia associated with increased adenosine triphosphate availability and turnover

    NARCIS (Netherlands)

    Beurskens, Charlotte J. P.; Aslami, Hamid; Kuipers, Maria T.; Horn, Janneke; Vroom, Margreeth B.; van Kuilenburg, André B. P.; Roelofs, Joris J. T. H.; Schultz, Marcus J.; Juffermans, Nicole P.

    2012-01-01

    Objective: To determine the effect of induced hypothermia on bacterial growth, lung injury, and mitochondrial function in a rat model of pneumococcal pneumosepsis. Design: Animal study. Setting: University research laboratory. Subjects: Male Sprague-Dawley rats. Interventions: Subjects were

  2. Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.

    Directory of Open Access Journals (Sweden)

    He Wang

    Full Text Available Hepatic stellate cell (HSC activation is an essential event during alcoholic liver fibrosis. Evidence suggests that adenosine aggravates liver fibrosis via the adenosine A2A receptor (A2AR. Caffeine, which is being widely consumed during daily life, inhibits the action of adenosine. In this study, we attempted to validate the hypothesis that caffeine influences acetaldehyde-induced HSC activation by acting on A2AR. Acetaldehyde at 50, 100, 200, and 400 μM significantly increased HSC-T6 cells proliferation, and cell proliferation reached a maximum at 48 h after exposure to 200 μM acetaldehyde. Caffeine and the A2AR antagonist ZM241385 decreased the cell viability and inhibited the expression of procollagen type I and type III in acetaldehyde-induced HSC-T6 cells. In addition, the inhibitory effect of caffeine on the expression of procollagen type I was regulated by A2AR-mediated signal pathway involving cAMP, PKA, SRC, and ERK1/2. Interestingly, caffeine's inhibitory effect on the expression of procollagen type III may depend upon the A2AR-mediated P38 MAPK-dependent pathway.Caffeine significantly inhibited acetaldehyde-induced HSC-T6 cells activation by distinct A2AR mediated signal pathway via inhibition of cAMP-PKA-SRC-ERK1/2 for procollagen type I and via P38 MAPK for procollagen type III.

  3. Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.

    Science.gov (United States)

    Wang, He; Guan, Wenjie; Yang, Wanzhi; Wang, Qi; Zhao, Han; Yang, Feng; Lv, Xiongwen; Li, Jun

    2014-01-01

    Hepatic stellate cell (HSC) activation is an essential event during alcoholic liver fibrosis. Evidence suggests that adenosine aggravates liver fibrosis via the adenosine A2A receptor (A2AR). Caffeine, which is being widely consumed during daily life, inhibits the action of adenosine. In this study, we attempted to validate the hypothesis that caffeine influences acetaldehyde-induced HSC activation by acting on A2AR. Acetaldehyde at 50, 100, 200, and 400 μM significantly increased HSC-T6 cells proliferation, and cell proliferation reached a maximum at 48 h after exposure to 200 μM acetaldehyde. Caffeine and the A2AR antagonist ZM241385 decreased the cell viability and inhibited the expression of procollagen type I and type III in acetaldehyde-induced HSC-T6 cells. In addition, the inhibitory effect of caffeine on the expression of procollagen type I was regulated by A2AR-mediated signal pathway involving cAMP, PKA, SRC, and ERK1/2. Interestingly, caffeine's inhibitory effect on the expression of procollagen type III may depend upon the A2AR-mediated P38 MAPK-dependent pathway. Caffeine significantly inhibited acetaldehyde-induced HSC-T6 cells activation by distinct A2AR mediated signal pathway via inhibition of cAMP-PKA-SRC-ERK1/2 for procollagen type I and via P38 MAPK for procollagen type III.

  4. Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury

    Science.gov (United States)

    Sharma, Ashish Kumar; Munajjam, Arshee; Vaishnav, Bhawna; Sharma, Richa; Sharma, Ashok; Kishore, Kunal; Sharma, Akash; Sharma, Divya; Kumari, Rita; Tiwari, Ashish; Singh, Santosh Kumar; Gaur, Samir; Jatav, Vijay Singh; Srinivasan, Barthu Parthi; Agarwal, Shyam Sunder

    2012-01-01

    The present study investigated the effect of garlic (Allium sativum Linn.) aqueous extracts on ischemic preconditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic preconditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized (0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0.01%), and the 0.05% dose was found to be the most effective. Higher doses (more than 0.05%) were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline (1,000 µmol/L) and 8-SPT (10 mg/kg, i.p.) and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide. PMID:23554727

  5. Salt stress-induced transcription of σB- and CtsR-regulated genes in persistent and non-persistent Listeria monocytogenes strains from food processing plants.

    Science.gov (United States)

    Ringus, Daina L; Ivy, Reid A; Wiedmann, Martin; Boor, Kathryn J

    2012-03-01

    Listeria monocytogenes is a foodborne pathogen that can persist in food processing environments. Six persistent and six non-persistent strains from fish processing plants and one persistent strain from a meat plant were selected to determine if expression of genes in the regulons of two stress response regulators, σ(B) and CtsR, under salt stress conditions is associated with the ability of L. monocytogenes to persist in food processing environments. Subtype data were also used to categorize the strains into genetic lineages I or II. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure transcript levels for two σ(B)-regulated genes, inlA and gadD3, and two CtsR-regulated genes, lmo1138 and clpB, before and after (t=10 min) salt shock (i.e., exposure of exponential phase cells to BHI+6% NaCl for 10 min at 37°C). Exposure to salt stress induced higher transcript levels relative to levels under non-stress conditions for all four stress and virulence genes across all wildtype strains tested. Analysis of variance (ANOVA) of induction data revealed that transcript levels for one gene (clpB) were induced at significantly higher levels in non-persistent strains compared to persistent strains (p=0.020; two-way ANOVA). Significantly higher transcript levels of gadD3 (p=0.024; two-way ANOVA) and clpB (p=0.053; two-way ANOVA) were observed after salt shock in lineage I strains compared to lineage II strains. No clear association between stress gene transcript levels and persistence was detected. Our data are consistent with an emerging model that proposes that establishment of L. monocytogenes persistence in a specific environment occurs as a random, stochastic event, rather than as a consequence of specific bacterial strain characteristics.

  6. Adenosine receptor neurobiology: overview.

    Science.gov (United States)

    Chen, Jiang-Fan; Lee, Chien-fei; Chern, Yijuang

    2014-01-01

    Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary. In the brain, adenosine functions as an important upstream neuromodulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways. By acting through four G-protein-coupled receptors, adenosine contributes critically to homeostasis and neuromodulatory control of a variety of normal and abnormal brain functions, ranging from synaptic plasticity, to cognition, to sleep, to motor activity to neuroinflammation, and cell death. This review begun with an overview of the gene and genome structure and the expression pattern of adenosine receptors (ARs). We feature several new developments over the past decade in our understanding of AR functions in the brain, with special focus on the identification and characterization of canonical and noncanonical signaling pathways of ARs. We provide an update on functional insights from complementary genetic-knockout and pharmacological studies on the AR control of various brain functions. We also highlight several novel and recent developments of AR neurobiology, including (i) recent breakthrough in high resolution of three-dimension structure of adenosine A2A receptors (A2ARs) in several functional status, (ii) receptor-receptor heterodimerization, (iii) AR function in glial cells, and (iv) the druggability of AR. We concluded the review with the contention that these new developments extend and strengthen the support for A1 and A2ARs in brain as therapeutic targets for neurologic and psychiatric diseases. © 2014 Elsevier Inc. All rights reserved.

  7. Visual and surface plasmon resonance sensor for zirconium based on zirconium-induced aggregation of adenosine triphosphate-stabilized gold nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Wenjing; Zhao, Jianming [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China); University of the Chinese Academy of Sciences, No. 19A Yuquanlu, Beijing 100049 (China); Zhang, Wei; Liu, Zhongyuan [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China); Xu, Min [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China); University of the Chinese Academy of Sciences, No. 19A Yuquanlu, Beijing 100049 (China); Anjum, Saima [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China); University of the Chinese Academy of Sciences, No. 19A Yuquanlu, Beijing 100049 (China); Department of Chemistry, Faculty of Science, The Islamia University of Bahawalpur, 63100 (Pakistan); Majeed, Saadat [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China); University of the Chinese Academy of Sciences, No. 19A Yuquanlu, Beijing 100049 (China); Department of Chemistry, Bahauddin Zakaryia University, Multan 60800 (Pakistan); Xu, Guobao, E-mail: guobaoxu@ciac.jl.cn [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China)

    2013-07-17

    Graphical abstract: Visual and surface plasmon resonance (SPR) sensor for Zr(IV) has been developed for the first time based on Zr(IV)-induced change of SPR absorption spectra of ATP-stabilized AuNP solutions. -- Highlights: •Visual and SPR absorption Zr{sup 4+} sensors have been developed for the first time. •The high affinity between Zr{sup 4+} and ATP makes sensor highly sensitive and selective. •A fast response to Zr{sup 4+} within 4 min. -- Abstract: Owing to its high affinity with phosphate, Zr(IV) can induce the aggregation of adenosine 5′-triphosphate (ATP)-stabilized AuNPs, leading to the change of surface plasmon resonance (SPR) absorption spectra and color of ATP-stabilized AuNP solutions. Based on these phenomena, visual and SPR sensors for Zr(IV) have been developed for the first time. The A{sub 660} {sub nm}/A{sub 518} {sub nm} values of ATP-stabilized AuNPs in SPR absorption spectra increase linearly with the concentrations of Zr(IV) from 0.5 μM to 100 μM (r = 0.9971) with a detection limit of 95 nM. A visual Zr(IV) detection is achieved with a detection limit of 30 μM. The sensor shows excellent selectivity against other metal ions, such as Cu{sup 2+}, Fe{sup 3+}, Cd{sup 2+}, and Pb{sup 2+}. The recoveries for the detection of 5 μM, 10 μM, 25 μM and 75 μM Zr(IV) in lake water samples are 96.0%, 97.0%, 95.6% and 102.4%, respectively. The recoveries of the proposed SPR method are comparable with those of ICP-OES method.

  8. In silico study of naphtha [1, 2-d] thiazol-2-amine with adenosine A 2A receptor and its role in antagonism of haloperidol-induced motor impairments in mice.

    Science.gov (United States)

    Luthra, Pratibha Mehta; Prakash, Amresh; Barodia, Sandeep Kumar; Kumari, Rita; Mishra, Chandra Bhushan; Kumar, J B Senthil

    2009-10-09

    Loss of dopaminergic nigrostriatal neurons in the substantia nigra leads to Parkinson's disease (PD). Adenosine A(2A) receptors (A(2A)Rs) have been anticipated as novel therapeutic target for PD. A(2A)Rs potentiate locomotor behavior and are predominantly expressed in striatum. Naphtha [1, 2-d] thiazol-2-amine (NATA), a tricyclic thiazole have been studied as new anti-Parkinsonian compound. AutoDock analysis and pharmacophore study of NATA with known A(2A)R antagonists explicit its efficacy as a possible adenosine receptor antagonist. In vivo pharmacology of NATA showed reduction of haloperidol (HAL)-induced motor impairments in Swiss albino male mice. Relatively elevated levels of dopamine in NATA pre-treated mice are suggestive of its possible role as neuromodulator in PD.

  9. Elevated Placental Adenosine Signaling Contributes to the Pathogenesis of Preeclampsia

    Science.gov (United States)

    Iriyama, Takayuki; Sun, Kaiqi; Parchim, Nicholas F.; Li, Jessica; Zhao, Cheng; Song, Anren; Hart, Laura A.; Blackwell, Sean C.; Sibai, Baha M.; Chan, Lee-Nien L.; Chan, Teh-Sheng; Hicks, M. John; Blackburn, Michael R.; Kellems, Rodney E.; Xia, Yang

    2016-01-01

    Background Preeclampsia (PE) is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be due to placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways leading to impaired placentas and maternal disease development remain elusive. Methods and Results By using two independent animal models of PE—1) genetically-engineered pregnant mice with elevated adenosine exclusively in placentas, and 2) a pathogenic autoantibody-induced PE mouse model—we demonstrated here that chronically elevated placental adenosine was sufficient to induce hallmark features of PE including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacologic approaches revealed that elevated placental adenosine coupled with excessive A2B adenosine receptor (ADORA2B) signaling contributed to the development of these features of PE. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to PE. Conclusions We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for PE. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of PE, and, thereby highlight novel therapeutic targets. PMID:25538227

  10. Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.

    Science.gov (United States)

    Iriyama, Takayuki; Sun, Kaiqi; Parchim, Nicholas F; Li, Jessica; Zhao, Cheng; Song, Anren; Hart, Laura A; Blackwell, Sean C; Sibai, Baha M; Chan, Lee-Nien L; Chan, Teh-Sheng; Hicks, M John; Blackburn, Michael R; Kellems, Rodney E; Xia, Yang

    2015-02-24

    Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A₂B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia. We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets. © 2014 American Heart Association, Inc.

  11. Transient and Persistent Pain Induced Connectivity Alterations in Pediatric Complex Regional Pain Syndrome

    Science.gov (United States)

    Linnman, Clas; Becerra, Lino; Lebel, Alyssa; Berde, Charles; Grant, P. Ellen; Borsook, David

    2013-01-01

    Evaluation of pain-induced changes in functional connectivity was performed in pediatric complex regional pain syndrome (CRPS) patients. High field functional magnetic resonance imaging was done in the symptomatic painful state and at follow up in the asymptomatic pain free/recovered state. Two types of connectivity alterations were defined: (1) Transient increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb vs. unaffected limb in the CRPS state, but with normalized connectivity patterns in the recovered state; and (2) Persistent increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb as compared to the unaffected limb that persisted also in the recovered state (recovered affected limb versus recovered unaffected limb). The data support the notion that even after symptomatic recovery, alterations in brain systems persist, particularly in amygdala and basal ganglia systems. Connectivity analysis may provide a measure of temporal normalization of different circuits/regions when evaluating therapeutic interventions for this condition. The results add emphasis to the importance of early recognition and management in improving outcome of pediatric CRPS. PMID:23526938

  12. Recovery of the Cell Cycle Inhibition in CCl4-Induced Cirrhosis by the Adenosine Derivative IFC-305

    Directory of Open Access Journals (Sweden)

    Victoria Chagoya de Sánchez

    2012-01-01

    Full Text Available Introduction. Cirrhosis is a chronic degenerative illness characterized by changes in normal liver architecture, failure of hepatic function, and impairment of proliferative activity. The aim of this study is to know how IFC-305 compound induces proliferation of the liver during reversion of cirrhosis. Methods. Once cirrhosis has been installed by CCl4 treatment for 10 weeks in male Wistar rats, they were divided into four groups: two received saline and two received the compound; all were euthanized at 5 and 10 weeks of treatment. Liver homogenate, mitochondria, and nucleus were used to measure cyclins, CDKs, and cell cycle regulatory proteins PCNA, pRb, p53, E2F, p21, p27, HGF, liver ATP, and mitochondrial function. Results. Diminution and small changes were observed in the studied proteins in the cirrhotic animals without treatment. The IFC-305-treated rats showed a clear increase in most of the proteins studied mainly in PCNA and CDK6, and a marked increased in ATP and mitochondrial function. Discussion/Conclusion. IFC-305 induces a recovery of the cell cycle inhibition promoting recovery of DNA damage through the action of PCNA and p53. The increase in energy and preservation of mitochondrial function contribute to recovering the proliferative function.

  13. Persistence of docetaxel-induced neuropathy and impact on quality of life among breast cancer survivors

    DEFF Research Database (Denmark)

    Eckhoff, L.; Knoop, A.; Jensen, M. B.

    2015-01-01

    BACKGROUND: This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer. METHODS: One thousand and thirty-one patients with early-stage breast cancer, who received...... at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality...

  14. Activation of Adenosine A3 Receptor Alleviates TNF-α-Induced Inflammation through Inhibition of the NF-κB Signaling Pathway in Human Colonic Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Tianhua Ren

    2014-01-01

    Full Text Available To investigate the expression of adenosine A3 receptor (A3AR in human colonic epithelial cells and the effects of A3AR activation on tumor necrosis factor alpha (TNF-α- induced inflammation in order to determine its mechanism of action in human colonic epithelial cells, human colonic epithelial cells (HT-29 cells were treated with different concentrations of 2-Cl-IB-MECA prior to TNF-α stimulation, followed by analysis of NF-κB signaling pathway activation and downstream IL-8 and IL-1β production. A3AR mRNA and protein were expressed in HT-29 cells and not altered by changes in TNF-α or 2-Cl-IB-MECA. Pretreatment with 2-Cl-IB-MECA prior to stimulation with TNF-α attenuated NF-κB p65 nuclear translocation as p65 protein decreased in the nucleus of cells and increased in the cytoplasm, inhibited the degradation of IκB-α, and reduced phosphorylated-IκB-α level significantly, compared to TNF-α-only-treated groups. Furthermore, 2-Cl-IB-MECA significantly decreased TNF-α-stimulated IL-8 and IL-1β mRNA expression and secretion, compared to the TNF-α-only treated group. These results confirm that A3AR is expressed in human colonic epithelial cells and demonstrate that its activation has an anti-inflammatory effect, through the inhibition of NF-κB signaling pathway, which leads to inhibition of downstream IL-8 and IL-1β expression. Therefore, A3AR activation may be a potential treatment for gut inflammatory diseases such as inflammatory bowel disease.

  15. The value of adenosine deaminase, interferon-gamma, and interferon-gamma induced protein of 10kD in the diagnosis of tuberculous pleuritis

    Directory of Open Access Journals (Sweden)

    Ya-kun DONG

    2015-07-01

    Full Text Available Objective To explore the value of adenosine deaminase (ADA activity, interferon-gamma (IFN-γ and IFN-γ induced protein of 10kD (IP-10 levels in pleural effusion for the diagnosis of tuberculous pleuritis. Methods ADA activity, IFN-γ and IP-10 levels in pleural effusion were determined in sixty-three patients with tuberculous pleuritis and 50 patients with malignant pleural effusion. Results The mean levels of ADA, IFN-γ and IP-10 in the tuberculous pleural effusion were significantly higher than those in malignant pleural effusion (P<0.01. When 45U/L was regarded as cut off value for ADA, the sensitivity, specificity and diagnostic odds ratio in the diagnosis of tuberculous pleurisy were 71.4%, 94.0% and 39.17 respectively. When 138.5pg/ml was regarded as cut off value for IFN-γ in tuberculous pleural effusion, the sensitivity, specificity and diagnostic odds ratio were 93.7%, 82.0% and 67.19 respectively. When 9.21μg/ml was regarded as cut off value for IP-10 in tuberculous pleural effusion, the sensitivity, specificity and diagnostic odds ratio were 85.7%, 90.0% and 54.00 respectively. The combined determination of the three markers for the diagnosis of tuberculous pleurisy had a sensitivity of 95.2%, specificity of 96.0% and diagnostic odds ratio of 72.16. Conclusion The accuracy of diagnosis for tuberculous pleurisy can be improved by combined determination of ADA, IFN-γ and IP-10. DOI: 10.11855/j.issn.0577-7402.2015.06.07

  16. A Meta-Analysis of Adenosine A2A Receptor Antagonists on Levodopa-Induced Dyskinesia In Vivo

    Directory of Open Access Journals (Sweden)

    Wen-Wen Wang

    2017-12-01

    Full Text Available BackgroundLong-term use of levodopa (l-dopa is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson’s disease.MethodsIn this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID.ResultsNine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD −0.00, 95% confidence interval (CI: −2.52 to 2.52, p = 1.0, superiority in improvement of motor disability (SMD −5.06, 95% CI: −9.25 to −0.87, p = 0.02 and more effective in control of AIM (SMD −1.82, 95% CI: −3.38 to −0.25, p = 0.02.ConclusionTo sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.

  17. Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells.

    Science.gov (United States)

    Mauro, Maurizio; Caradonna, Fabio; Klein, Catherine B

    2016-03-01

    The mechanisms by which arsenic-induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT-PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose-dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome-wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long-lasting arsenic-induced genomic instability that manifests in several ways, including aberrant chromosomal effects. © 2015 Wiley Periodicals, Inc.

  18. Long-stay psychiatric patients: a prospective study revealing persistent antipsychotic-induced movement disorder.

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    P Roberto Bakker

    Full Text Available OBJECTIVE: The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD, parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness. METHOD: Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. RESULTS: The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder. CONCLUSIONS: Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.

  19. Inducing Sadness and Anxiousness through Visual Media: Measurement Techniques and Persistence

    Science.gov (United States)

    Kuijsters, Andre; Redi, Judith; de Ruyter, Boris; Heynderickx, Ingrid

    2016-01-01

    The persistence of negative moods (sadness and anxiousness) induced by three visual Mood Induction Procedures (MIP) was investigated. The evolution of the mood after the MIP was monitored for a period of 8 min with the Self-Assessment Manikin (SAM; every 2 min) and with recordings of skin conductance level (SCL) and electrocardiography (ECG). The SAM pleasure ratings showed that short and longer film fragments were effective in inducing a longer lasting negative mood, whereas the negative mood induced by the IAPS slideshow was short lived. The induced arousal during the anxious MIPs diminished quickly after the mood induction; nevertheless, the SCL data suggest longer lasting arousal effects for both movies. The decay of the induced mood follows a logarithmic function; diminishing quickly in the first minutes, thereafter returning slowly back to baseline. These results reveal that caution is needed when investigating the effects of the induced mood on a task or the effect of interventions on induced moods, because the induced mood diminishes quickly after the mood induction. PMID:27536260

  20. Comorbidities in Neurology: Is Adenosine the Common Link?

    Science.gov (United States)

    Boison, Detlev; Aronica, Eleonora

    2015-01-01

    Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions. PMID:25979489

  1. Anesthetic Cardioprotection: The Role of Adenosine

    Science.gov (United States)

    Bonney, Stephanie; Hughes, Kelly; Eckle, Tobias

    2014-01-01

    Brief periods of cardiac ischemia and reperfusion exert a protective effect against subsequent longer ischemic periods, a phenomenon coined ischemic preconditioning. Similar, repeated brief episodes of coronary occlusion and reperfusion at the onset of reperfusion, called post-conditioning, dramatically reduce infarct sizes. Interestingly, both effects can be achieved by the administration of any volatile anesthetic. In fact, cardio-protection by volatile anesthetics is an older phenomenon than ischemic pre- or post-conditioning. Although the mechanism through which anesthetics can mimic ischemic pre- or post-conditioning is still unknown, adenosine generation and signaling are the most redundant triggers in ischemic pre- or postconditioning. In fact, adenosine signaling has been implicated in isoflurane-mediated cardioprotection. Adenosine acts via four receptors designated as A1, A2a, A2b, and A3. Cardioprotection has been associated with all subtypes, although the role of each remains controversial. Much of the controversy stems from the abundance of receptor agonists and antagonists that are, in fact, capable of interacting with multiple receptor subtypes. Recently, more specific receptor agonists and new genetic animal models have become available paving way towards new discoveries. As such, the adenosine A2b receptor was shown to be the only 1 of the adenosine receptors whose cardiac expression is induced by ischemia in both mice and humans and whose function is implicated in ischemic pre- or post-conditioning. In the current review, we will focus on adenosine signaling in the context of anesthetic cardioprotection and will highlight new discoveries, which could lead to new therapeutic concepts to treat myocardial ischemia using anesthetic preconditioning. PMID:24502579

  2. Effects of milrinone on contractility and cyclic adenosine monophosphate production induced by beta1- and beta2-adrenergic receptor activation in human myocardium.

    Science.gov (United States)

    Carceles, Mafía D; Fuentes, Teodomiro; Aroca, Vicente; Lopez, Jesús; Hernández, Jesús

    2007-08-01

    Because milrinone is a widely used phosphodiesterase-3 (PDE3) inhibitor, it would be of interest to know whether it interacts with beta1- and beta2-adrenergic receptor (AR) agonists in human myocardium. This in vitro study was conducted to test whether milrinone differentially regulates cyclic adenosine-3',5'-monophosphate (cAMP) production and to examine the effect of milrinone on the positive inotropic responses and cAMP production induced by activation of the beta1-AR with norepinephrine (NE) and activation of the beta2-AR with epinephrine (EPI) in human atrial myocardium. Right atrial trabeculae were obtained from patients undergoing cardiac surgery for valve repair. Concentration-response curves for inotropic responses mediated through the beta1-AR (NE in the presence of the beta2-blocker ICI 118, 551) and the beta2-AR (EPI in the presence of the beta1-blocker CGP 20712A) were obtained in the absence and presence of milrinone 1 micromol/L. This concentration of milrinone was chosen because it corresponded to its 50% inhibitory concentration as a PDE3 inhibitor and its therapeutic plasma concentration. The production of cAMP induced by exposure to selective beta1- and beta2-AR stimulation was also measured in the absence and presence of milrinone. Right atrial tissue samples were obtained from 12 white patients (7 women, 5 men; mean [SE] age, 64.6 [6.3] years) undergoing cardiac surgery for valve repair (8 mitral, 4 aortic). The presence of milrinone was associated with leftward shifts in the concentration-response curves for both NE and EPI. cAMP production in myocardial tissue samples in the presence of milrinone was increased only with NE induction (mean [SEM], 745.0 [136.7] pmol/g in the absence of milrinone vs 1620.5 [372.3] pmol/g in the presence of milrinone; P < 0.05). In this preliminary study in human atrial myocardium, milrinone potentiated the contractile responses to both NE and EPI. However, only the effect of NE on tissue levels of cAMP was

  3. Sustained Adenosine Exposure Causes Lung Endothelial Barrier Dysfunction via Nucleoside Transporter–Mediated Signaling

    Science.gov (United States)

    Newton, Julie; Hsiao, Vivian; Shamirian, Paul; Blackburn, Michael R.; Pedroza, Mesias

    2012-01-01

    Previous studies by our group as well as others have shown that acute adenosine exposure enhances lung vascular endothelial barrier integrity and protects against increased permeability lung edema. In contrast, there is growing evidence that sustained adenosine exposure has detrimental effects on the lungs, including lung edema. It is well established that adenosine modulates lung inflammation. However, little is known concerning the effect of sustained adenosine exposure on lung endothelial cells (ECs), which are critical to the maintenance of the alveolar–capillary barrier. We show that exogenous adenosine plus adenosine deaminase inhibitor caused sustained elevation of adenosine in lung ECs. This sustained adenosine exposure decreased EC barrier function, elevated cellular reactive oxygen species levels, and activated p38, JNK, and RhoA. Inhibition of equilibrative nucleoside transporters (ENTs) prevented sustained adenosine-induced p38 and JNK activation and EC barrier dysfunction. Inhibition of p38, JNK, or RhoA also partially attenuated sustained adenosine-induced EC barrier dysfunction. These data indicate that sustained adenosine exposure causes lung EC barrier dysfunction via ENT-dependent intracellular adenosine uptake and subsequent activation of p38, JNK, and RhoA. The antioxidant N-acetylcysteine and the NADPH inhibitor partially blunted sustained adenosine-induced JNK activation but were ineffective in attenuation of p38 activation or barrier dysfunction. p38 was activated exclusively in mitochondria, whereas JNK was activated in mitochondria and cytoplasm by sustained adenosine exposure. Our data further suggest that sustained adenosine exposure may cause mitochondrial oxidative stress, leading to activation of p38, JNK, and RhoA in mitochondria and resulting in EC barrier dysfunction. PMID:22744860

  4. Specificity of Adenosine Inhibition of cAMP-Induced Responses in Dictyostelium Resembles That of the P Site of Higher Organisms

    NARCIS (Netherlands)

    Lookeren Campagne, Michiel M. van; Schaap, Pauline; Haastert, Peter J.M. van

    1986-01-01

    Adenosine acts as a cyclic AMP antagonist in Dictyostelium discoideum. It inhibits the binding of cyclic AMP to cell surface receptors and the induction of postaggregative differentiation by cyclic AMP. We investigated the nucleoside specificity and dose dependency of both inhibitory effects of

  5. Effects of caffeine intake prior to stress cardiac magnetic resonance perfusion imaging on regadenoson- versus adenosine-induced hyperemia as measured by T1 mapping

    NARCIS (Netherlands)

    van Dijk, R; Kuijpers, D; Kaandorp, T A M; van Dijkman, P R M; Vliegenthart, R; van der Harst, P; Oudkerk, M

    2017-01-01

    The antagonistic effects of caffeine on adenosine receptors are a possible cause of false-negative stress perfusion imaging. The purpose of this study was to determine the effects of coffee intake <4 h prior to stress perfusion cardiac magnetic resonance imaging (CMR) in regadenoson- versus

  6. Repetitive stimulation of adenosine A1 receptors in vivo : Changes in receptor numbers, G-proteins and A1 receptor agonist-induced hypothermia

    NARCIS (Netherlands)

    Roman, Viktor; Keijser, Johannes; Luiten, Paul G. M.; Meerlo, Peter

    2008-01-01

    Adenosine is an important neuromodulator and neuroprotective molecule, which is produced in the brain as a function of neuronal activity, coupling energy expenditure to energy supply. Under conditions of increased need and reduced availability of energy, including hypoxia and prolonged wakefulness,

  7. Activation of A(2) adenosine receptors dilates cortical efferent arterioles in mouse

    DEFF Research Database (Denmark)

    Al-Mashhadi, Rozh H; Skøtt, Ole; Vanhoutte, Paul M

    2009-01-01

    Adenosine can induce vasodilatation and vasoconstriction of the renal afferent arteriole of the mouse. We determined here its direct effect on efferent arterioles of mouse kidneys. Using isolated-perfused cortical efferent arterioles, we measured changes in luminal diameter in response to adenosine....... Extraluminal application of adenosine and cyclohexyladenosine had no effect on the luminal diameter. When the vessels were constricted by the thromboxane mimetic U46619, application of adenosine and 5'-N-ethylcarboxamido-adenosine dilated the efferent arterioles in a dose-dependent manner. We also found...... that the adenosine-induced vasodilatation was inhibited by the A(2)-specific receptor blocker 3,7-dimethyl-1-propargylxanthine. In the presence of this inhibitor, adenosine failed to alter the basal vessel diameter of quiescent efferent arterioles. Using primer-specific polymerase chain reaction we found...

  8. Cryotherapy-Induced Persistent Vasoconstriction After Cutaneous Cooling: Hysteresis Between Skin Temperature and Blood Perfusion

    Science.gov (United States)

    Khoshnevis, Sepideh; Craik, Natalie K.; Matthew Brothers, R.; Diller, Kenneth R.

    2016-01-01

    The goal of this study was to investigate the persistence of cold-induced vasoconstriction following cessation of active skin-surface cooling. This study demonstrates a hysteresis effect that develops between skin temperature and blood perfusion during the cooling and subsequent rewarming period. An Arctic Ice cryotherapy unit (CTU) was applied to the knee region of six healthy subjects for 60 min of active cooling followed by 120 min of passive rewarming. Multiple laser Doppler flowmetry perfusion probes were used to measure skin blood flow (expressed as cutaneous vascular conductance (CVC)). Skin surface cooling produced a significant reduction in CVC (P cryotherapy. PMID:26632263

  9. Rat cardiac myocyte adenosine transport and metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Ford, D.A.; Rovetto, M.J.

    1987-01-01

    Based on the importance of myocardial adenosine and adenine nucleotide metabolism, the adenosine salvage pathway in ventricular myocytes was studied. Accurate estimates of transport rates, separate from metabolic fllux, were determined. Adenosine influx was constant between 3 and 60 s. Adenosine metabolism maintained intracellular adenosine concentrations < 10% of the extracellular adenosine concentrations and thus unidirectional influx could be measured. Myocytes transported adenosine via saturable and nonsaturable processes. A minimum estimate of the V/sub max/ of myocytic adenosine kinase indicated the saturable component of adenosine influx was independent of adenosine kinase activity. Saturable transport was inhibited by nitrobenzylthioinosine and verapamil. Extracellular adenosine taken up myocytes was rapidly phosphorylated to adenine taken up by myocytes was rapidly phosphorylated to adenine nucleotides. Not all extracellular adenosine, though, was phosphorylated on entering myocytes, since free, as opposed to protein-bound, intracellular adenosine was detected after digitonin extraction of cells in the presence of 1 mM ethylene-diaminetetraacetic acid.

  10. Modulation of bladder function by luminal adenosine turnover and A1 receptor activation

    Science.gov (United States)

    Prakasam, H. Sandeep; Herrington, Heather; Roppolo, James R.; Jackson, Edwin K.

    2012-01-01

    The bladder uroepithelium transmits information to the underlying nervous and musculature systems, is under constant cyclical strain, expresses all four adenosine receptors (A1, A2A, A2B, and A3), and is a site of adenosine production. Although adenosine has a well-described protective effect in several organs, there is a lack of information about adenosine turnover in the uroepithelium or whether altering luminal adenosine concentrations impacts bladder function or overactivity. We observed that the concentration of extracellular adenosine at the mucosal surface of the uroepithelium was regulated by ecto-adenosine deaminase and by equilibrative nucleoside transporters, whereas adenosine kinase and equilibrative nucleoside transporters modulated serosal levels. We further observed that enriching endogenous adenosine by blocking its routes of metabolism or direct activation of mucosal A1 receptors with 2-chloro-N6-cyclopentyladenosine (CCPA), a selective agonist, stimulated bladder activity by lowering the threshold pressure for voiding. Finally, CCPA did not quell bladder hyperactivity in animals with acute cyclophosphamide-induced cystitis but instead exacerbated their irritated bladder phenotype. In conclusion, we find that adenosine levels at both surfaces of the uroepithelium are modulated by turnover, that blocking these pathways or stimulating A1 receptors directly at the luminal surface promotes bladder contractions, and that adenosine further stimulates voiding in animals with cyclophosphamide-induced cystitis. PMID:22552934

  11. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients.

    Science.gov (United States)

    Clavo, Bernardino; Santana-Rodriguez, Norberto; Llontop, Pedro; Gutierrez, Dominga; Ceballos, Daniel; Méndez, Charlin; Rovira, Gloria; Suarez, Gerardo; Rey-Baltar, Dolores; Garcia-Cabrera, Laura; Martínez-Sánchez, Gregorio; Fiuza, Dolores

    2015-01-01

    Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n = 12) previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83%) patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52-119). Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p ozone therapy, respectively (p = 0.008). Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

  12. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients

    Directory of Open Access Journals (Sweden)

    Bernardino Clavo

    2015-01-01

    Full Text Available Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n=12 previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83% patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52–119. Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p<0.001 and the number of endoscopy treatments from 37 to 4 (p=0.032. Hemoglobin levels changed from 11.1 (7–14 g/dL to 13 (10–15 g/dL, before and after ozone therapy, respectively (p=0.008. Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

  13. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit.

    Science.gov (United States)

    Anthony, Todd E; Dee, Nick; Bernard, Amy; Lerchner, Walter; Heintz, Nathaniel; Anderson, David J

    2014-01-30

    The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septohippocampal axis also plays an important role. The lateral septum (LS) is thought to suppress fear and anxiety through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons whose functional connectivity we have investigated using optogenetics. Crfr2(+) cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2(+) neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2(+) outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states and provide a cellular point of entry to LS circuitry. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Further observations on the utilization of adenosine triphosphate in rat mast cells during histamine release induced by the ionophore A23187

    DEFF Research Database (Denmark)

    Johansen, Torben

    1980-01-01

    in the adenosine triphosphate (ATP) content and the rate of lactate production of A23187-primed mast cells. 3 Ethacrynic acid by itself decreased the rate of glycolytic ATP production. 4 By measurement of the ATP content and the lactate production of mast cells with or without secretory activity, the increased...... demand of energy for exocytosis was estimated to be equivalent to 0.14 pmol of ATP pr 10(3) mast cells....

  15. Dynamics of the mechanoluminescence induced by elastic deformation of persistent luminescent crystals

    Energy Technology Data Exchange (ETDEWEB)

    Chandra, V.K. [Department of Electrical and Electronics Engineering, Chhatrapati Shivaji Institute of Technology, Shivaji Nagar, Kolihapuri, Durg 491001 (C.G.) (India); Chandra, B.P., E-mail: bpchandra4@yahoo.co.in [Disha Academy of Research and Education, Disha Institute of Management and Technology, Satya Vihar, Vidhansabha-Chandrakhuri Marg, Raipur 492101 (C.G.) (India)

    2012-03-15

    When a composite of suitable dimension formed by mixing the microcrystalline or nanocrystalline persistent luminescent materials in epoxy resin is deformed at a fixed pressing rate, then the elastico mechanoluminescence (EML) emission takes place after a threshold pressure, in which the EML intensity increases linearly with the applied pressure. When the applied pressure is kept constant or decreased linearly, then the EML intensity decreases with time, in which depending on the prevailing condition, the EML intensity initially decreases at a fast rate and then at a slow rate or sometimes it decreases exponentially having only one decay time. When a small ball is dropped from a low height onto the film of a persistent luminescent material, then initially the EML intensity increases with time, attains a peak value and then it decreases initially at a fast rate and later on at a slow rate. In this case, both the peak EML intensity and the total EML intensity increase linearly with the height through which the ball is dropped onto the film. Considering the piezoelectrically induced detrapping model based on successive detrapping of exponentially distributed traps a theoretical approach is made to the dynamics of light emission induced by elastic deformation of persistent luminescent crystals and thin films. It is shown that the EML intensity depends on several parameters such as pressure, pressing rate or strain rate, temperature, density of filled electron traps, piezoelectric constant near defect centers, etc. Both, in the case of slow deformation and impact stress, the fast decay time is related to the time-constant for the decrease of pressing rate of the samples and the slow decay time of EML is related to the lifetime of electrons in the shallow traps lying in the normal piezoelectric region of the crystals. Both, the EML produced during the release of pressure and the EML produced during the successive applications of pressure take place due to the detrapping

  16. Adenosine contributes to blood flow regulation in the exercising human leg by increasing prostaglandin and nitric oxide formation

    DEFF Research Database (Denmark)

    Mortensen, Stefan; Nyberg, Michael; Thaning, Pia

    2009-01-01

    Adenosine can induce vasodilation in skeletal muscle, but to what extent adenosine exerts its effect via formation of other vasodilators and whether there is redundancy between adenosine and other vasodilators remain unclear. We tested the hypothesis that adenosine, prostaglandins, and NO act...... in synergy to regulate skeletal muscle hyperemia by determining the following: (1) the effect of adenosine receptor blockade on skeletal muscle exercise hyperemia with and without simultaneous inhibition of prostaglandins (indomethacin; 0.8 to 1.8 mg/min) and NO (N(G)-mono-methyl-l-arginine; 29 to 52 mg....../min); (2) whether adenosine-induced vasodilation is mediated via formation of prostaglandins and/or NO; and (3) the femoral arterial and venous plasma adenosine concentrations during leg exercise with the microdialysis technique in a total of 24 healthy, male subjects. Inhibition of adenosine receptors...

  17. Induced seismicity in EGS reservoir : analysis of persistent multiplets at Soultz-sous-Forêts, France

    Science.gov (United States)

    Cauchie, Léna; Lengliné, Olivier; Schmittbuhl, Jean

    2017-04-01

    Abundant seismicity is generally observed during the exploitation of geothermal reservoirs, especially during phases of hydraulic stimulations. At the Enhanced Geothermal System of Soultz-Sous-Forêts in France, the induced seismicity has been thoroughly studied over the years of exploitation and the mechanism at its origin has been related to both fluid pressure increase during stimulation and aseismic creeping movements. The fluid-induced seismic events often exhibit a high degree of similarity and the mechanism at the origin of these repeated events is thought to be associated with slow slip process where asperities on the rupture zone act several times. In order to improve our knowledge on the mechanisms associated with such events and on the damaged zones involved during the hydraulic stimulations, we investigate the behaviour of the multiplets and their persistent nature, if it prevails, over several water injection intervals. For this purpose, we analysed large datasets recorded from a downhole seismic network for several water injection periods (1993, 2000, …). For each stimulation interval, thousands of events are recorded at depth. We detected the events using the continuous kurtosis-based migration method and classified them into families of comparable waveforms using an approach based on cross-correlation analysis. We obtain precise relative locations of the multiplets using differential arrival times obtained through cross-correlation of similar waveforms. Finally, the properties of the similar fluid-induced seismic events are derived (magnitude, spectral content) and examined over the several hydraulic tests. Hopefully these steps will lead to a better understanding of the repetitive nature of these events and the investigation of their persistence will outline the heterogeneities of the structures (temperatures anomalies, regional stress perturbations, fluid flow channelling) regularly involved during the different stimulations.

  18. Genetics Home Reference: adenosine deaminase 2 deficiency

    Science.gov (United States)

    ... Twitter Home Health Conditions Adenosine deaminase 2 deficiency Adenosine deaminase 2 deficiency Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description Adenosine deaminase 2 (ADA2) deficiency is a disorder characterized ...

  19. Adenosine through the A2A adenosine receptor increases IL-1β in the brain contributing to anxiety

    Science.gov (United States)

    Chiu, Gabriel S.; Darmody, Patrick T.; Walsh, John P.; Moon, Morgan L.; Kwakwa, Kristin A.; Bray, Julie K.; McCusker, Robert H.; Freund, Gregory G.

    2014-01-01

    Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1β in the brain by two-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1β in the brain. PMID:24907587

  20. Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling

    Science.gov (United States)

    Mi, Tiejuan; Abbasi, Shahrzad; Zhang, Hong; Uray, Karen; Chunn, Janci L.; Xia, Ling Wei; Molina, Jose G.; Weisbrodt, Norman W.; Kellems, Rodney E.; Blackburn, Michael R.; Xia, Yang

    2008-01-01

    Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A2B adenosine receptor–mediated (A2BR-mediated) cAMP and cGMP induction was required for elevated adenosine–induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A2BR activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A2BR signaling in both Ada–/– and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A2BR activation may prove beneficial in the treatment of this disorder. PMID:18340377

  1. Porcine epidemic diarrhea virus (PEDV) co-infection induced chlamydial persistence/stress does not require viral replication.

    Science.gov (United States)

    Schoborg, Robert V; Borel, Nicole

    2014-01-01

    Chlamydiae may exist at the site of infection in an alternative replicative form, called the aberrant body (AB). ABs are produced during a viable but non-infectious developmental state termed "persistence" or "chlamydial stress." As persistent/stressed chlamydiae: (i) may contribute to chronic inflammation observed in diseases like trachoma; and (ii) are more resistant to current anti-chlamydial drugs of choice, it is critical to better understand this developmental stage. We previously demonstrated that porcine epidemic diarrhea virus (PEDV) co-infection induced Chlamydia pecorum persistence/stress in culture. One critical characteristic of persistence/stress is that the chlamydiae remain viable and can reenter the normal developmental cycle when the stressor is removed. Thus, we hypothesized that PEDV-induced persistence would be reversible if viral replication was inhibited. Therefore, we performed time course experiments in which Vero cells were C. pecorum/PEDV infected in the presence of cycloheximide (CHX), which inhibits viral but not chlamydial protein synthesis. CHX-exposure inhibited PEDV replication, but did not inhibit induction of C. pecorum persistence at 24 h post-PEDV infection, as indicated by AB formation and reduced production of infectious EBs. Interestingly, production of infectious EBs resumed when CHX-exposed, co-infected cells were incubated 48-72 h post-PEDV co-infection. These data demonstrate that PEDV co-infection-induced chlamydial persistence/stress is reversible and suggest that this induction (i) does not require viral replication in host cells; and (ii) does not require de novo host or viral protein synthesis. These data also suggest that viral binding and/or entry may be required for this effect. Because the PEDV host cell receptor (CD13 or aminopeptidase N) stimulates cellular signaling pathways in the absence of PEDV infection, we suspect that PEDV co-infection might alter CD13 function and induce the chlamydiae to enter the

  2. Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine.

    Science.gov (United States)

    Birnbaum, Yochai; Birnbaum, Gilad D; Birnbaum, Itamar; Nylander, Sven; Ye, Yumei

    2016-12-01

    Ticagrelor inhibits the equilibrative-nucleoside-transporter-1 and thereby, adenosine cell re-uptake. Ticagrelor limits infarct size (IS) in non-diabetic rats and the effect is adenosine-dependent. Statins, via ecto-5'-nucleotidase activation, also increase adenosine levels and limit IS. Ticagrelor and rosuvastatin have additive effects on myocardial adenosine levels, and therefore, on IS and post-reperfusion activation of the NLRP3-inflammasome. Diabetic ZDF rats received via oral gavage; water (control), ticagrelor (150 mg/kg/d), prasugrel (7.5 mg/kg/d), rosuvastatin (5 mg/kg/d), ticagrelor + rosuvastatin and prasugrel + rosuvastatin for 3d. On day 4, rats underwent 30 min coronary artery occlusion and 24 h of reperfusion. Two additional groups received, ticagrelor + rosuvastatin or water in combination with CGS15943 (CGS, an adenosine receptor antagonist, 10 mg/kg i.p. 1 h before ischemia). Both ticagrelor and rosuvastatin increased myocardial adenosine levels with an additive effect of the combination whereas prasugrel had no effect. Similarly, both ticagrelor and rosuvastatin significantly reduced IS with an additive effect of the combination whereas prasugrel had no effect. The effect on IS was adenosine dependent as CGS15943 reversed the effect of ticagrelor + rosuvastatin. The ischemia-reperfusion injury increased myocardial mRNA levels of NLRP3, ASC, IL-1β and IL-6. Ticagrelor and rosuvastatin, but not prasugrel, significantly decreased these pro-inflammatory mediators with a trend to an additive effect of the combination. The combination also increased the levels of anti-inflammatory 15-epilipoxin A4. Ticagrelor and rosuvastatin when given in combination have an additive effect on local myocardial adenosine levels in the setting of ischemia reperfusion. This translates into an additive cardioprotective effect mediated by adenosine-induced effects including downregulation of pro- but upregulation of anti-inflammatory mediators.

  3. Estimation of TiO₂ nanoparticle-induced genotoxicity persistence and possible chronic gastritis-induction in mice.

    Science.gov (United States)

    Mohamed, Hanan Ramadan Hamad

    2015-09-01

    Titanium dioxide (TiO2) nanoparticles are widely used as a food additive and coloring agent in many consumer products however limited data is available on the nano-TiO2 induced genotoxicity persistence. Thus, this study investigated the persistence of nano-TiO2 induced genotoxicity and possible induction of chronic gastritis in mice. The mice were orally administered 5, 50 or 500 mg/kg body weight nano-TiO2 for five consecutive days, and then mice from each dosage group were sacrificed 24 h or one or two weeks after the last treatment. The administration of nano-TiO2 resulted in persistent apoptotic DNA fragmentation and mutations in p53 exons (5-8) as well as significant persistent elevations in malondialdehyde and nitric oxide levels and decreases in the reduced glutathione level and catalase activity compared with the control mice in a dose- and time-dependent manner. Necrosis and inflammation were evident upon histological examination. These findings could be attributed to the persistent accumulation of nano-TiO2 at the tested doses at all three time points. Based on these findings, we conclude that the administration of nano-TiO2, even at low doses, leads to persistent accumulation of nano-TiO2 in mice, resulting in persistent inflammation, apoptosis and oxidative stress, ultimately leading to the induction of chronic gastritis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. [Persistent type 2 lepra reaction (erythema nodosum) and clofazimine-induced lethal enteropathy].

    Science.gov (United States)

    Rodríguez, Gerzain; Pinto, Rafael; López, Fernando; Gómez, Yenny

    2009-03-01

    Clofazimine enterophathy is a serious complication of clofazimine when used at high doses for treatment of type 2 lepra or or erythema nodosum leprosum. Objective. A woman is presented who had a delayed diagnosis of leprosy, persistent type 2 lepra reaction and lethal clofazimine enteropathy. A 31-year-old woman presented leprosy symptoms over a 16-year period without medical diagnosis of her disease. During this period, type 2 lepra episodes occurred, but were not accurately diagnosed. These episodes became more severe during her second pregnancy. The patient and her family were interviewed, and her clinical history reviewed. After twelve years of medical consults, lepromatous leprosy was diagnosed, based on perforation of her nasal septum, with a bacterial index of 5. Her husband and a 12-year-old daughter have leprosy symptoms. During multidrug therapy, she presented with repeated type 2 lepra reaction episodes for which she received daily clofazimine 400 mg doses. Two months after this treatment, severe and frequent episodes of intense abdominal pain began to occur. These persisted for more than a year and were managed with in-hospital administration of several classes of painkillers and antispasmodic medication, including morphine. She also presented with sporadic diarrhea, constipation, nausea, weight loss and mesenteric adenopathies. She died finally due to this intestinal condition. No autopsy was performed. The patient's clinical presentation suggested a clofazimine-induced lethal enteropathy, a complication not previously seen in Colombia. This connection was not recognized by the medical officers that treated the patient.

  5. Amphetamine- and nicotine-induced cross-sensitization in adolescent rats persists until adulthood.

    Science.gov (United States)

    Santos, Gabriela C; Marin, Marcelo T; Cruz, Fábio C; Delucia, Roberto; Planeta, Cleopatra S

    2009-07-01

    Nicotine and psychostimulants are often abused in combination and drug abuse often begins during adolescence and can have long-term consequences. Behavioral sensitization has been suggested as an animal model of neuroplasticity implicated in the development of drug addiction. We evaluated whether the pretreatment with nicotine (0.4 mg/kg; s.c.) or amphetamine (5.0 mg/kg; i.p.) in adolescent rats [from postnatal day (P) 28 to P34] could induce cross-sensitization to nicotine and amphetamine when animals were challenged during both adolescence (P37) and adulthood (P70), in separate groups of animals. Adolescent animals pretreated with amphetamine displayed behavioral sensitization to nicotine, which persisted until adulthood. Moreover, adolescent animals pretreated with nicotine showed sensitized locomotor response to amphetamine in the adulthood. These data suggest that adolescents who abuse nicotine may be particularly susceptible to the effects of amphetamine and vice versa. Moreover, this increased vulnerability may persist through their development until adulthood.

  6. Persistence of yellow fever vaccine-induced antibodies after solid organ transplantation.

    Science.gov (United States)

    Wyplosz, B; Burdet, C; François, H; Durrbach, A; Duclos-Vallée, J C; Mamzer-Bruneel, M-F; Poujol, P; Launay, O; Samuel, D; Vittecoq, D; Consigny, P H

    2013-09-01

    Immunization using live attenuated vaccines represents a contra-indication after solid organ transplantation (SOT): consequently, transplant candidates planning to travel in countries where yellow fever is endemic should be vaccinated prior to transplantation. The persistence of yellow fever vaccine-induced antibodies after transplantation has not been studied yet. We measured yellow-fever neutralizing antibodies in 53 SOT recipients vaccinated prior to transplantation (including 29 kidney recipients and 18 liver recipients). All but one (98%) had protective titers of antibodies after a median duration of 3 years (min.: 0.8, max.: 21) after transplantation. The median antibody level was 40 U/L (interquartile range: 40-80). For the 46 patients with a known or estimated date of vaccination, yellow-fever antibodies were still detectable after a median time of 13 years (range: 2-32 years) post-immunization. Our data suggest there is long-term persistence of antibodies to yellow fever in SOT recipients who have been vaccinated prior to transplantation. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

  7. Tween 20-stabilized gold nanoparticles combined with adenosine triphosphate-BODIPY conjugates for the fluorescence detection of adenosine with more than 1000-fold selectivity

    Energy Technology Data Exchange (ETDEWEB)

    Hung, Szu-Ying; Shih, Ya-Chen [Department of Chemistry, National Sun Yat-sen University, Taiwan (China); Tseng, Wei-Lung, E-mail: tsengwl@mail.nsysu.edu.tw [Department of Chemistry, National Sun Yat-sen University, Taiwan (China); School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Taiwan (China); Center for Nanoscience and Nanotechnology, National Sun Yat-sen University, Taiwan (China); Center for Stem Cell Research, Kaohsiung Medical University, Taiwan (China)

    2015-02-01

    Graphical abstract: A simple, enzyme-free, label-free, sensitive and selective system was developed for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles as an efficient quencher for boron dipyrromethene-conjugated adenosine 5′-triphosphate and as a recognition element for adenosine. - Highlights: • The proposed method can detect adenosine with more than 1000-fold selectivity. • The analysis of adenosine is rapid (∼6 min) using the proposed method. • This method provided better sensitivity for adenosine as compared to aptamer-based sensors. • This method can be applied for the determination of adenosine in urine. - Abstract: This study describes the development of a simple, enzyme-free, label-free, sensitive, and selective system for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles (Tween 20-AuNPs) as an efficient fluorescence quencher for boron dipyrromethene-conjugated adenosine 5′-triphosphate (BODIPY-ATP) and as a recognition element for adenosine. BODIPY-ATP can interact with Tween 20-AuNPs through the coordination between the adenine group of BODIPY-ATP and Au atoms on the NP surface, thereby causing the fluorescence quenching of BODIPY-ATP through the nanometal surface energy transfer (NSET) effect. When adenosine attaches to the NP surface, the attached adenosine exhibits additional electrostatic attraction to BODIPY-ATP. As a result, the presence of adenosine enhances the efficiency of AuNPs in fluorescence quenching of BODIPY-ATP. The AuNP-induced fluorescence quenching of BODIPY-ATP progressively increased with an increase in the concentration of adenosine; the detection limit at a signal-to-noise ratio of 3 for adenosine was determined to be 60 nM. The selectivity of the proposed system was more than 1000-fold for adenosine over any adenosine analogs and other nucleotides. The proposed system combined with a phenylboronic acid-containing column was successfully applied to the

  8. Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia

    DEFF Research Database (Denmark)

    Jensen, Vivi Flou Hjorth; Mølck, Anne-Marie; Heydenreich, Annette

    2016-01-01

    New insulin analogues with a longer duration of action and a flatter pharmacodynamic profile are developed to improve convenience and safety for diabetic patients. During the nonclinical development of such analogues, safety studies must be conducted in nondiabetic rats, which consequently...... are rendered chronically hypoglycemic. A rat comparator model using human insulin would be valuable, as it would enable differentiation between effects related to either persistent insulin-induced hypoglycemia (IIH) or a new analogue per se. Such a model could alleviate the need for an in...... nerve and skeletal myofiber degeneration within the same animals. This suggests that the model can serve as a nonclinical comparator model during development of long-acting insulin analogues....

  9. Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features.

    Science.gov (United States)

    Lerner, Arturo G; Gelkopf, Marc; Skladman, Irena; Rudinski, Dmitri; Nachshon, Hanna; Bleich, Avi

    2003-03-01

    An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appear during the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen persisting perception disorder (HPPD) is a condition in which the re-experiencing of one or more perceptual symptoms causes significant distress or impairment in social, occupational or other important areas of functioning and may be extremely debilitating. Benzodiazepines are one of the recommended agents for the treatment of HPPD but it is unclear which of them may be more helpful. The goal of our investigation was to assess the efficacy of clonazepam in the treatment of LSD-induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of HPPD with anxiety features for at least 3 months and were drug free at least 3 months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued for 6 months. They were weekly evaluated during the 2 months of clonazepam administration and monthly during the follow-up period using the Clinical Global Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients reported a significant relief and the presence of only mild symptomatology during the clonazepam administration. This improvement was clearly sustained and persisted during a 6-month follow-up period. This study suggests that high potency benzodiazepines like clonazepam, which has serotonergic properties, may be more effective than low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

  10. Regadenoson provides perfusion results comparable to adenosine in heterogeneous patient populations: a quantitative analysis from the ADVANCE MPI trials.

    Science.gov (United States)

    Mahmarian, John J; Peterson, Leif E; Xu, Jiaqiong; Cerqueira, Manuel D; Iskandrian, Ami E; Bateman, Timothy M; Thomas, Gregory S; Nabi, Faisal

    2015-04-01

    Total and reversible left ventricular (LV) perfusion defect size (PDS) predict patient outcome. Limited data exist as to whether regadenoson induces similar perfusion abnormalities as observed with adenosine. We sought to determine whether regadenoson induces a similar LV PDS as seen with adenosine across varying patient populations. ADVANCE MPI were prospective, double-blind randomized trials comparing regadenoson to standard adenosine myocardial perfusion tomography (SPECT). Following an initial adenosine SPECT, patients were randomized to either regadenoson (N = 1284) or a second adenosine study (N = 660). SPECT quantification was performed blinded to randomization and image sequence. Propensity analysis was used to define comparability of regadenoson and adenosine perfusion results. Baseline clinical and SPECT results were similar in the two randomized groups. There was a close correlation between adenosine and regadenoson-induced total (r (2) = 0.98, P regadenoson vs adenosine, respectively, and irrespective of age, gender, diabetic status, body mass index, or prior cardiovascular history. By propensity analysis, regadenoson-induced total PDS was significantly larger than observed with adenosine. This is the first study to show that regadenoson induces similar, if not larger, perfusion defects than those observed with adenosine across different patient populations and demonstrates the value of quantitative analysis for defining serial changes in SPECT perfusion results. Regadenoson should provide comparable diagnostic and prognostic SPECT information to that obtained with adenosine.

  11. Interstitial and plasma adenosine stimulate nitric oxide and prostacyclin formation in human skeletal muscle

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Mortensen, Stefan Peter; Thaning, Pia

    2010-01-01

    One major unresolved issue in muscle blood flow regulation is that of the role of circulating versus interstitial vasodilatory compounds. The present study determined adenosine-induced formation of NO and prostacyclin in the human muscle interstitium versus in femoral venous plasma to elucidate....... In young healthy humans, microdialysate was collected at rest, during arterial infusion of adenosine, and during interstitial infusion of adenosine through microdialysis probes inserted into musculus vastus lateralis. Muscle interstitial NO and prostacyclin increased with arterial and interstitial infusion...... of adenosine. The addition of adenosine to skeletal muscle cells increased NO formation (fluorochrome 4-amino-5-methylamino-2',7-difluorescein fluorescence), whereas prostacyclin levels remained unchanged. The addition of adenosine to microvascular endothelial cells induced an increase in NO and prostacyclin...

  12. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

    Science.gov (United States)

    2013-01-01

    Background Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. Methods Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. Results LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. Conclusions We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF. PMID:23363775

  13. Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity

    DEFF Research Database (Denmark)

    Heinonen, Ilkka H.A.; Kemppainen, Jukka; Kaskinoro, Kimmo

    2010-01-01

    Adenosine is a widely used pharmacological agent to induce a 'high flow' control condition to study the mechanisms of exercise hyperemia, but it is not known how well adenosine infusion depicts exercise-induced hyperemia especially in terms of blood flow distribution at the capillary level in human...... muscle. Additionally, it remains to be determined what proportion of adenosine-induced flow elevation is specifically directed to muscle only. In the present study we measured thigh muscle capillary nutritive blood flow in nine healthy young men using positron emission tomography at rest and during...... femoral artery infusion of adenosine (1 mg * min(-1) * litre thigh volume(-1)), which has previously been shown to induce maximal whole thigh blood flow of ~8 L/min. This response was compared to the blood flow induced by moderate-high intensity one-leg dynamic knee extension exercise. Adenosine increased...

  14. Chlamydia trachomatis responds to heat shock, penicillin induced persistence, and IFN-gamma persistence by altering levels of the extracytoplasmic stress response protease HtrA

    Directory of Open Access Journals (Sweden)

    Mathews Sarah A

    2008-11-01

    Full Text Available Abstract Background Chlamydia trachomatis, an obligate intracellular human pathogen, is the most prevalent bacterial sexually transmitted infection worldwide and a leading cause of preventable blindness. HtrA is a virulence and stress response periplasmic serine protease and molecular chaperone found in many bacteria. Recombinant purified C. trachomatis HtrA has been previously shown to have both activities. This investigation examined the physiological role of Chlamydia trachomatis HtrA. Results The Chlamydia trachomatis htrA gene complemented the lethal high temperature phenotype of Escherichia coli htrA- (>42°C. HtrA levels were detected to increase by western blot and immunofluorescence during Chlamydia heat shock experiments. Confocal laser scanning microscopy revealed a likely periplasmic localisation of HtrA. During penicillin induced persistence of Chlamydia trachomatis, HtrA levels (as a ratio of LPS were initially less than control acute cultures (20 h post infection but increased to more than acute cultures at 44 h post infection. This was unlike IFN-γ persistence where lower levels of HtrA were observed, suggesting Chlamydia trachomatis IFN-γ persistence does not involve a broad stress response. Conclusion The heterologous heat shock protection for Escherichia coli, and increased HtrA during cell wall disruption via penicillin and heat shock, indicates an important role for HtrA during high protein stress conditions for Chlamydia trachomatis.

  15. Endogenous adenosine and hemorrhagic shock: effects of caffeine administration or caffeine withdrawal.

    OpenAIRE

    Conlay, L A; Evoniuk, G; Wurtman, R J

    1988-01-01

    Plasma adenosine concentrations doubled when rats were subjected to 90 min of profound hemorrhagic shock. Administration of caffeine (20 mg per kg of body weight), an adenosine-receptor antagonist, attenuated the hemorrhage-induced decrease in blood pressure. In contrast, chronic caffeine consumption (0.1% in drinking water), followed by a brief period of caffeine withdrawal, amplified the hypotensive response to hemorrhage. These data suggest that endogenous adenosine participates in the hyp...

  16. An adenosine A3 receptor agonist inhibits DSS-induced colitis in mice through modulation of the NF-κB signaling pathway

    Science.gov (United States)

    Ren, Tianhua; Tian, Ting; Feng, Xiao; Ye, Shicai; Wang, Hao; Wu, Weiyun; Qiu, Yumei; Yu, Caiyuan; He, Yanting; Zeng, Juncheng; Cen, Junwei; Zhou, Yu

    2015-01-01

    The role of the adenosine A3 receptor (A3AR) in experimental colitis is controversial. The A3AR agonist N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) has been shown to have a clinical benefit, although studies in A3AR-deficient mice suggest a pro-inflammatory role. However, there are no studies on the effect of 2-Cl-IB-MECA and the molecular mechanism of action of A3AR in murine colitis models in vivo. Is it the same as that observed in vitro? The interaction between 2-CL-IB-MECA and A3AR in a murine colitis model and the signaling pathways associated with this interaction remain unclear. Here we demonstrate a role for the NF-κB signaling pathway and its effect on modifying the activity of proinflammatory factors in A3AR-mediated biological processes. Our results demonstrated that A3AR activation possessed marked effects on experimental colitis through the NF-κB signaling pathway. PMID:25762375

  17. Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice.

    Science.gov (United States)

    Liao, Hsien-Yin; Hsieh, Ching-Liang; Huang, Chun-Ping; Lin, Yi-Wen

    2017-02-13

    Pain is associated with several conditions, such as inflammation, that result from altered peripheral nerve properties. Electroacupuncture (EA) is a common Chinese clinical medical technology used for pain management. Using an inflammatory pain mouse model, we investigated the effects of EA on the regulation of neurons, microglia, and related molecules. Complete Freund's adjuvant (CFA) injections produced a significant mechanical and thermal hyperalgesia that was reversed by EA or a transient receptor potential V1 (TRPV1) gene deletion. The expression of the astrocytic marker glial fibrillary acidic protein (GFAP), the microglial marker Iba-1, S100B, receptor for advanced glycation end-products (RAGE), TRPV1, and other related molecules was dramatically increased in the dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) of CFA-treated mice. This effect was reversed by EA and TRPV1 gene deletion. In addition, endomorphin (EM) and N6-cyclopentyladenosine (CPA) administration reliably reduced mechanical and thermal hyperalgesia, thereby suggesting the involvement of opioid and adenosine receptors. Furthermore, blocking of opioid and adenosine A1 receptors reversed the analgesic effects of EA. Our study illustrates the substantial therapeutic effects of EA against inflammatory pain and provides a novel and detailed mechanism underlying EA-mediated analgesia via neuronal and non-neuronal pathways.

  18. Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice

    Science.gov (United States)

    Liao, Hsien-Yin; Hsieh, Ching-Liang; Huang, Chun-Ping; Lin, Yi-Wen

    2017-01-01

    Pain is associated with several conditions, such as inflammation, that result from altered peripheral nerve properties. Electroacupuncture (EA) is a common Chinese clinical medical technology used for pain management. Using an inflammatory pain mouse model, we investigated the effects of EA on the regulation of neurons, microglia, and related molecules. Complete Freund’s adjuvant (CFA) injections produced a significant mechanical and thermal hyperalgesia that was reversed by EA or a transient receptor potential V1 (TRPV1) gene deletion. The expression of the astrocytic marker glial fibrillary acidic protein (GFAP), the microglial marker Iba-1, S100B, receptor for advanced glycation end-products (RAGE), TRPV1, and other related molecules was dramatically increased in the dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) of CFA-treated mice. This effect was reversed by EA and TRPV1 gene deletion. In addition, endomorphin (EM) and N6-cyclopentyladenosine (CPA) administration reliably reduced mechanical and thermal hyperalgesia, thereby suggesting the involvement of opioid and adenosine receptors. Furthermore, blocking of opioid and adenosine A1 receptors reversed the analgesic effects of EA. Our study illustrates the substantial therapeutic effects of EA against inflammatory pain and provides a novel and detailed mechanism underlying EA-mediated analgesia via neuronal and non-neuronal pathways. PMID:28211895

  19. Cold-induced vasoconstriction may persist long after cooling ends: an evaluation of multiple cryotherapy units.

    Science.gov (United States)

    Khoshnevis, Sepideh; Craik, Natalie K; Diller, Kenneth R

    2015-09-01

    Localized cooling is widely used in treating soft tissue injuries by modulating swelling, pain, and inflammation. One of the primary outcomes of localized cooling is vasoconstriction within the underlying skin. It is thought that in some instances, cryotherapy may be causative of tissue necrosis and neuropathy via cold-induced ischaemia leading to nonfreezing cold injury (NFCI). The purpose of this study is to quantify the magnitude and persistence of vasoconstriction associated with cryotherapy. Data are presented from testing with four different FDA approved cryotherapy devices. Blood perfusion and skin temperature were measured at multiple anatomical sites during baseline, active cooling, and passive rewarming periods. Local cutaneous blood perfusion was depressed in response to cooling the skin surface with all devices, including the DonJoy (DJO, p = 2.6 × 10(-8)), Polar Care 300 (PC300, p = 1.1 × 10(-3)), Polar Care 500 Lite (PC500L, p = 0.010), and DeRoyal T505 (DR505, p = 0.016). During the rewarming period, parasitic heat gain from the underlying tissues and the environment resulted in increased temperatures of the skin and pad for all devices, but blood perfusion did not change significantly, DJO (n.s.), PC300 (n.s.), PC500L (n.s.), and DR505 (n.s.). The results demonstrate that cryotherapy can create a deep state of vasoconstriction in the local area of treatment. In the absence of independent stimulation, the condition of reduced blood flow persists long after cooling is stopped and local temperatures have rewarmed towards the normal range, indicating that the maintenance of vasoconstriction is not directly dependent on the continuing existence of a cold state. The depressed blood flow may dispose tissue to NFCI.

  20. Baicalein reverts L-valine-induced persistent sodium current up-modulation in primary cortical neurons.

    Science.gov (United States)

    Caioli, Silvia; Candelotti, Elena; Pedersen, Jens Z; Saba, Luana; Antonini, Alessia; Incerpi, Sandra; Zona, Cristina

    2016-04-01

    L-valine is a branched-chain amino acid (BCAA) largely used as dietary integrator by athletes and involved in some inherited rare diseases such as maple syrup urine disease. This pathology is caused by an altered BCAA metabolism with the accumulation of toxic keto acids in tissues and body fluids with consequent severe neurological symptoms. In animal models of BCAA accumulation, increased oxidative stress levels and lipid peroxidation have been reported. The aim of this study was to analyze both whether high BCAA concentrations in neurons induce reactive oxygen species (ROS) production and whether, by performing electrophysiological recordings, the neuronal functional properties are modified. Our results demonstrate that in primary cortical cultures, a high dose of valine increases ROS production and provokes neuronal hyperexcitability because the action potential frequencies and the persistent sodium current amplitudes increase significantly compared to non-treated neurons. Since Baicalein, a flavone obtained from the Scutellaria root, has been shown to act as a strong antioxidant with neuroprotective effects, we evaluated its possible antioxidant activity in primary cortical neurons chronically exposed to L-valine. The preincubation of cortical neurons with Baicalein prevents the ROS production and is able to revert both the neuronal hyperexcitability and the increase of the persistent sodium current, indicating a direct correlation between the ROS production and the altered physiological parameters. In conclusion, our data show that the electrophysiological alterations of cortical neurons elicited by high valine concentration are due to the increase in ROS production, suggesting much caution in the intake of BCAA dietary integrators. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Penicillin induced persistence in Chlamydia trachomatis: high quality time lapse video analysis of the developmental cycle.

    Directory of Open Access Journals (Sweden)

    Rachel J Skilton

    Full Text Available BACKGROUND: Chlamydia trachomatis is a major human pathogen with a unique obligate intracellular developmental cycle that takes place inside a modified cytoplasmic structure known as an inclusion. Following entry into a cell, the infectious elementary body (EB differentiates into a non-infectious replicative form known as a reticulate body (RB. RBs divide by binary fission and at the end of the cycle they redifferentiate into EBs. Treatment of C.trachomatis with penicillin prevents maturation of RBs which survive and enlarge to become aberrant RBs within the inclusion in a non-infective persistent state. Persistently infected individuals may be a reservoir for chlamydial infection. The C.trachomatis genome encodes the enzymes for peptidoglycan (PG biosynthesis but a PG sacculus has never been detected. This coupled to the action of penicillin is known as the chlamydial anomaly. We have applied video microscopy and quantitative DNA assays to the chlamydial developmental cycle to assess the effects of penicillin treatment and establish a framework for investigating penicillin induced chlamydial persistence. PRINCIPAL FINDINGS: Addition of penicillin at the time of cell infection does not prevent uptake and the establishment of an inclusion. EB to RB transition occurs but bacterial cytokinesis is arrested by the second binary fission. RBs continue to enlarge but not divide in the presence of penicillin. The normal developmental cycle can be recovered by the removal of penicillin although the large, aberrant RBs do not revert to the normal smaller size but remain present to the completion of the developmental cycle. Chromosomal and plasmid DNA replication is unaffected by the addition of penicillin but the arrest of bacterial cytokinesis under these conditions results in RBs accumulating multiple copies of the genome. CONCLUSIONS: We have applied video time lapse microscopy to the study of the chlamydial developmental cycle. Linked with accurate

  2. Adenosine hypothesis of schizophrenia –opportunities for pharmacotherapy

    Science.gov (United States)

    Boison, Detlev; Singer, Philipp; Shen, Hai-Ying; Feldon, Joram; Yee, Benjamin K.

    2011-01-01

    Pharmacotherapy of schizophrenia based on the dopamine hypothesis remains unsatisfactory for the negative and cognitive symptoms of the disease. Enhancing N-methyl-d-aspartate receptors (NMDAR) function is expected to alleviate such persistent symptoms, but successful development of novel clinically effective compounds remains challenging. Adenosine is a homeostatic bioenergetic network modulator that is able to affect complex networks synergistically at different levels (receptor dependent pathways, biochemistry, bioenergetics, and epigenetics). By affecting brain dopamine and glutamate activities it represents a promising candidate for restoring the functional imbalance in these neurotransmitter systems believed to underlie the genesis of schizophrenia symptoms, as well as restoring homeostasis of bioenergetics. Suggestion of an adenosine hypothesis of schizophrenia further posits that adenosinergic dysfunction might contribute to the emergence of multiple neurotransmitter dysfunctionscharacteristic of schizophrenia via diverse mechanisms. Given the importance of adenosine in early brain development and regulation of brain immune response, it also bears direct relevance to the aetiology of schizophrenia. Here, we provide an overview of the rationale and evidence in support of the therapeutic potential of multiple adenosinergic targets, including the high-affinity adenosine receptors (A1R and A2AR), and the regulatory enzyme adenosine kinase (ADK). Key preliminary clinical data and preclinical findings are reviewed. PMID:21315743

  3. Swimming training prevents alterations in ecto-NTPDase and adenosine deaminase activities in lymphocytes from Nω-nitro-L-arginine methyl ester hydrochloride induced hypertension rats.

    Science.gov (United States)

    Cardoso, Andréia Machado; Abdalla, Fátima Husein; Bagatini, Margarete Dulce; Martins, Caroline Curry; Zanini, Daniela; Schmatz, Roberta; Jaques, Jeandre Augusto; Leal, Daniela Bitencourt Rosa; Morsch, Vera Maria; Schetinger, Maria Rosa Chitolina

    2015-04-01

    Hypertension is accompanied by inflammatory process and purinergic system has been recognized as having an important role in modulating immune functions. Physical training is being considered one of the major lifestyle changes that contributes to the cardiovascular health as well as has an important role in regulating purinergic system. Thus, the aim of this study was to investigate the effect of chronic swimming training on lymphocytic purinergic system enzymes activities related to inflammatory process, as well as in lipid profile and classic inflammatory markers in rats that developed hypertension in response to the oral administration of N-nitro-L-arginine methyl ester hydrochloride (L-NAME). After 6 weeks of training, lymphocytes and serum were separated to be analysed. L-NAME-treated group displayed an increase in SBP as well as in ecto-NTPDase and adenosine deaminase (ADA) activities (P hypertension.

  4. Adenosine-Associated Delivery Systems

    Science.gov (United States)

    Kazemzadeh-Narbat, Mehdi; Annabi, Nasim; Tamayol, Ali; Oklu, Rahmi; Ghanem, Amyl; Khademhosseini, Ali

    2016-01-01

    Adenosine is a naturally occurring purine nucleoside in every cell. Many critical treatments such as modulating irregular heartbeat (arrhythmias), regulation of central nervous system (CNS) activity, and inhibiting seizural episodes can be carried out using adenosine. Despite the significant potential therapeutic impact of adenosine and its derivatives, the severe side effects caused by their systemic administration have significantly limited their clinical use. In addition, due to adenosine’s extremely short half-life in human blood (less than 10 s), there is an unmet need for sustained delivery systems to enhance efficacy and reduce side effects. In this paper, various adenosine delivery techniques, including encapsulation into biodegradable polymers, cell-based delivery, implantable biomaterials, and mechanical-based delivery systems, are critically reviewed and the existing challenges are highlighted. PMID:26453156

  5. Adenosine formation in contracting primary rat skeletal muscle cells and endothelial cells in culture

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Frandsen, Ulrik

    1997-01-01

    1. The present study examined the capacity for adenosine formation, uptake and metabolism in contracting primary rat muscle cells and in microvascular endothelial cells in culture. 2. Strong and moderate electrical simulation of skeletal muscle cells led to a significantly greater increase...... in the extracellular adenosine concentration (421 +/- 91 and 235 +/- 30 nmol (g protein)-1, respectively; P muscle cells (161 +/- 20 nmol (g protein)-1). The ATP concentration was lower (18%; P muscle cells....... 3. Addition of microvascular endothelial cells to the cultured skeletal muscle cells enhanced the contraction-induced accumulation of extracellular adenosine (P cells in culture alone did not cause extracellular accumulation of adenosine. 4. Skeletal muscle cells were...

  6. Acute hyperammonemia and systemic inflammation is associated with increased extracellular brain adenosine in rats

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Dale, Nicholas; Larsen, Fin Stolze

    2015-01-01

    Acute liver failure (ALF) can lead to brain edema, cerebral hyperperfusion and intracranial hypertension. These complications are thought to be mediated by hyperammonemia and inflammation leading to altered brain metabolism. As increased levels of adenosine degradation products have been found...... in brain tissue of patients with ALF we investigated whether hyperammonemia could induce adenosine release in brain tissue. Since adenosine is a potent vasodilator and modulator of cerebral metabolism we furthermore studied the effect of adenosine receptor ligands on intracranial pressure (ICP......) and cerebral blood flow (CBF). We measured the adenosine concentration with biosensors in rat brain slices exposed to ammonia and in a rat model with hyperammonemia and systemic inflammation. Exposure to ammonia in concentrations from 0.15-10 mM led to increases in the cortical adenosine concentration up to 18...

  7. Exploring Tinnitus-Induced Disablement by Persistent Frustration in Aging Individuals: A Grounded Theory Study.

    Science.gov (United States)

    Dauman, Nicolas; Erlandsson, Soly I; Albarracin, Dolorès; Dauman, René

    2017-01-01

    Background: Qualitative research can help to improve the management of patients, meet their expectations and assist physicians in alleviating their suffering. The perception of moment-to-moment variability in tinnitus annoyance is an emerging field of exploration. This study sought to enlighten variability in tinnitus-induced disablement using a qualitative approach. Methods: Twelve participants (six females, six males, aged 51-79) were recruited via the French Tinnitus Association Journal for participation in recorded semi-structured interviews. Each participant had three interviews lasting 1 h, the sessions being separated one from the other by 2 weeks. Following recommendations of Charmaz (2014), the second and third interviews were aimed at gathering rich data, by enhancing the participants' reflexivity in the circumstances of distress caused by tinnitus. After transcription, the data ( n = 36 interviews) were analyzed using the approach to Grounded Theory proposed by Strauss and Corbin (1998). Results: Tinnitus as persistent frustration emerged as being the core category uniting all the other categories of the study. Hence, the core category accounted for the broader scope in participants' experience of chronic tinnitus. It is suggested that tinnitus-induced disablement varied according to the degree of frustration felt by the participants in not being able to achieve their goals. The implications of this were analyzed using the following categories: "Losing body ownership," "Lacking perspectives," and "Persevering through difficulties." Based on these findings, we draw a substantive theory of tinnitus tolerance that promotes an active, disciplined and individualized approach to tinnitus-induced disablement. The model distinguishes pathways from sustained suffering to reduced annoyance (i.e., emerging tolerance). It accounts for difficulties that the participants experienced with a perceived unchanged annoyance over time. Furthermore, this model identifies a

  8. Exploring Tinnitus-Induced Disablement by Persistent Frustration in Aging Individuals: A Grounded Theory Study

    Science.gov (United States)

    Dauman, Nicolas; Erlandsson, Soly I.; Albarracin, Dolorès; Dauman, René

    2017-01-01

    Background: Qualitative research can help to improve the management of patients, meet their expectations and assist physicians in alleviating their suffering. The perception of moment-to-moment variability in tinnitus annoyance is an emerging field of exploration. This study sought to enlighten variability in tinnitus-induced disablement using a qualitative approach. Methods: Twelve participants (six females, six males, aged 51–79) were recruited via the French Tinnitus Association Journal for participation in recorded semi-structured interviews. Each participant had three interviews lasting 1 h, the sessions being separated one from the other by 2 weeks. Following recommendations of Charmaz (2014), the second and third interviews were aimed at gathering rich data, by enhancing the participants' reflexivity in the circumstances of distress caused by tinnitus. After transcription, the data (n = 36 interviews) were analyzed using the approach to Grounded Theory proposed by Strauss and Corbin (1998). Results: Tinnitus as persistent frustration emerged as being the core category uniting all the other categories of the study. Hence, the core category accounted for the broader scope in participants' experience of chronic tinnitus. It is suggested that tinnitus-induced disablement varied according to the degree of frustration felt by the participants in not being able to achieve their goals. The implications of this were analyzed using the following categories: “Losing body ownership,” “Lacking perspectives,” and “Persevering through difficulties.” Based on these findings, we draw a substantive theory of tinnitus tolerance that promotes an active, disciplined and individualized approach to tinnitus-induced disablement. The model distinguishes pathways from sustained suffering to reduced annoyance (i.e., emerging tolerance). It accounts for difficulties that the participants experienced with a perceived unchanged annoyance over time. Furthermore, this model

  9. Adenosine A(2A) receptor dynamics studied with the novel fluorescent agonist Alexa488-APEC.

    Science.gov (United States)

    Brand, Frank; Klutz, Athena M; Jacobson, Kenneth A; Fredholm, Bertil B; Schulte, Gunnar

    2008-08-20

    G protein-coupled receptors, such as the adenosine A(2A) receptor, are dynamic proteins, which undergo agonist-dependent redistribution from the cell surface to intracellular membranous compartments, such as endosomes. In order to study the kinetics of adenosine A(2A) receptor redistribution in living cells, we synthesized a novel fluorescent agonist, Alexa488-APEC. Alexa488-APEC binds to adenosine A(2A) (K(i)=149+/-27 nM) as well as A(3) receptors (K(i)=240+/-160 nM) but not to adenosine A(1) receptors. Further, we characterized the dose-dependent increase in Alexa488-APEC-induced cAMP production as well as cAMP response element binding (CREB) protein phosphorylation, verifying the ligand's functionality at adenosine A(2A) but not A(2B) receptors. In live-cell imaging studies, Alexa488-APEC-induced adenosine A(2A) receptor internalization, which was blocked by the competitive reversible antagonist ZM 241385 and hyperosmolaric sucrose. Further, internalized adenosine A(2A) receptors co-localized with clathrin and Rab5, indicating that agonist stimulation promotes adenosine A(2A) receptor uptake through a clathrin-dependent mechanism to Rab5-positive endosomes. The basic characterization of Alexa488-APEC described here showed that it provides a useful tool for tracing adenosine A(2A) receptors in vitro.

  10. The role of carotid chemoreceptors in the sympathetic activation by adenosine in humans.

    Science.gov (United States)

    Timmers, Henri J L M; Rongen, Gerard A; Karemaker, John M; Wieling, Wouter; Marres, Henri A M; Lenders, Jacques W M

    2004-01-01

    The direct vasodilatory and negative chronotropic effects of adenosine in humans are counterbalanced by a reflex increase in sympathetic nerve traffic. A suggested mechanism for this reflex includes peripheral chemoreceptor activation. We, therefore, assessed the contribution of carotid chemoreceptors to sympatho-excitation by adenosine. Muscle sympathetic nerve activity was recorded during adenosine infusion (140 microg.kg(-1).min(-1) for 5 min) in five patients lacking carotid chemoreceptors after bilateral carotid body tumour resection (one male and four female, mean age 51 +/- 11 years) and in six healthy controls (two male and four female, mean age 50 +/- 7 years). Sympathetic responses to sodium nitroprusside injections were assessed to measure baroreceptor-mediated sympathetic activation. In response to adenosine, controls showed no change in blood pressure, an increase in heart rate (+48.2 +/- 13.2%; Pactivity (+195 +/- 103%; Pactivity. Adenosine-induced hypotension in individual patients elicited less sympathetic activation than equihypotensive sodium nitroprusside injections. In humans lacking carotid chemoreceptors, adenosine infusion elicits hypotension due to the absence of significant sympatho-excitation. Chemoreceptor activation is essential for counterbalancing the direct vasodilation by adenosine. In addition, blunting of the baroreflex sympathetic response to adenosine-induced hypotension may indicate a direct sympatho-inhibitory effect of adenosine.

  11. Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

    Science.gov (United States)

    Tanishima, Hiroyuki; Tominaga, Toshiji; Kimura, Masamichi; Maeda, Tsunehiro; Shirai, Yasutsugu; Horiuchi, Tetsuya

    2017-05-01

    Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8 mg/m2, and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

  12. Persistence of Space Radiation Induced Cytogenetic Damage in the Blood Lymphocytes of Astronauts

    Science.gov (United States)

    George, Kerry; Cucinotta, Francis A.

    2008-01-01

    Cytogenetic damage in astronaut's peripheral blood lymphocytes is a useful in vivo marker of space radiation induced damage. Moreover, if radiation induced chromosome translocations persist in peripheral blood lymphocytes for many years, as has been assumed, they could potentially be used to measure retrospective doses or prolonged low dose rate exposures. However, as more data becomes available, evidence suggests that the yield of translocations may decline with time after exposure, at least in the case of space radiation exposures. We present our latest follow-up measurements of chromosome aberrations in astronauts blood lymphocytes assessed by FISH painting and collected a various times beginning directly after return from space to several years after flight. For most individuals the analysis of individual time-courses for translocations revealed a temporal decline of yields with different half-lives. Since the level of stable aberrations depends on the interplay between natural loss of circulating T-lymphocytes and replenishment from the stem or progenitor cells, the differences in the rates of decay could be explained by inter-individual variation in lymphocyte turn over. Biodosimetry estimates derived from cytogenetic analysis of samples collected a few days after return to earth lie within the range expected from physical dosimetry. However, a temporal decline in yields may indicate complications with the use of stable aberrations for retrospective dose reconstruction, and the differences in the decay time may reflect individual variability in risk from space radiation exposure. In addition, limited data on multiple flights show a lack of correlation between time in space and translocation yields. Data from one crewmember who has participated in two separate long-duration space missions and has been followed up for over 10 years provides limited information on the effect of repeat flights and show a possible adaptive response to space radiation exposure.

  13. Environmentally persistent free radicals induce airway hyperresponsiveness in neonatal rat lungs

    Directory of Open Access Journals (Sweden)

    Lominiki Slawo

    2011-03-01

    Full Text Available Abstract Background Increased asthma risk/exacerbation in children and infants is associated with exposure to elevated levels of ultrafine particulate matter (PM. The presence of a newly realized class of pollutants, environmentally persistent free radicals (EPFRs, in PM from combustion sources suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma. Methods Neonatal rats (7-days of age were exposed to EPFR-containing combustion generated ultrafine particles (CGUFP, non-EPFR containing CGUFP, or air for 20 minutes per day for one week. Pulmonary function was assessed in exposed rats and age matched controls. Lavage fluid was isolated and assayed for cellularity and cytokines and in vivo indicators of oxidative stress. Pulmonary histopathology and characterization of differential protein expression in lung homogenates was also performed. Results Neonates exposed to EPFR-containing CGUFP developed significant pulmonary inflammation, and airway hyperreactivity. This correlated with increased levels of oxidative stress in the lungs. Using differential two-dimensional electrophoresis, we identified 16 differentially expressed proteins between control and CGUFP exposed groups. In the rats exposed to EPFR-containing CGUFP; peroxiredoxin-6, cofilin1, and annexin A8 were upregulated. Conclusions Exposure of neonates to EPFR-containing CGUFP induced pulmonary oxidative stress and lung dysfunction. This correlated with alterations in the expression of various proteins associated with the response to oxidative stress and the regulation of glucocorticoid receptor translocation in T lymphocytes.

  14. LSD-induced hallucinogen persisting perception disorder treatment with clonidine: an open pilot study.

    Science.gov (United States)

    Lerner, A G; Gelkopf, M; Oyffe, I; Finkel, B; Katz, S; Sigal, M; Weizman, A

    2000-01-01

    A pilot open study was conducted in order to evaluate the efficacy of clonidine in the treatment of LSD-induced hallucinogen persisting perception disorder (HPPD). Eight patients fulfilled entrance criteria. All complained of HPPD for at least 3 months and were drug free at least 3 months. They received fixed low doses of clonidine, 0.025 mg, three times a day for 2 months. They were evaluated by the Clinical Global Impression Scale (CGI) and a self-report scale on the severity of symptoms (graded 0-5). Patients scored an average of 5.25 (SD = 0.46) on the CGI and 4 on the self-report scale at baseline, indicating marked psychopathology. One patient dropped out at week 3 and a second patient dropped out at week 5. Of the six patients remaining at the end of 2 months, the average CGI score was 2.5 (SD = 0.55) and the self-report scale score was 2, indicating mild symptomatology. LSD-related flashbacks associated with excessive sympathetic nervous activity may be alleviated with clonidine in some patients.

  15. Persistence of threat-induced errors in police officers' shooting decisions.

    Science.gov (United States)

    Nieuwenhuys, Arne; Savelsbergh, Geert J P; Oudejans, Raôul R D

    2015-05-01

    This study tested whether threat-induced errors in police officers' shooting decisions may be prevented through practice. Using a video-based test, 57 Police officers executed shooting responses against a suspect who rapidly appeared with (shoot) or without (don't shoot) a firearm. Threat was manipulated by switching on (high-threat) or switching off (low-threat) a "shootback canon" that could fire small plastic bullets at the officers. After an initial pretest, officers were divided over four different practice groups and practiced their shooting decisions for three consecutive weeks. Effects of practice were evaluated on a posttest. On the pretest, all groups experienced more anxiety and executed more false-positive responses under high-threat. Despite practice, these effects persisted on the posttest and remained equally strong for all practice groups. It is concluded that the impact of threat on police officers' shooting decisions is robust and may be hard to prevent within the limits of available practice. Copyright © 2014 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  16. Endogenous descending facilitation and inhibition differ in control of formalin intramuscularly induced persistent muscle nociception.

    Science.gov (United States)

    Lei, Jing; You, Hao-Jun

    2013-10-01

    In conscious rats, intramuscular injection of 2.5% formalin into the gastrocnemius muscle, at volumes between 25 and 200 μl, evoked dose-dependent biphasic persistent flinching activities: phase 1 (0-10 min) and phase 2 (10-60 min). During this intramuscular formalin-induced ipsilateral muscle nociception, bilateral secondary mechanical hyperalgesia and heat hypoalgesia assessed by measuring thresholds of paw withdrawal reflex to noxious mechanical and heat stimuli were observed (Pnociception, and the occurrence of bilateral secondary mechanical hyperalgesia was significantly delayed (Pnociceptive behavior in the late part (30-60 min) of phase 2, and the bilateral secondary heat hypoalgesia was temporarily prevented (Pnociception, and that bilateral secondary mechanical hyperalgesia and heat hypoalgesia are differentially controlled by endogenous descending facilitation and inhibition respectively. It is further suggested that thalamic MD nucleus and VM nucleus constitute an endogenous discriminative, modulatory system that exerts, via pathways in the DF and DLF, descending facilitatory and inhibitory actions on responses to peripheral afferent activity evoked by noxious mechanical and heat stimulation. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Persistent Nociception Induces Anxiety-like Behavior in Rodents: Role of Endogenous Neuropeptide S

    Science.gov (United States)

    Zhang, Shuzhuo; Jin, Xu; You, Zerong; Wang, Shuxing; Lim, Grewo; Yang, Jinsheng; McCabe, Michael; Li, Na; Marota, John; Chen, Lucy; Mao, Jianren

    2014-01-01

    Anxiety disorder is a comorbid condition of chronic pain. Analgesics and anxiolytics, subject to addiction and abuse, are currently used to manage pain and anxiety symptoms. However, the cellular mechanism underlying chronic pain and anxiety interaction remains to be elucidated. We report that persistent nociception following peripheral nerve injury induced anxiety-like behavior in rodents. Brain expression and release of neuropeptide S (NPS), a proposed endogenous anxiolytic peptide, was diminished in rodents with co-existing nociceptive and anxiety-like behaviors. Intracerebroventricular administration of exogenous NPS concurrently improved both nociceptive and anxiety-like behaviors. At the cellular level, NPS enhanced intra-amygdaloidal inhibitory transmission by increasing presynaptic GABA release from interneurons. These findings indicate that the interaction between nociceptive and anxiety-like behaviors in rodents may be regulated by the altered NPS-mediated intra-amygdaloidal GABAergic inhibition. The data suggest that enhancing the brain NPS function may be a new strategy to manage comorbid pain and anxiety. PMID:24793908

  18. Enhanced cellular adenosine uptake limits adenosine receptor stimulation in patients with hyperhomocysteinemia.

    NARCIS (Netherlands)

    Riksen, N.P.; Rongen, G.A.; Boers, G.H.J.; Blom, H.J.; Broek, P.H.H. van den; Smits, P.

    2005-01-01

    OBJECTIVE: Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells

  19. Regulation of Cardiovascular Development by Adenosine and Adenosine-Mediated Embryo Protection

    OpenAIRE

    Rivkees, Scott A; Wendler, Christopher C.

    2012-01-01

    Few signaling molecules have the potential to influence the developing mammal as the nucleoside adenosine. Adenosine levels increase rapidly with tissue hypoxia and inflammation. Adenosine antagonists include the methlyxanthines caffeine and theophylline. The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (ARs). We examined how adenosine acts via A1ARs to influence embryo development.

  20. Modulating effects of hesperidin on key carbohydrate-metabolizing enzymes, lipid profile, and membrane-bound adenosine triphosphatases against 7,12-dimethylbenz(a)anthracene-induced breast carcinogenesis.

    Science.gov (United States)

    Nandakumar, N; Rengarajan, T; Balamurugan, A; Balasubramanian, M P

    2014-05-01

    The aim of this study was to document the effect of hesperidin on the key enzyme activities of carbohydrate metabolism, lipid profile, and membrane-bound adenosine triphosphatases (ATPases) during 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis. Hesperidin has been reported to have multiple biological properties. Breast cancer was induced by single dose of DMBA (20 mg/kg body weight (bw)). The results revealed that there was a significant increase in the activities of hexokinase, phosphoglucoisomerase, and aldolase and a concomitant decrease in the activities of glucose-6-phosphatase and fructose-1,6-diphosphatase in cancer-induced animals. The activities of ATPases were found to be decreased both in erythrocyte membrane and in the liver of mammary cancer-bearing animals. The lipid profiles such as total cholesterol, free cholesterol, phospholipids, triglycerides, and free fatty acids significantly increased and in contrast the ester cholesterol in plasma was found to be decreased, whereas it was found to be elevated in the liver of cancer-bearing groups. The altered levels of the above-mentioned biochemical parameters in cancer-bearing animals were significantly ameliorated by the administration of hesperidin at the dosage of 30 mg/kg bw for 45 days. The histopathological analysis of breast and liver tissues were well supported the modulatory property of hesperidin, and this might be associated with normalizing the gluconeogenesis process, stabilization of cell membranes, and modulation of lipid biosynthesis.

  1. Nasal obstructive disorders induce medical treatment failure in paediatric persistent allergic rhinitis (The NODPAR Study).

    Science.gov (United States)

    Mariño-Sánchez, Franklin S; Valls-Mateus, Meritxell; Ruiz-Echevarría, Karen; Alobid, Isam; Cardenas-Escalante, Paulina; Jiménez-Feijoo, Rosa; Lozano-Blasco, Jaime; Giner-Muñoz, María T; Rodríguez-Jorge, Jesús; Haag, Oliver; Plaza-Martin, Ana M; Mullol, Joaquim

    2017-03-01

    Allergic rhinitis (AR) is the most common chronic disease among children. To characterize the disease, a modified classification of severity (m-ARIA) has recently been validated in AR children. When medical treatment fails, surgery for nasal obstructive disorders (NOD) may be a therapeutic option. Our objective was to assess the prevalence of NOD and their influence in medical treatment response among children with persistent AR (PER). In a prospective, real-life study, 130 paediatric PER patients (13.1 ± 2.8 years, females 31.5%, severe rhinitis 49%) referred from Allergy to ENT department were assessed for their response (R, responders; NR, non-responders) to medical treatment (intranasal steroids and antihistamines or antileukotrienes) by direct questioning and nasal symptom visual analogue scale, the presence of NOD (septal deformity, turbinate enlargement and adenoidal hyperplasia), comorbidities, nasal symptoms, rhinitis severity (modified ARIA criterion) and asthma control (International Consensus On Pediatric Asthma criterion). After 2 months of treatment, the NR group presented a higher prevalence of obstructive septal deformity and severe inferior turbinate enlargement when compared with the R group. Higher septal deformity and turbinate enlargement scores were strongly associated with treatment refractoriness. The prevalence of severe PER was also higher for the NR group. Higher asthma control scores were associated with the probability of treatment-induced improvement. In paediatric PER patients, medical therapy refractoriness was associated with NOD, mainly septal deformity and turbinate enlargement. In those patients, ENT examination will facilitate an early NOD diagnosis in order to indicate potential corrective surgery. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

    Science.gov (United States)

    Franklin, Tina C; Wohleb, Eric S; Zhang, Yi; Fogaça, Manoela; Hare, Brendan; Duman, Ronald S

    2018-01-01

    Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  3. IL-4 amplifies the pro-inflammatory effect of adenosine in human mast cells by changing expression levels of adenosine receptors.

    Directory of Open Access Journals (Sweden)

    Xiaoyang Hua

    Full Text Available Adenosine inhalation produces immediate bronchoconstriction in asthmatics but not in normal subjects. The bronchospastic effect of adenosine is largely mediated through adenosine-induced mast cell activation, the mechanism of which is poorly understood due to limitations in culturing human primary mast cells. Here, we show that human umbilical cord blood -derived mast cells incubated with the Th2 cytokine IL-4 develop increased sensitivity to adenosine. Potentiation of anti-IgE- induced and calcium ionophore/PMA-induced degranulation was augmented in mast cells cultured with IL-4, and this effect was reduced or abolished by pre-treatment with A(2BsiRNA and selective A(2B receptor antagonists, respectively. IL-4 incubation resulted in the increased expression of A(2B and reduced expression of A(2A adenosine receptors on human mast cells. These results suggest that Th2 cytokines in the asthmatic lung may alter adenosine receptor expression on airway mast cells to promote increased responsiveness to adenosine.

  4. IL-4 Amplifies the Pro-Inflammatory Effect of Adenosine in Human Mast Cells by Changing Expression Levels of Adenosine Receptors

    Science.gov (United States)

    Hua, Xiaoyang; Chason, Kelly D.; Patel, Janki Y.; Naselsky, Warren C.; Tilley, Stephen L.

    2011-01-01

    Adenosine inhalation produces immediate bronchoconstriction in asthmatics but not in normal subjects. The bronchospastic effect of adenosine is largely mediated through adenosine-induced mast cell activation, the mechanism of which is poorly understood due to limitations in culturing human primary mast cells. Here, we show that human umbilical cord blood -derived mast cells incubated with the Th2 cytokine IL-4 develop increased sensitivity to adenosine. Potentiation of anti-IgE- induced and calcium ionophore/PMA-induced degranulation was augmented in mast cells cultured with IL-4, and this effect was reduced or abolished by pre-treatment with A2BsiRNA and selective A2B receptor antagonists, respectively. IL-4 incubation resulted in the increased expression of A2B and reduced expression of A2A adenosine receptors on human mast cells. These results suggest that Th2 cytokines in the asthmatic lung may alter adenosine receptor expression on airway mast cells to promote increased responsiveness to adenosine. PMID:21966389

  5. Observation of current-induced, long-lived persistent spin polarization in a topological insulator: A rechargeable spin battery.

    Science.gov (United States)

    Tian, Jifa; Hong, Seokmin; Miotkowski, Ireneusz; Datta, Supriyo; Chen, Yong P

    2017-04-01

    Topological insulators (TIs), with their helically spin-momentum-locked topological surface states (TSSs), are considered promising for spintronics applications. Several recent experiments in TIs have demonstrated a current-induced electronic spin polarization that may be used for all-electrical spin generation and injection. We report spin potentiometric measurements in TIs that have revealed a long-lived persistent electron spin polarization even at zero current. Unaffected by a small bias current and persisting for several days at low temperature, the spin polarization can be induced and reversed by a large "writing" current applied for an extended time. Although the exact mechanism responsible for the observed long-lived persistent spin polarization remains to be better understood, we speculate on possible roles played by nuclear spins hyperfine-coupled to TSS electrons and dynamically polarized by the spin-helical writing current. Such an electrically controlled persistent spin polarization with unprecedented long lifetime could enable a rechargeable spin battery and rewritable spin memory for potential applications in spintronics and quantum information.

  6. Role of A3 adenosine receptor in diabetic neuropathy.

    Science.gov (United States)

    Yan, Heng; Zhang, Enshui; Feng, Chang; Zhao, Xin

    2016-10-01

    Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo.

    Directory of Open Access Journals (Sweden)

    T N A van den Berg

    Full Text Available In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo.In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation.Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations.In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor.ClinicalTrials.gov NCT01996735.

  8. Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo

    Science.gov (United States)

    Rongen, G. A.; van den Broek, P. H. H.; Bilos, A.; Donders, A. R. T.; Gomes, M. E.; Riksen, N. P.

    2015-01-01

    Background and Purpose In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. Experimental Approach In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation. Key Results Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations. Conclusion and Implications In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor. Trial Registration ClinicalTrials.gov NCT01996735 PMID:26509673

  9. Extracellular guanosine regulates extracellular adenosine levels

    Science.gov (United States)

    Cheng, Dongmei; Jackson, Travis C.; Verrier, Jonathan D.; Gillespie, Delbert G.

    2013-01-01

    The aim of this investigation was to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels. Rat preglomerular vascular smooth muscle cells were incubated with adenosine, guanosine, or both. Guanosine (30 μmol/l) per se had little effect on extracellular adenosine levels. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) were 0.125 ± 0.020 μmol/l, indicating rapid disposition of extracellular adenosine. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) plus guanosine (30 μmol/l) were 1.173 ± 0.061 μmol/l, indicating slow disposition of extracellular adenosine. Cell injury increased extracellular levels of endogenous adenosine and guanosine, and the effects of cell injury on endogenous extracellular adenosine were modulated by altering the levels of endogenous extracellular guanosine with exogenous purine nucleoside phosphorylase (converts guanosine to guanine) or 8-aminoguanosine (inhibits purine nucleoside phosphorylase). Extracellular guanosine also slowed the disposition of extracellular adenosine in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts, and kidney epithelial cells and in human aortic and coronary artery vascular smooth muscle cells and coronary artery endothelial cells. The effects of guanosine on adenosine levels were not mimicked or attenuated by 5-iodotubericidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3-nonyl)-adenine (adenosine deaminase inhibitor), 5-aminoimidazole-4-carboxamide (guanine deaminase inhibitor), aristeromycin (S-adenosylhomocysteine hydrolase inhibitor), low sodium (inhibits concentrative nucleoside transporters), S-(4-nitrobenzyl)−6-thioinosine [inhibits equilibrative nucleoside transporter (ENT) type 1], zidovudine (inhibits ENT type 2), or acadesine (known modulator of adenosine levels). Guanosine also increases extracellular inosine, uridine, thymidine, and cytidine, yet decreases

  10. Adenosine Deaminase Activity in Subjects with Normal Pregnancy ...

    African Journals Online (AJOL)

    METHODS: One hundred and twenty-five pregnant women comprising 35 normal non-pregnant women, 35 normal pregnant women, 35 pregnant women with pregnancy induced hypertension and 20 patients with pre-eclampsia were recruited for the study. Serum adenosine deaminase enzyme (ADA) activity was ...

  11. Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib.

    Science.gov (United States)

    Wei, Jia-You; Liu, Cui-Cui; Ouyang, Han-Dong; Ma, Chao; Xie, Man-Xiu; Liu, Meng; Lei, Wan-Long; Ding, Huan-Huan; Wu, Shao-Ling; Xin, Wen-Jun

    2017-10-01

    Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p-STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p-STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. The ischemic preconditioning effect of adenosine in patients with ischemic heart disease

    Directory of Open Access Journals (Sweden)

    Berglund Margareta

    2009-11-01

    Full Text Available Abstract Introduction In vivo and in vitro evidence suggests that adenosine and its agonists play key roles in the process of ischemic preconditioning. The effects of low-dose adenosine infusion on ischemic preconditioning have not been thoroughly studied in humans. Aims We hypothesised that a low-dose adenosine infusion could reduce the ischemic burden evoked by physical exercise and improve the regional left ventricular (LV systolic function. Materials and methods We studied nine severely symptomatic male patients with severe coronary artery disease. Myocardial ischemia was induced by exercise on two separate occasions and quantified by Tissue Doppler Echocardiography. Prior to the exercise test, intravenous low-dose adenosine or placebo was infused over ten minutes according to a randomized, double blind, cross-over protocol. The LV walls were defined as ischemic if a reduction, no increment, or an increment of Results PSV increased from baseline to maximal exercise in non-ischemic walls both during placebo (P = 0.0001 and low-dose adenosine infusion (P = 0.0009. However, in the ischemic walls, PSV increased only during low-dose adenosine infusion (P = 0.001, while no changes in PSV occurred during placebo infusion (P = NS. Conclusion Low-dose adenosine infusion reduced the ischemic burden and improved LV regional systolic function in the ischemic walls of patients with exercise-induced myocardial ischemia, confirming that adenosine is a potential preconditioning agent in humans.

  13. Persistent mechanoluminescence induced by elastic deformation of ZrO{sub 2}:Ti phosphors

    Energy Technology Data Exchange (ETDEWEB)

    Chandra, B.P., E-mail: bpchandra4@yahoo.co.i [Disha Academy of Research and Education, Disha Institute of Management and Technology, Satya Vihar, Vidhansabha-Chandrakhuri Marg, Raipur 492101(C.G.) (India)

    2010-11-15

    ZrO{sub 2}:Ti phosphors show such a strong mechanoluminescence (ML) that it can be seen in day light with naked eye. When a pellet of ZrO{sub 2}:Ti phosphor mixed in epoxy resin is deformed in the elastic region at a fixed strain rate using a testing machine, ML intensity increases linearly with time, and when the deformation is stopped, ML intensity decreases exponentially with time. For a given strain rate, ML intensity increases linearly with pressure, and for a given pressure, ML intensity increases linearly with the strain rate. The total ML intensity, in the deformation region, increases quadratically with pressure; however, the total ML intensity in the post-deformation region increases linearly with pressure. ML intensity decreases with successive number of pressings, whereby the reduced ML intensity can be recovered by UV-irradiation of the sample. ML intensity increases linearly with density of filled electron traps and it is optimum for a particular concentration of Ti in ZrO{sub 2}. ML intensity should change with increasing temperature of the phosphors. Although ZrO{sub 2} is non-piezoelectric as a whole, it seems that the local structures near the Ti ions in ZrO{sub 2} crystals are in the piezoelectric phase. The elastico ML in ZrO{sub 2} phosphors can be understood on the basis of the localized piezoelectrification-induced detrapping model. According to this model, the localized piezoelectric field near Ti ions causes detrapping of electrons and subsequently the detrapped electrons moving in the conduction band are captured by the energy state of excited Ti{sup 4+} ions, whereby excited Ti{sup 4+} ions are produced and consequently the decay of excited Ti{sup 4+} ions gives rise to the light emission. The expressions derived on the basis of this model are able to explain satisfactorily the characteristics of ML. The relaxation time of localized piezoelectric charges and the threshold pressure for the ML emission can be determined from ML measurements

  14. Insulin/adenosine axis linked signalling

    NARCIS (Netherlands)

    Silva, Luis; Subiabre, Mario; Araos, Joaquín; Sáez, Tamara; Salsoso, Rocío; Pardo, Fabián; Leiva, Andrea; San Martín, Rody; Toledo, Fernando; Sobrevia, Luis

    Regulation of blood flow depends on systemic and local release of vasoactive molecules such as insulin and adenosine. These molecules cause vasodilation by activation of plasma membrane receptors at the vascular endothelium. Adenosine activates at least four subtypes of adenosine receptors (A(1)AR,

  15. Mechanism of A2 adenosine receptor activation. I. Blockade of A2 adenosine receptors by photoaffinity labeling

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, M.J.; Klotz, K.N.; Schwabe, U.

    1991-04-01

    It has previously been shown that covalent incorporation of the photoreactive adenosine derivative (R)-2-azido-N6-p-hydroxy-phenylisopropyladenosine ((R)-AHPIA) into the A1 adenosine receptor of intact fat cells leads to a persistent activation of this receptor, resulting in a reduction of cellular cAMP levels. In contrast, covalent incorporation of (R)-AHPIA into human platelet membranes, which contain only stimulatory A2 adenosine receptors, reduces adenylate cyclase stimulation via these receptors. This effect of (R)-AHPIA is specific for the A2 receptor and can be prevented by the adenosine receptor antagonist theophylline. Binding studies indicate that up to 90% of A2 receptors can be blocked by photoincorporation of (R)-AHPIA. However, the remaining 10-20% of A2 receptors are sufficient to mediate an adenylate cyclase stimulation of up to 50% of the control value. Similarly, the activation via these 10-20% of receptors occurs with a half-life that is only 2 times longer than that in control membranes. This indicates the presence of a receptor reserve, with respect to both the extent and the rate of adenylate cyclase stimulation. These observations require a modification of the models of receptor-adenylate cyclase coupling.

  16. Adenosine promotes alternative macrophage activation via A2A and A2B receptors

    Science.gov (United States)

    Csóka, Balázs; Selmeczy, Zsolt; Koscsó, Balázs; Németh, Zoltán H.; Pacher, Pál; Murray, Peter J.; Kepka-Lenhart, Diane; Morris, Sidney M.; Gause, William C.; Leibovich, S. Joseph; Haskó, György

    2012-01-01

    Adenosine has been implicated in suppressing the proinflammatory responses of classically activated macrophages induced by Th1 cytokines. Alternative macrophage activation is induced by the Th2 cytokines interleukin (IL)-4 and IL-13; however, the role of adenosine in governing alternative macrophage activation is unknown. We show here that adenosine treatment of IL-4- or IL-13-activated macrophages augments the expression of alternative macrophage markers arginase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and macrophage galactose-type C-type lectin-1. The stimulatory effect of adenosine required primarily A2B receptors because the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) increased both arginase activity (EC50=261.8 nM) and TIMP-1 production (EC50=80.67 nM), and both pharmacologic and genetic blockade of A2B receptors prevented the effect of NECA. A2A receptors also contributed to the adenosine augmentation of IL-4-induced TIMP-1 release, as both adenosine and NECA were less efficacious in augmenting TIMP-1 release by A2A receptor-deficient than control macrophages. Of the transcription factors known to drive alternative macrophage activation, CCAAT-enhancer-binding protein β was required, while cAMP response element-binding protein and signal transducer and activator of transcription 6 were dispensable in mediating the effect of adenosine. We propose that adenosine receptor activation suppresses inflammation and promotes tissue restitution, in part, by promoting alternative macrophage activation.—Csóka, B., Selmeczy, Z., Koscsó, B., Németh, Z. H., Pacher, P., Murray, P. J., Kepka-Lenhart, D., Morris S. M., Jr., Gause, W. C., Leibovich, S. J., Haskó, G. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. PMID:21926236

  17. Persistent hiccups in cancer patient: A presentation of syndrome of inappropriate antidiuretic hormone induced hyponatremia

    Directory of Open Access Journals (Sweden)

    Alka Goyal

    2013-01-01

    Full Text Available Hyponatremia is quite common in cancer patients, but the presentation as persistent hiccups is not common. Literature over hiccups development due to hyponatremia is quite scant. Hiccups are of various types, persistent hiccups are those that last more than 48 h and remains less than 1 month. Hiccups lasting more than 24 h require investigation for an underlying organic etiology, with hyponatremia included in the differential diagnosis. This paper discusses a carcinoma lip patient presented with the persistent hiccups and unconsciousness post-operatively. The patient was initially responded with trials of both metoclopramide and Ryle′s tube insertion, but eventually, his hiccups resolved only after treatment of hyponatremia. Patient′s clinical course and investigations suggest an etiology of syndrome of inappropriate antidiuretic hormone (SIADH secretion behind the hyponatremia. Study suggested that SIADH linked hyponatremia should be considered in the differential diagnosis of cancer patients with refractory hiccups.

  18. Ultrasonography and hormone profiles of adrenocorticotrophic hormone (ACTH)-induced persistent ovarian follicles (cysts) in cattle.

    Science.gov (United States)

    Dobson, H; Ribadu, A Y; Noble, K M; Tebble, J E; Ward, W R

    2000-11-01

    The objective of this study was to develop a model for the study of abnormal ovarian follicles in cattle by treating heifers with adrenocorticotrophic hormone (ACTH) (100 iu at 12 h intervals for 7 days, beginning on day 15 of the oestrous cycle). Cortisol concentrations increased (P follicular structures were present for 20 days, but ceased to secrete oestradiol after approximately 12 days. In the heifers with persistent follicular structures, new follicles emerged when the persistent follicle became non-oestrogenic. During the last 2 days of normal follicular growth, the concentration of oestradiol was greater than it was during prolonged or persistent follicle development (P follicular activity. The aberrations were probably caused by the interruption of pulsatile secretion of LH (but not FSH) leading to decreased but prolonged oestradiol secretion.

  19. Persistent and acute chlamydial infections induce different structural changes in the Golgi apparatus.

    Science.gov (United States)

    Zhu, Huiling; Li, Hongmei; Wang, Pu; Chen, Mukai; Huang, Zengwei; Li, Kunpeng; Li, Yinyin; He, Jian; Han, Jiande; Zhang, Qinfen

    2014-07-01

    Chlamydia trachomatis causes a wide range of diseases that have a significant impact on public health. Acute chlamydial infections can cause fragmentation of the Golgi compartment ensuring the lipid transportation from the host cell. However, the changes that occur in the host cell Golgi apparatus after persistent infections are unclear. Here, we examined Golgi-associated gene (golga5) transcription and expression along with the structure of the Golgi apparatus in cells persistently infected with Chlamydia trachomatis. The results showed that persistent infections caused little fragmentation of the Golgi. The results also revealed that Golgi fragmentation might be associated with the suppression of transcription of the gene golga5. Copyright © 2014 Elsevier GmbH. All rights reserved.

  20. The role of muscarinic receptors in the beneficial effects of adenosine against myocardial reperfusion injury in rats.

    Directory of Open Access Journals (Sweden)

    Lei Sun

    Full Text Available Adenosine, a catabolite of ATP, displays a wide variety of effects in the heart including regulation of cardiac response to myocardial ischemia and reperfusion injury. Nonetheless, the precise mechanism of adenosine-induced cardioprotection is still elusive. Isolated Sprague-Dawley rat hearts underwent 30 min global ischemia and 120 min reperfusion using a Langendorff apparatus. Both adenosine and acetylcholine treatment recovered the post-reperfusion cardiac function associated with adenosine and muscarinic receptors activation. Simultaneous administration of adenosine and acetylcholine failed to exert any additive protective effect, suggesting a shared mechanism between the two. Our data further revealed a cross-talk between the adenosine and acetylcholine receptor signaling in reperfused rat hearts. Interestingly, the selective M(2 muscarinic acetylcholine receptor antagonist methoctramine significantly attenuated the cardioprotective effect of adenosine. In addition, treatment with adenosine upregulated the expression and the maximal binding capacity of muscarinic acetylcholine receptor, which were inhibited by the selective A(1 adenosine receptor antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX and the nitric oxide synthase inhibitor N(ω-nitro-L-arginine methyl ester (L-NAME. These data suggested a possible functional coupling between the adenosine and muscarinic receptors behind the observed cardioprotection. Furthermore, nitric oxide was found involved in triggering the response to each of the two receptor agonist. In summary, there may be a cross-talk between the adenosine and muscarinic receptors in ischemic/reperfused myocardium with nitric oxide synthase might serve as the distal converging point. In addition, adenosine contributes to the invigorating effect of adenosine on muscarinic receptor thereby prompting to regulation of cardiac function. These findings argue for a potentially novel mechanism behind the adenosine

  1. Hemodynamic significance of coronary stenosis by vessel attenuation measurement on CT compared with adenosine perfusion MRI

    NARCIS (Netherlands)

    den Dekker, Martijn A. M.; Pelgrim, Gert Jan; Pundziute, Gabija; van den Heuvel, Edwin R.; Oudkerk, Matthijs; Vliegenthart, Rozemarijn

    Purpose: We assessed the association between corrected contrast opacification (CCO) based on coronary computed tomography angiography (cCTA) and inducible ischemia by adenosine perfusion magnetic resonance imaging (APMR). Methods: Sixty cardiac asymptomatic patients with extra-cardiac arterial

  2. Colossal X-Ray-Induced Persistent Photoconductivity in Current-Perpendicular-to-Plane Ferroelectric/Semiconductor Junctions

    KAUST Repository

    Hu, Weijin

    2017-12-07

    Persistent photoconductivity (PPC) is an intriguing physical phenomenon, where electric conduction is retained after the termination of electromagnetic radiation, which makes it appealing for applications in a wide range of optoelectronic devices. So far, PPC has been observed in bulk materials and thin-film structures, where the current flows in the plane, limiting the magnitude of the effect. Here using epitaxial Nb:SrTiO3/Sm0.1Bi0.9FeO3/Pt junctions with a current-perpendicular-to-plane geometry, a colossal X-ray-induced PPC (XPPC) is achieved with a magnitude of six orders. This PPC persists for days with negligible decay. Furthermore, the pristine insulating state could be fully recovered by thermal annealing for a few minutes. Based on the electric transport and microstructure analysis, this colossal XPPC effect is attributed to the X-ray-induced formation and ionization of oxygen vacancies, which drives nonvolatile modification of atomic configurations and results in the reduction of interfacial Schottky barriers. This mechanism differs from the conventional mechanism of photon-enhanced carrier density/mobility in the current-in-plane structures. With their persistent nature, such ferroelectric/semiconductor heterojunctions open a new route toward X-ray sensing and imaging applications.

  3. p21 and Notch signalings in the persistently altered vagina induced by neonatal diethylstilbestrol exposure in mice.

    Science.gov (United States)

    Nakamura, Takeshi; Miyagawa, Shinichi; Katsu, Yoshinao; Mizutani, Takeshi; Sato, Tomomi; Takeuchi, Takashi; Iguchi, Taisen; Ohta, Yasuhiko

    2012-12-01

    Female reproductive organs show organ-specific morphological changes during estrous cycles. Perinatal exposure to natural and synthetic estrogens including diethylstilbestrol (DES) or estrogenic chemicals induces estrogen-independent persistent proliferation of vaginal epithelium in mice. To understand the underlying mechanism of the estrogen-independent persistent vaginal changes induced by perinatal DES exposure, we examined global gene expressions in the vaginae of ovariectomized adult mice exposed neonatally to DES using a microarray. The cell cycle-related gene, p21, a cyclin-dependent kinase inhibitor, showed upregulation in the vagina, and p21 protein was localized in the basal layer of the vaginal epithelium in mice exposed neonatally to DES and an estrogen receptor α agonist, propyl pyrazole triol (PPT). The expressions of Notch receptors and Notch ligands were unchanged; however, the mRNAs of hairy-related basic helix-loop-helix (bHLH) transcription factor genes, Hes1, Hey1 and Heyl were persistently downregulated in the vagina, indicating estrogen-independent epithelial cell proliferation in mice exposed neonatally to DES and PPT.

  4. Persistent attenuation and enhancement of the earthworm main muscle contraction generator response induced by repeated stimulation of a peripheral neuron

    Directory of Open Access Journals (Sweden)

    Y.C. Chang

    1998-10-01

    Full Text Available Responses evoked in the earthworm, Amynthas hawayanus, main muscle contraction generator M-2 (postsynaptic mechanical-stimulus-sensitive neuron by threshold mechanical stimuli in 2-s intertrial intervals (ITI were used as the control or unconditioned responses (UR. Their attenuation induced by decreasing these intervals in non-associative conditioning and their enhancement induced by associating the unconditioned stimuli (US to a train of short (0.1 s hyperpolarizing electrical substitutive conditioning stimuli (SCS in the Peri-Kästchen (PK neuron were measured in four parameters, i.e., peak numbers (N and amplitude (averaged from 120 responses, sum of these amplitudes (SAMP and the highest peak amplitude (V over a period of 4 min. Persistent attenuation similar to habituation was induced by decreasing the control ITI to 0.5 s and 2.0 s in non-associative conditioning within less than 4 min. Dishabituation was induced by randomly pairing one of these habituated US to an electrical stimulus in the PK neuron. All four parameters of the UR were enhanced by forward (SCS-US, but not backward (US-SCS, association of the US with 25, 100 and 250-Hz trains of SCS with 40-ms interstimulus intervals (ISI for 4 min and persisted for another 4 min after turning off the SCS. The enhancement of these parameters was proportional to the SCS frequencies in the train. No UR was evoked by the SCS when the US was turned off after 4 min of classical conditioning.

  5. MyD88 and TRIF mediate the cyclic adenosine monophosphate (cAMP induced corticotropin releasing hormone (CRH expression in JEG3 choriocarcinoma cell line

    Directory of Open Access Journals (Sweden)

    Kocak Hande

    2009-07-01

    Full Text Available Abstract Background Classically protein kinase A (PKA and transcription factor activator protein 1 (AP-1 mediate the cyclic AMP (cAMP induced-corticotrophin releasing hormone (CRH expression in the placenta. However enteric Gram (- bacterial cell wall component lipopolysaccharide (LPS may also induce-CRH expression via Toll like receptor (TLR4 and its adaptor molecule Myd88. Here we investigated the role of MyD88, TRIF and IRAK2 on cAMP-induced CRH promoter activation in JEG3 cells in the absence of LPS/TLR4 stimulation. Methods JEG3 cells were transfected with CRH-luciferase and Beta-galactosidase expression vectors and either empty or dominant-negative (DN-MyD88, DN-TRIF or DN-IRAK2 vectors using Fugene6 (Roche. cAMP-induced CRH promoter activation was examined by using a luminometer and luciferase assay. Calorimetric Beta-galactosidase assays were performed to correct for transfection efficiency. Luciferase expression vectors of cAMP-downstream molecules, CRE and AP-1, were used to further examine the signaling cascades. Results cAMP stimulation induced AP-1 and CRE promoter expression and led to dose-dependent CRH promoter activation in JEG3 cells. Inhibition of MyD88 signaling blocked cAMP-induced CRE and CRH promoter activation. Inhibition of TRIF signaling blocked cAMP-induced CRH but not CRE expression, while inhibition of IRAK2 did not have an effect on cAMP-induced CRH expression. Conclusion MyD88 and TRIF exert direct regulatory effect on cAMP-induced CRH promoter activation in JEG3 cells in the absence of infection. MyD88 most likely interacts with molecules upstream of IRAK2 to regulate cAMP-induced CRH expression.

  6. The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects

    DEFF Research Database (Denmark)

    Birk, S; Petersen, K.A.; Kruuse, Christina Rostrup

    2005-01-01

    Adenosine is an endogenous neurotransmitter that is released from the brain during hypoxia and relaxes isolated human cerebral arteries. Many cerebral artery dilators cause migraine attacks. However, the effect of intravenous adenosine on headache and cerebral artery diameter has not previously...... been investigated in man and reports regarding the effect of intravenous adenosine on cerebral blood flow are conflicting. Twelve healthy participants received adenosine 80, 120 microg kg(-1) min(-1) and placebo intravenously for 20 min, in a double-blind, three-way, crossover, randomized design......(-1) min(-1) and six during 120 microg kg(-1) min(-1) compared with none on placebo (P = 0.006). The headache was very mild and predominantly described as a pressing sensation. When correcting data for adenosine-induced hyperventilation, no significant changes in rCBF (P = 0.22) or V(MCA) (P = 0...

  7. The respiratory syncytial virus G protein conserved domain induces a persistent and protective antibody response in rodents.

    Directory of Open Access Journals (Sweden)

    Thien N Nguyen

    Full Text Available Respiratory syncytial virus (RSV is an important cause of severe upper and lower respiratory disease in infants and in the elderly. There are 2 main RSV subtypes A and B. A recombinant vaccine was designed based on the central domain of the RSV-A attachment G protein which we had previously named G2Na (aa130-230. Here we evaluated immunogenicity, persistence of antibody (Ab response and protective efficacy induced in rodents by: (i G2Na fused to DT (Diphtheria toxin fragments in cotton rats. DT fusion did not potentiate neutralizing Ab responses against RSV-A or cross-reactivity to RSV-B. (ii G2Nb (aa130-230 of the RSV-B G protein either fused to, or admixed with G2Na. G2Nb did not induce RSV-B-reactive Ab responses. (iii G2Na at low doses. Two injections of 3 µg G2Na in Alum were sufficient to induce protective immune responses in mouse lungs, preventing RSV-A and greatly reducing RSV-B infections. In cotton rats, G2Na-induced RSV-reactive Ab and protective immunity against RSV-A challenge that persisted for at least 24 weeks. (iv injecting RSV primed mice with a single dose of G2Na/Alum or G2Na/PLGA [poly(D,L-lactide-co-glycolide]. Despite the presence of pre-existing RSV-specific Abs, these formulations effectively boosted anti-RSV Ab titres and increased Ab titres persisted for at least 21 weeks. Affinity maturation of these Abs increased from day 28 to day 148. These data indicate that G2Na has potential as a component of an RSV vaccine formulation.

  8. Origin of the visible light induced persistent luminescence of Cr3+-doped zinc gallate

    Science.gov (United States)

    Gourier, Didier; Bessière, Aurélie; Sharma, Suchinder. K.; Binet, Laurent; Viana, Bruno; Basavaraju, Neelima; Priolkar, Kaustubh R.

    2014-07-01

    ZnGa2O4:Cr3+ (ZGO:Cr) is a very bright persistent phosphor able to emit a near infrared light for hours following a UV (band to band excitation) or visible (Cr3 excitation) illumination. As such it serves as an outstanding biomarker for in vivo imaging. Persistent luminescence, due to trapping of electrons/holes at point defects, is studied here on a series of ZGO:Cr spinel compounds where the introduction of defects is controlled by varying the Zn/(Ga+Cr) nominal ratio during synthesis. Simulation of Electron Paramagnetic Resonance spectra revealed up to six types of Cr3+ ions with different neighboring defects and correlated to four emission lines in low temperature photoluminescence spectroscopy. Of particular importance, three EPR signals were attributed to Cr3+ with a pair of neighboring ZnGa' and GaZn0° antisite defects. They were identified to the emission line N2 that plays a key role in the persistent luminescence mechanism for both storage of visible excitation and persistent luminescence emission. A model is proposed whereby the local electric field at Cr3+ created by the two neighboring antisite defects triggers the electron-hole separation and trapping upon excitation of Cr3+. The process is equivalent to a photoinduced electron transfer from a donor (here ZnGa') to an acceptor (here GaZn0°) observed in some molecular systems.

  9. Persistent shoreline shape induced from offshore geologic framework: Effects of shoreface connected ridges

    Science.gov (United States)

    Safak, Ilgar; List, Jeffrey; Warner, John C.; Schwab, William C.

    2017-01-01

    Mechanisms relating offshore geologic framework to shoreline evolution are determined through geologic investigations, oceanographic deployments, and numerical modeling. Analysis of shoreline positions from the past 50 years along Fire Island, New York, a 50 km long barrier island, demonstrates a persistent undulating shape along the western half of the island. The shelf offshore of these persistent undulations is characterized with shoreface-connected sand ridges (SFCR) of a similar alongshore length scale, leading to a hypothesis that the ridges control the shoreline shape through the modification of flow. To evaluate this, a hydrodynamic model was configured to start with the US East Coast and scale down to resolve the Fire Island nearshore. The model was validated using observations along western Fire Island and buoy data, and used to compute waves, currents and sediment fluxes. To isolate the influence of the SFCR on the generation of the persistent shoreline shape, simulations were performed with a linearized nearshore bathymetry to remove alongshore transport gradients associated with shoreline shape. The model accurately predicts the scale and variation of the alongshore transport that would generate the persistent shoreline undulations. In one location, however, the ridge crest connects to the nearshore and leads to an offshore-directed transport that produces a difference in the shoreline shape. This qualitatively supports the hypothesized effect of cross-shore fluxes on coastal evolution. Alongshore flows in the nearshore during a representative storm are driven by wave breaking, vortex force, advection and pressure gradient, all of which are affected by the SFCR.

  10. Persistent Shoreline Shape Induced From Offshore Geologic Framework: Effects of Shoreface Connected Ridges

    Science.gov (United States)

    Safak, Ilgar; List, Jeffrey H.; Warner, John C.; Schwab, William C.

    2017-11-01

    Mechanisms relating offshore geologic framework to shoreline evolution are determined through geologic investigations, oceanographic deployments, and numerical modeling. Analysis of shoreline positions from the past 50 years along Fire Island, New York, a 50 km long barrier island, demonstrates a persistent undulating shape along the western half of the island. The shelf offshore of these persistent undulations is characterized with shoreface-connected sand ridges (SFCR) of a similar alongshore length scale, leading to a hypothesis that the ridges control the shoreline shape through the modification of flow. To evaluate this, a hydrodynamic model was configured to start with the US East Coast and scale down to resolve the Fire Island nearshore. The model was validated using observations along western Fire Island and buoy data, and used to compute waves, currents and sediment fluxes. To isolate the influence of the SFCR on the generation of the persistent shoreline shape, simulations were performed with a linearized nearshore bathymetry to remove alongshore transport gradients associated with shoreline shape. The model accurately predicts the scale and variation of the alongshore transport that would generate the persistent shoreline undulations. In one location, however, the ridge crest connects to the nearshore and leads to an offshore-directed transport that produces a difference in the shoreline shape. This qualitatively supports the hypothesized effect of cross-shore fluxes on coastal evolution. Alongshore flows in the nearshore during a representative storm are driven by wave breaking, vortex force, advection and pressure gradient, all of which are affected by the SFCR.

  11. Adenosine diphosphate as an intracellular regulator of insulin secretion.

    Science.gov (United States)

    Nichols, C G; Shyng, S L; Nestorowicz, A; Glaser, B; Clement, J P; Gonzalez, G; Aguilar-Bryan, L; Permutt, M A; Bryan, J

    1996-06-21

    Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels couple the cellular metabolic state to electrical activity and are a critical link between blood glucose concentration and pancreatic insulin secretion. A mutation in the second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy generated KATP channels that could be opened by diazoxide but not in response to metabolic inhibition. The hamster SUR, containing the analogous mutation, had normal ATP sensitivity, but unlike wild-type channels, inhibition by ATP was not antagonized by adenosine diphosphate (ADP). Additional mutations in NBF2 resulted in the same phenotype, whereas an equivalent mutation in NBF1 showed normal sensitivity to MgADP. Thus, by binding to SUR NBF2 and antagonizing ATP inhibition of KATP++ channels, intracellular MgADP may regulate insulin secretion.

  12. Persistence of T-cell immune response induced by two acellular pertussis vaccines in children five years after primary vaccination.

    Science.gov (United States)

    Palazzo, Raffaella; Carollo, Maria; Bianco, Manuela; Fedele, Giorgio; Schiavoni, Ilaria; Pandolfi, Elisabetta; Villani, Alberto; Tozzi, Alberto E; Mascart, Françoise; Ausiello, Clara M

    2016-01-01

    The resurgence of pertussis suggests the need for greater efforts to understand the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of T memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac® vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa® (Infanrix) (Glaxo-SmithKline Biologicals). We evaluated magnitude and duration of T-cell responses to pertussis toxin (PT) by measuring T-cell proliferation, cytokines (IL-2 and IFNγ) production and memory subsets in two groups of children 5 years after primary vaccination. Some of the enrolled children received only primary vaccination, while others had the pre-school boost dose. Positive T-cell responses to PT were detected in 36% of children. Percentage of responsive children, T-cell proliferation and CD4IL-2+ cells were significantly higher in the children primed with Hexavac than in those who received Infanrix vaccine. No major effects of the boost on PT-specific proliferation were observed. Overall, our data documented a persistence of T-cell memory against PT in a minor fraction of children 5 years after primary vaccination. The different responses induced by Hexavac and Infanrix vaccine could rely on differences in PT inactivation process or excipients/adjuvants formulations.

  13. Persistent sciatica induced by quadratus femoris muscle tear and treated by surgical decompression: a case report

    Directory of Open Access Journals (Sweden)

    Tzanakakis George

    2010-08-01

    Full Text Available Abstract Introduction Quadratus femoris tear is an uncommon injury, which is only rarely reported in the literature. In the majority of cases the correct diagnosis is delayed due to non-specific symptoms and signs. A magnetic resonance imaging scan is crucial in the differential diagnosis since injuries to contiguous soft tissues may present with similar symptoms. Presentation with sciatica is not reported in the few cases existing in the English literature and the reported treatment has always been conservative. Case presentation We report here on a case of quadratus femoris tear in a 22-year-old Greek woman who presented with persistent sciatica. She was unresponsive to conservative measures and so was treated with surgical decompression. Conclusion The correct diagnosis of quadratus muscle tear is a challenge for physicians. The treatment is usually conservative, but in cases of persistent sciatica surgical decompression is an alternative option.

  14. Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

    DEFF Research Database (Denmark)

    Rattenborg, Thomas; Gjermandsen, Irene; Bonefeld-Jørgensen, Eva Cecilie

    2002-01-01

    BACKGROUND: Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved in the init......BACKGROUND: Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved...... in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter...

  15. Release of adenosine from human neutrophils stimulated by platelet activating factor, leukotriene B4 and opsonized zymosan

    Directory of Open Access Journals (Sweden)

    S. Sipka

    1992-01-01

    Full Text Available Isolated human polymorphonuclear leukocytes (PMNL stimulated by platelet activating factor (PAF, leukotriene B4 (LTB4 or opsonized zymosan (OZ released adenosine measured by thermospray high performance liquid chromatography mass spectrometry in the cell-free supernatants. Stimulation by PAF or LTB4 resulted in a bellshaped concentration-effect curve; 5 × 10−7 M PAF, 10−8 M LTB4 and 500 μg ml−1 OZ induced peak adenosine release, thus cytotoxic concentrations did not elevate adenosine level in the supernatants. Therefore adenosine release was characteristic of viable cells. As calculated from concentration-effect curves, the rank order of potency for adenosine release was PAF > LTB > OZ. These resuits suggest that adenosine, when bound specifically to membrane receptor sites, may initiate signal transduction, and, in co-operation with other inflammatory mediators, may modulate phagocyte function, e.g. production of chemoluminescence (CL.

  16. Staphylococcus aureus-induced clotting of plasma is an immune evasion mechanism for persistence within the fibrin network.

    Science.gov (United States)

    Loof, Torsten G; Goldmann, Oliver; Naudin, Clément; Mörgelin, Matthias; Neumann, Yvonne; Pils, Marina C; Foster, Simon J; Medina, Eva; Herwald, Heiko

    2015-03-01

    Recent work has shown that coagulation and innate immunity are tightly interwoven host responses that help eradicate an invading pathogen. Some bacterial species, including Staphylococcus aureus, secrete pro-coagulant factors that, in turn, can modulate these immune reactions. Such mechanisms may not only protect the micro-organism from a lethal attack, but also promote bacterial proliferation and the establishment of infection. Our data showed that coagulase-positive S. aureus bacteria promoted clotting of plasma which was not seen when a coagulase-deficient mutant strain was used. Furthermore, in vitro studies showed that this ability constituted a mechanism that supported the aggregation, survival and persistence of the micro-organism within the fibrin network. These findings were also confirmed when agglutination and persistence of coagulase-positive S. aureus bacteria at the local focus of infection were studied in a subcutaneous murine infection model. In contrast, the coagulase-deficient S. aureus strain which was not able to induce clotting failed to aggregate and to persist in vivo. In conclusion, our data suggested that coagulase-positive S. aureus have evolved mechanisms that prevent their elimination within a fibrin clot. © 2015 The Authors.

  17. Novel aspects of extracellular adenosine dynamics revealed by adenosine sensor cells

    Directory of Open Access Journals (Sweden)

    Kunihiko Yamashiro

    2017-01-01

    Full Text Available Adenosine modulates diverse physiological and pathological processes in the brain, including neuronal activities, blood flow, and inflammation. However, the mechanisms underlying the dynamics of extracellular adenosine are not fully understood. We have recently developed a novel biosensor, called an adenosine sensor cell, and we have characterized the neuronal and astrocytic pathways for elevating extracellular adenosine. In this review, the physiological implications and therapeutic potential of the pathways revealed by the adenosine sensor cells are discussed. We propose that the multiple pathways regulating extracellular adenosine allow for the diverse functions of this neuromodulator, and their malfunctions cause various neurological and psychiatric disorders.

  18. Activation of adenosine A2A receptors by polydeoxyribonucleotide increases vascular endothelial growth factor and protects against testicular damage induced by experimental varicocele in rats.

    Science.gov (United States)

    Minutoli, Letteria; Arena, Salvatore; Bonvissuto, Giulio; Bitto, Alessandra; Polito, Francesca; Irrera, Natasha; Arena, Francesco; Fragalà, Eugenia; Romeo, Carmelo; Nicotina, Piero Antonio; Fazzari, Carmine; Marini, Herbert; Implatini, Alessandra; Grimaldi, Silvia; Cantone, Noemi; Di Benedetto, Vincenzo; Squadrito, Francesco; Altavilla, Domenica; Morgia, Giuseppe

    2011-03-15

    In rat experimental varicocele, polydeoxyribonucleotide (PDRN) induces vascular endothelial growth factor (VEGF) production, thereby enhancing testicular function. This may point to a new therapeutic approach in human varicocele. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation.

    Directory of Open Access Journals (Sweden)

    Guoqing Wang

    Full Text Available Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE, we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p1.5, with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

  20. Endogenous Production of Extracellular Adenosine by Trabecular Meshwork Cells: Potential Role in Outflow Regulation

    Science.gov (United States)

    Wu, Jing; Li, Guorong; Luna, Coralia; Spasojevic, Ivan; Epstein, David L.; Gonzalez, Pedro

    2012-01-01

    Purpose. To investigate the mechanisms for endogenous production of extracellular adenosine in trabecular meshwork (TM) cells and evaluate its physiological relevance to the regulation of aqueous humor outflow facility. Methods. Extra-cellular levels of adenosine monophosphate (AMP) and adenosine in porcine trabecular meshwork (PTM) cells treated with adenosine triphosphate (ATP), AMP, cAMP or forskolin with or without specific inhibitors of phosphodiesterases (IBMX) and CD73 (AMPCP) were determined by high-pressure liquid chromatography fluorometry. Extracellular adenosine was also evaluated in cell cultures subjected to cyclic mechanical stress (CMS) (20% stretching; 1 Hz) and after disruption of lipid rafts with methyl-β-cyclodextrin. Expression of CD39 and CD73 in porcine TM cells and tissue were examined by Q-PCR and Western blot. The effect of inhibition of CD73 on outflow facility was evaluated in perfused living mouse eyes. Results. PTM cells generated extracellular adenosine from extracellular ATP and AMP but not from extracellular cAMP. Increased intracellular cAMP mediated by forskolin led to a significant increase in extracellular adenosine production that was not prevented by IBMX. Inhibition of CD73 resulted, in all cases, in a significant decrease in extracellular adenosine. CMS induced a significant activation of extracellular adenosine production. Inhibition of CD73 activity with AMPCP in living mouse eyes resulted in a significant decrease in outflow facility. Conclusions. These results support the concept that the extracellular adenosine pathway might play an important role in the homeostatic regulation of outflow resistance in the TM, and suggest a novel mechanism by which pathologic alteration of the TM, such as increased tissue rigidity, could lead to abnormal elevation of IOP in glaucoma. PMID:22997289

  1. High dose adenosine for suboptimal myocardial reperfusion after primary PCI : A randomized placebo-controlled pilot study

    NARCIS (Netherlands)

    Stoel, Martin G.; Marques, Koen M. J.; de Cock, Carel C.; Bronzwaer, Jean G. F.; von Birgelen, Clemens; Zijlstra, Felix

    2008-01-01

    Objectives: This study was designed to investigate the influence of high dose intracoronary adenosine on persistent ST-segment elevation after primary percutaneous coronary intervention (PCI). Background: After successful PCI for acute myocardial infarction 40-50% of patients show persistent

  2. LSD-induced Hallucinogen Persisting Perception Disorder with depressive features treated with reboxetine: case report.

    Science.gov (United States)

    Lerner, Arturo G; Shufman, Emi; Kodesh, Arad; Kretzmer, Gavin; Sigal, Mircea

    2002-01-01

    We would like to present the case of a patient who had a prior history of cannabis, ecstasy (MDMA) and LSD abuse and who developed both Hallucinogen Persisting Perception Disorder (HPPD) and a major depressive episode. Following two unsuccessful SSRIs trials, reboxetine was prescribed. During a six-month follow-up period on reboxetine 6 mg./day, no exacerbation of the visual disturbance or recurrence of the depressive features were reported. Reboxetine may have an alpha 2 adrenoreceptor modulating effect on both noradrenaline and serotonin release, thus reboxetine's alpha 2 adrenoreceptor modulating effect on noradrenaline release may affect sympathetic activity and be involved in the recovery process.

  3. Adenosine monophosphate activated protein kinase (AMPK), a mediator of estradiol-induced apoptosis in long-term estrogen deprived breast cancer cells.

    Science.gov (United States)

    Chen, Haiyan; Wang, Ji-Ping; Santen, Richard J; Yue, Wei

    2015-06-01

    Estrogens stimulate growth of hormone-dependent breast cancer but paradoxically induce tumor regress under certain circumstances. We have shown that long-term estrogen deprivation (LTED) enhances the sensitivity of hormone dependent breast cancer cells to estradiol (E2) so that physiological concentrations of estradiol induce apoptosis in these cells. E2-induced apoptosis involve both intrinsic and extrinsic pathways but precise mechanisms remain unclear. We found that exposure of LTED MCF-7 cells to E2 activated AMP activated protein kinase (AMPK). In contrast, E2 inhibited AMPK activation in wild type MCF-7 cells where E2 prevents apoptosis. As a result of AMPK activation, the transcriptional activity of FoxO3, a downstream factor of AMPK, was up-regulated in E2 treatment of LTED. Increased activity of FoxO3 was demonstrated by up-regulation of three FoxO3 target genes, Bim, Fas ligand (FasL), and Gadd45α. Among them, Bim and FasL mediate intrinsic and extrinsic apoptosis respectively and Gadd45α causes cell cycle arrest at the G2/M phase. To further confirm the role of AMPK in apoptosis, we used AMPK activator AICAR in wild type MCF-7 cells and examined apoptosis, proliferation and expression of Bim, FasL, and Gadd45α. The effects of AICAR on these parameters recapitulated those observed in E2-treated LTED cells. Activation of AMPK by AICAR also increased expression of Bax in MCF-7 cells and its localization to mitochondria, which is a required process for apoptosis. These results reveal that AMPK is an important factor mediating E2-induced apoptosis in LTED cells, which is implicative of therapeutic potential for relapsing breast cancer after hormone therapy.

  4. Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist.

    Science.gov (United States)

    Zhao, Gong; Messina, Eric; Xu, Xiaobin; Ochoa, Manuel; Sun, Hai-Ling; Leung, Kwan; Shryock, John; Belardinelli, Luiz; Hintze, Thomas H

    2007-06-01

    Effects of caffeine on regadenoson-induced coronary vasodilation and changes in hemodynamics were examined in conscious dogs. Sixteen dogs were chronically instrumented for measurements of coronary blood flow (CBF), mean arterial pressure (MAP), and heart rate (HR). Regadenoson (5 microg/kg, IV) increased CBF from 34 +/- 2 to 191 +/- 7 mL/min. The duration of the 2-fold increase in CBF was 515 +/- 71 seconds. Regadenoson decreased MAP by 15 +/- 2% and increased HR by 114 +/- 14%. Regadenoson-induced maximum increases in CBF were not significantly lower in the presence of caffeine at 1, 2, 4, and 10 mg/kg (2 +/- 3, 0.7 +/- 3, 16 +/- 5, and 13 +/- 8%, respectively; all P > 0.05). Caffeine at 1, 2, 4, and 10 mg/kg significantly decreased the duration of the 2-fold increase in CBF induced by regadenoson by 17% +/- 4%, 48% +/- 8%, 62% +/- 5%, and 82% +/- 5%, respectively (all P regadenoson on MAP and HR. The results indicate that 1 to 10 mg/kg caffeine dose-dependently reduced the duration, but not the peak increase of CBF caused by 5 microg/kg regadenoson.

  5. Intracellular signalling pathways in the vasoconstrictor response of mouse afferent arterioles to adenosine

    DEFF Research Database (Denmark)

    Hansen, Pernille B. Lærkegaard; Friis, Ulla Glenert; Uhrenholt, Torben Rene

    2007-01-01

    the protein kinase C inhibitor calphostin C had no effect. The calcium-activated chloride channel inhibitor IAA-94 (30 microM) inhibited the adenosine-mediated constriction. Patch clamp experiments showed that adenosine treatment induced a depolarizing current in preglomerular smooth muscle cells which...... was abolished by IAA-94. Furthermore, the vasoconstriction caused by adenosine was significantly inhibited by 5 microM nifedipine (control 8.3 +/- 0.2 microM, ado 3.6 +/- 0.6 microM, ado + nifedipine 6.8 +/- 0.2 microM) suggesting involvement of voltage-dependent calcium channels. CONCLUSION: We conclude...

  6. Persistent luminescence induced by near infra-red photostimulation in chromium-doped zinc gallate for in vivo optical imaging

    Science.gov (United States)

    Sharma, Suchinder K.; Gourier, Didier; Teston, Eliott; Scherman, Daniel; Richard, Cyrille; Viana, Bruno

    2017-01-01

    The analysis of the optical spectroscopy of the Cr3+ doped spinel was initiated by Prof. Georges Boulon more than twenty years ago. More recently persistent luminescence nanoparticles of Cr doped zinc gallate have found interest for in vivo imaging of small animals. Here we evaluated near infra-red (NIR) excitation (or NIR photostimulation) via photo-transfer mechanism as an additional tool for in vivo optical imaging. Investigation of the persistent luminescence induced by NIR photostimulation is studied after either a primary UV (band-to-band excitation) or visible irradiation (direct Cr 3d-3d excitation). UV or visible pre-excited ZnGa2O4:Cr (ZGO:Cr) nanoparticles are kept active during several days thanks to deep traps (with depths 1 eV-1.2 eV) observed in these samples which can be probed through thermally stimulated luminescence (TSL) technique showing glow curve maximums at 470 K and 530 K upon visible light excitation. These deep traps are stable at room temperature but can be emptied by NIR light photostimulation. Experiments were carried out to study the photostimulation induced trapping-detrapping in the ZGO:Cr phosphor. Photostimulation was also tested in vivo for small animal optical imaging to offer new perspectives and modalities.

  7. Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

    Science.gov (United States)

    Bouvier, E; Brouillard, F; Molet, J; Claverie, D; Cabungcal, J-H; Cresto, N; Doligez, N; Rivat, C; Do, K Q; Bernard, C; Benoliel, J-J; Becker, C

    2017-12-01

    Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

  8. Adenosine derived from Staphylococcus aureus-engulfed macrophages functions as a potent stimulant for the induction of inflammatory cytokines in mast cells

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Kim, Chan-Hee; Ryu, Kyoung-Hwa

    2011-01-01

    In this study, we attempted to isolate novel mast cell-stimulating molecules from Staphylococcus aureus. Water-soluble extract of S. aureus cell lysate strongly induced human interleukin- 8 in human mast cell line-1 and mouse interleukin-6 in mouse bone marrow-derived mast cells. The active...... adenosine receptor blocker, verified that purified adenosine can induce interleukin-8 production via adenosine receptors on mast cells. Moreover, adenosine was purified from S. aureusengulfed RAW264.7 cells, a murine macrophage cell line, used to induce phagocytosis of S. aureus. These results show a novel...

  9. Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma

    DEFF Research Database (Denmark)

    Hermansen, Mette Northman; Nielsen, Kim Gjerum; Buchvald, Frederik

    2006-01-01

    -controlled, crossover study of the immediate effect of formoterol, 9 microg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction. PATIENTS: Twenty-four 7- to 15-year-old children with persistent asthma....... INTERVENTIONS: The children performed standardized treadmill exercise tests, breathing dry air, with a submaximal workload. Study medication was administered 5 min after exercise if FEV1 dropped > or = 15% within 5 min after exercise. FEV1 and forced expiratory flows were measured repeatedly until 60 min after......% of the maximum increase for both. Median times to recovery within 5% of baseline FEV1 were 5.0 min and 7.4 min for formoterol and terbutaline, respectively (p = 0.33). CONCLUSION: Single-dose formoterol, 9 microg, via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB...

  10. EPR persistence measurements of UV-induced melanin free radicals in whole skin

    Energy Technology Data Exchange (ETDEWEB)

    Collins, B.; Poehler, T.O. [Johns Hopkins Univ., Baltimore, MD (United States); Bryden, W.A. [Johns Hopkins Univ., Laurel, MD (United States). Applied Physics Lab.

    1995-09-01

    Electron paramagnetic resonance is used to detect the formation of free radicals caused by exposure to ultraviolet radiation in chemically untreated rabbit skin. A fast jump in EPR signal level, occurring over a few seconds, is observed immediately after a skin sample is exposed to UV. This is followed by a slower increase toward an elevated steady-state signal over a period of hours as the skin is continuously exposed to a UV light source. Upon cessation of UV light exposure, EPR signal levels undergo an abrupt drop followed by a slower decay toward natural levels. Elevated free radical concentrations following UV exposure are found to persist for several hours in whole skin. These results are consistent with time resolved EPR measurements of photoinduced radicals in various natural melanins. (Author).

  11. Diagnostic performance of combined noninvasive anatomic and functional assessment with dual-source CT and adenosine-induced stress dual-energy CT for detection of significant coronary stenosis.

    Science.gov (United States)

    Ko, Sung Min; Choi, Jin Woo; Hwang, Hweung Kon; Song, Meong Gun; Shin, Je Kyoun; Chee, Hyun Keun

    2012-03-01

    The purpose of our study was to prospectively evaluate the incremental diagnostic value of combined dual-source coronary CT angiography (CTA) and CT myocardial perfusion imaging (MPI) for the detection of significant coronary stenoses. Forty-five patients with known coronary artery disease detected by dual-source coronary CTA were investigated by adenosine-induced stress dual-source CTA and conventional coronary angiography. Analysis was performed in three steps: classification of coronary stenosis severity using dual-source coronary CTA, identification of myocardial perfusion defects using rest and stress CT MPI, and reclassification of coronary stenosis severity according to combined dual-source coronary CTA and CT MPI. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of dual-source coronary CTA before and after CT MPI were calculated on a per-vessel basis compared with conventional coronary angiography as the standard of reference. Dual-source coronary CTA revealed 87 significantly stenotic vessels in 45 patients. Conventional coronary angiography revealed significant stenoses in 73 vessels in 42 patients. CT MPI showed myocardial perfusion defects in 81 vessel territories in 43 patients. After the CT MPI analysis, dual-source coronary CTA identified significant stenoses in 77 coronary vessels in 42 patients. Sensitivity, specificity, PPV, and NPV of the dual-source coronary CTA on a per-vessel basis before CT MPI were 91.8%, 67.7%, 73.6%, and 87.5%, respectively, and after CT MPI were 93.2%, 85.5%, 88.3%, and 91.4%, respectively. The area under the receiver operating characteristic curve increased significantly from 0.798 to 0.893 (p = 0.004). Combined dual-source coronary CTA and CT MPI provides incremental diagnostic value compared with dual-source coronary CTA alone for the detection of significant coronary stenoses.

  12. Nonintegrating Lentiviral Vector-Based Vaccine Efficiently Induces Functional and Persistent CD8+ T Cell Responses in Mice

    Directory of Open Access Journals (Sweden)

    Donatella R. M. Negri

    2010-01-01

    Full Text Available CD8+ T cells are an essential component of an effective host immune response to tumors and viral infections. Genetic immunization is particularly suitable for inducing CTL responses, because the encoded proteins enter the MHC class I processing pathway through either transgene expression or cross-presentation. In order to compare the efficiency and persistence of immune response induced by genetic vaccines, BALB/c mice were immunized either twice intramuscularly with DNA plasmid expressing a codon-optimized HIV-1 gp120 Envelope sequence together with murine GM-CSF sequence or with a single immunization using an integrase defective lentiviral vector (IDLV expressing the same proteins. Results strongly indicated that the schedule based on IDLV vaccine was more efficient in inducing specific immune response, as evaluated three months after the last immunization by IFN ELISPOT in both splenocytes and bone marrow- (BM- derived cells, chromium release assay in splenocytes, and antibody detection in sera. In addition, IDLV immunization induced high frequency of polyfunctional CD8+ T cells able to simultaneously produce IFN, TNF, and IL2.

  13. Warm spring temperatures induce persistent season-long changes in shoot development in grapevines.

    Science.gov (United States)

    Keller, Markus; Tarara, Julie M

    2010-07-01

    The influence of temperature on the timing of budbreak in woody perennials is well known, but its effect on subsequent shoot growth and architecture has received little attention because it is understood that growth is determined by current temperature. Seasonal shoot development of grapevines (Vitis vinifera) was evaluated following differences in temperature near budbreak while minimizing the effects of other microclimatic variables. Dormant buds and emerging shoots of field-grown grapevines were heated above or cooled below the temperature of ambient buds from before budbreak until individual flowers were visible on inflorescences, at which stage the shoots had four to eight unfolded leaves. Multiple treatments were imposed randomly on individual plants and replicated across plants. Shoot growth and development were monitored during two growing seasons. Higher bud temperatures advanced the date of budbreak and accelerated shoot growth and leaf area development. Differences were due to higher rates of shoot elongation, leaf appearance, leaf-area expansion and axillary-bud outgrowth. Although shoots arising from heated buds grew most vigorously, apical dominance in these shoots was reduced, as their axillary buds broke earlier and gave rise to more vigorous lateral shoots. In contrast, axillary-bud outgrowth was minimal on the slow-growing shoots emerging from buds cooled below ambient. Variation in shoot development persisted or increased during the growing season, well after temperature treatments were terminated and despite an imposed soil water deficit. The data indicate that bud-level differences in budbreak temperature may lead to marked differences in shoot growth, shoot architecture and leaf-area development that are maintained or amplified during the growing season. Although growth rates commonly are understood to reflect current temperatures, these results demonstrate a persistent effect of early-season temperatures, which should be considered in future

  14. Regulation of neutrophil function by adenosine

    Science.gov (United States)

    Barletta, Kathryn E.; Ley, Klaus; Mehrad, Borna

    2012-01-01

    Adenosine is an endogenously released purine nucleoside that signals via four widely expressed G-protein coupled receptors: A1, A2A, A2B, and A3. In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all four adenosine receptor subtypes. At low concentrations, adenosine can act via the A1 and A3 adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A2A and A2B receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and non-infectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function. PMID:22423037

  15. Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells: Implications for Aging Hematopoietic Stem Cells.

    Science.gov (United States)

    Greco, Steven J; Yehia, Ghassan; Potian, Julius A; Molina, Carlos A; Rameshwar, Pranela

    2017-02-01

    Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as CREM and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: CD34(+)CD38(-)/c-kit (+) (primitive progenitor), CD34(+)CD38(+)/c-kit(low) (mature progenitor) and CD34(-)CD38(+/-)/c-kit(low/-) (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of CD34(+)/CD38(-) cells. Phospho (p)-CREM was also present suggesting a balance between ICER and p-CREM in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.

  16. Immunosuppression in early postnatal days induces persistent and allergen-specific immune tolerance to asthma in adult mice.

    Directory of Open Access Journals (Sweden)

    Yan Chen

    Full Text Available Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma.

  17. Hydrogen sulfide inhibits A2A adenosine receptor agonist induced β-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway.

    Directory of Open Access Journals (Sweden)

    Bhushan Vijay Nagpure

    Full Text Available Alzheimer's disease (AD is the leading cause of senile dementia in today's society. Its debilitating symptoms are manifested by disturbances in many important brain functions, which are influenced by adenosine. Hence, adenosinergic system is considered as a potential therapeutic target in AD treatment. In the present study, we found that sodium hydrosulfide (NaHS, an H2S donor, 100 µM attenuated HENECA (a selective A2A receptor agonist, 10-200 nM induced β-amyloid (1-42 (Aβ42 production in SH-SY5Y cells. NaHS also interfered with HENECA-stimulated production and post-translational modification of amyloid precursor protein (APP by inhibiting its maturation. Measurement of the C-terminal APP fragments generated from its enzymatic cleavage by β-site amyloid precursor protein cleaving enzyme 1 (BACE1 showed that NaHS did not have any significant effect on β-secretase activity. However, the direct measurements of HENECA-elevated γ-secretase activity and mRNA expressions of presenilins suggested that the suppression of Aβ42 production in NaHS pretreated cells was mediated by inhibiting γ-secretase. NaHS induced reductions were accompanied by similar decreases in intracellular cAMP levels and phosphorylation of cAMP responsive element binding protein (CREB. NaHS significantly reduced the elevated cAMP and Aβ42 production caused by forskolin (an adenylyl cyclase, AC agonist alone or forskolin in combination with IBMX (a phosphodiesterase inhibitor, but had no effect on those caused by IBMX alone. Moreover, pretreatment with NaHS significantly attenuated HENECA-elevated AC activity and mRNA expressions of various AC isoforms. These data suggest that NaHS may preferentially suppress AC activity when it was stimulated. In conclusion, H2S attenuated HENECA induced Aβ42 production in SH-SY5Y neuroblastoma cells through inhibiting γ-secretase via a cAMP dependent pathway.

  18. Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

    OpenAIRE

    Nam, Hyung Wook; Bruner, Robert C.; Choi, Doo-Sup

    2013-01-01

    Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, ...

  19. Persistent ER stress induces the spliced leader RNA silencing pathway (SLS, leading to programmed cell death in Trypanosoma brucei.

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    Hanoch Goldshmidt

    2010-01-01

    Full Text Available Trypanosomes are parasites that cycle between the insect host (procyclic form and mammalian host (bloodstream form. These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR. However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS pathway. SLS elicits shut-off of spliced leader RNA (SL RNA transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD, evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS production, increase in cytoplasmic Ca(2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM. ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.

  20. Comparison of intravenous adenosine and intravenous regadenoson for the measurement of pressure-derived coronary fractional flow reserve.

    Science.gov (United States)

    Arumugham, Pradeep; Figueredo, Vincent M; Patel, Parul B; Morris, D Lynn

    2013-02-22

    Defining the clinical and physiologic significance of an intermediate coronary artery stenosis is aided by measurement of fractional flow reserve (FFR). Adenosine is the most common agent used in the cardiac catheterisation laboratory for the measurement of FFR. Regadenoson, a selective adenosine receptor agonist, with fewer side effects than adenosine has been used extensively in stress testing to induce hyperaemia. We postulated that FFR measurements would be equivalent following administration of regadenoson and adenosine. Twenty patients with an angiographic intermediate coronary artery stenosis (50% to 80%) were included in the study. FFR was measured during three minutes of intravenous (IV) adenosine infusion and for five minutes after an injection of regadenoson. The mean difference between the FFR measured by IV adenosine and IV regadenoson was 0.0040 (min -0.04, max +0.04, standard deviation [SD] 0.025). There was a strong linear correlation between the FFR measured by IV adenosine and IV regadenoson (R2 linear=0.933). The FFR at maximum hyperaemia was achieved earlier using regadenoson than adenosine (59±24.5 sec vs. 93±44.5 sec, p=0.01). Regadenoson produces similar pressure-derived FFR compared to IV adenosine infusion.

  1. Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents: an in vitro study.

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    Robert Edward Sims

    Full Text Available Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K(+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state.

  2. Sleep-Wake Sensitive Mechanisms of Adenosine Release in the Basal Forebrain of Rodents: An In Vitro Study

    Science.gov (United States)

    Sims, Robert Edward; Wu, Houdini Ho Tin; Dale, Nicholas

    2013-01-01

    Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state. PMID:23326515

  3. A stress-induced anxious state in male rats: corticotropin-releasing hormone induces persistent changes in associative learning and startle reactivity.

    Science.gov (United States)

    Servatius, Richard J; Beck, Kevin D; Moldow, Roberta L; Salameh, Gabriel; Tumminello, Tara P; Short, Kenneth R

    2005-04-15

    Exposure to intense inescapable stressors induces a persistent anxious state in rats. The anxious state is evident as increased sensory reactivity and enhanced associative learning. We examine whether similar neurobehavioral changes are observed after intracerebroventricular (ICV) administration of corticotropin releasing hormone (CRH). Two behaviors were observed: acoustic startle responses (ASRs) and acquisition of the classically conditioned eyeblink response. Male Sprague-Dawley rats were administered ICV CRH either in a single dose (1.0 microg/rat) or in three doses each separated by 30 min. Exaggerated ASRs were evident 2 hours after either CRH treatment; however, only the rats given three injections exhibited a persistently exaggerated ASR apparent 24 hours after CRH treatment. Rats administered three injections of CRH also exhibited faster acquisition of the eyeblink conditioned response beginning 24 hours after treatment. Yet, we did not find evidence for a persistent activation of the HPA-axis response; three CRH injections did not lead to elevated basal plasma corticosterone levels the following morning. Repeated treatment with CRH over a 1.5-hour period models some of the behavioral changes observed after exposure to intense inescapable stressors.

  4. Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells.

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    Shanaz A Ghandhi

    Full Text Available We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected up to 8 months after irradiation. Regression analysis showed significant induction of micronuclei in NHP blood cells that persisted with a gradual decline over the 8-month study period, suggesting long-term DNA damage in blood lymphocytes after WTLI. We also report transcriptomic changes in blood up to 30 days after WTLI. We isolated total RNA from peripheral blood at 3 days before and then at 2, 5 and 30 days after irradiation. We identified 1187 transcripts that were significantly changed across the 30-day time course. From changes in gene expression, we identified biological processes related to immune responses, which persisted across the 30-day study. Response to oxygen-containing compounds and bacteria were implicated by gene-expression changes at the earliest day 2 and latest, day 30 time-points. Gene expression changes suggest a persistent altered state of the immune system, specifically response to infection, for at least a month after WTLI.

  5. Persistence of threat-induced errors in police officers' shooting decisions

    NARCIS (Netherlands)

    Nieuwenhuys, A.; Savelsbergh, G.J.P.; Oudejans, R.R.D.

    2015-01-01

    This study tested whether threat-induced errors in police officers' shooting decisions may be prevented through practice. Using a video-based test, 57 Police officers executed shooting responses against a suspect who rapidly appeared with (shoot) or without (don't shoot) a firearm. Threat was

  6. Learning induces the translin/trax RNase complex to express activin receptors for persistent memory

    NARCIS (Netherlands)

    Park, Alan Jung; Havekes, Robbert; Fu, Xiuping; Hansen, Rolf; Tudor, Jennifer C; Peixoto, Lucia; Li, Zhi; Wu, Yen-Ching; Poplawski, Shane G; Baraban, Jay M; Abel, Ted

    2017-01-01

    Long-lasting forms of synaptic plasticity and memory require de novo protein synthesis. Yet, how learning triggers this process to form memory is unclear. Translin/trax is a candidate to drive this learning-induced memory mechanism by suppressing microRNA-mediated translational silencing at

  7. Inflammatory responses to induced infectious endometritis in mares resistant or susceptible to persistent endometritis

    Directory of Open Access Journals (Sweden)

    Christoffersen Mette

    2012-03-01

    Full Text Available Abstract Background The objective of the study was to evaluate the gene expression of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-α, IL-1 receptor antagonist [ra] and serum amyloid A (SAA in endometrial tissue and circulating leukocytes in response to uterine inoculation of 105 colony forming units (CFU Escherichia coli in mares. Before inoculation, mares were classified as resistant or susceptible to persistent endometritis based on their uterine inflammatory response to infusion of 109 killed spermatozoa and histological assessment of the endometrial quality. Endometrial biopsies were obtained 3, 12, 24 and 72 hours (h after bacterial inoculation and blood samples were obtained during the 7 day period post bacterial inoculation. Expression levels of cytokines and SAA were determined by quantitative real-time reverse transcriptase PCR (qRT-PCR. Results Compared to levels in a control biopsy (obtained in the subsequent estrous, resistant mares showed an up-regulation of IL-1β, IL-6, IL-8 and TNF-α at 3 h after E. coli inoculation, while susceptible mares showed increased gene expression of IL-6 and IL-1ra. Susceptible mares had a significant lower gene expression of TNF-α,IL-6 and increased expression of IL-1ra 3 h after E. coli inoculation compared to resistant mares. Susceptible mares showed a sustained and prolonged inflammatory response with increased gene expression levels of IL-1β, IL-8, IL-1ra and IL-1β:IL-1ra ratio throughout the entire study period (72 h, whereas levels in resistant mares returned to estrous control levels by 12 hours. Endometrial mRNA transcripts of IL-1β and IL-1ra were significantly higher in mares with heavy uterine bacterial growth compared to mares with no/mild growth. All blood parameters were unaffected by intrauterine E. coli infusion, except for a lower gene expression of IL-10 at 168 h and an increased expression of IL-1ra at 48 h observed in susceptible

  8. Persistent Arthralgia Induced by Chikungunya Virus Infection is Associated with Interleukin-6 and Granulocyte Macrophage Colony-Stimulating Factor

    Science.gov (United States)

    Chow, Angela; Her, Zhisheng; Ong, Edward K. S.; Chen, Jin-miao; Dimatatac, Frederico; Kwek, Dyan J. C.; Barkham, Timothy; Yang, Henry; Rénia, Laurent; Leo, Yee-Sin

    2011-01-01

    Background. Chikungunya virus (CHIKV) infection induces arthralgia. The involvement of inflammatory cytokines and chemokines has been suggested, but very little is known about their secretion profile in CHIKV-infected patients. Methods. A case-control longitudinal study was performed that involved 30 adult patients with laboratory-confirmed Chikungunya fever. Their profiles of clinical disease, viral load, and immune mediators were investigated. Results. When patients were segregated into high viral load and low viral load groups during the acute phase, those with high viremia had lymphopenia, lower levels of monocytes, neutrophilia, and signs of inflammation. The high viral load group was also characterized by a higher production of pro-inflammatory cytokines, such as interferon-α and interleukin (IL)–6, during the acute phase. As the disease progressed to the chronic phase, IL-17 became detectable. However, persistent arthralgia was associated with higher levels of IL-6 and granulocyte macrophage colony-stimulating factor, whereas patients who recovered fully had high levels of Eotaxin and hepatocyte growth factor. Conclusions. The level of CHIKV viremia during the acute phase determined specific patterns of pro-inflammatory cytokines, which were associated with disease severity. At the chronic phase, levels of IL-6, and granulocyte macrophage colony-stimulating factor found to be associated with persistent arthralgia provide a possible explanation for the etiology of arthralgia that plagues numerous CHIKV-infected patients. PMID:21288813

  9. Propofol Exposure in Pregnant Rats Induces Neurotoxicity and Persistent Learning Deficit in the Offspring

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    Ming Xiong

    2014-05-01

    Full Text Available Propofol is a general anesthetic widely used in surgical procedures, including those in pregnant women. Preclinical studies suggest that propofol may cause neuronal injury to the offspring of primates if it is administered during pregnancy. However, it is unknown whether those neuronal changes would lead to long-term behavioral deficits in the offspring. In this study, propofol (0.4 mg/kg/min, IV, 2 h, saline, or intralipid solution was administered to pregnant rats on gestational day 18. We detected increased levels of cleaved caspase-3 in fetal brain at 6 h after propofol exposure. The neuronal density of the hippocampus of offspring was reduced significantly on postnatal day 10 (P10 and P28. Synaptophysin levels were also significantly reduced on P28. Furthermore, exploratory and learning behaviors of offspring rats (started at P28 were assessed in open-field trial and eight-arm radial maze. The offspring from propofol-treated dams showed significantly less exploratory activity in the open-field test and less spatial learning in the eight-arm radial maze. Thus, this study suggested that propofol exposure during pregnancy in rat increased cleaved caspsase-3 levels in fetal brain, deletion of neurons, reduced synaptophysin levels in the hippocampal region, and persistent learning deficits in the offspring.

  10. Light-Induced Peroxide Formation in ZnO: Origin of Persistent Photoconductivity

    Science.gov (United States)

    Kang, Youngho; Nahm, Ho-Hyun; Han, Seungwu

    2016-10-01

    The persistent photoconductivity (PPC) in ZnO has been a critical problem in opto-electrical devices employing ZnO such as ultraviolet sensors and thin film transistors for the transparent display. While the metastable state of oxygen vacancy (VO) is widely accepted as the microscopic origin of PPC, recent experiments on the influence of temperature and oxygen environments are at variance with the VO model. In this study, using the density-functional theory calculations, we propose a novel mechanism of PPC that involves the hydrogen-zinc vacancy defect complex (2H-VZn). We show that a substantial amount of 2H-VZn can exist during the growth process due to its low formation energy. The light absorption of 2H-VZn leads to the metastable state that is characterized by the formation of (peroxide) around the defect, leaving the free carriers in the conduction band. Furthermore, we estimate the lifetime of photo-electrons to be ~20 secs, which is similar to the experimental observation. Our model also explains the experimental results showing that PPC is enhanced (suppressed) in oxygen-rich (low-temperature) conditions. By revealing a convincing origin of PPC in ZnO, we expect that the present work will pave the way for optimizing optoelectronic properties of ZnO.

  11. Surgical treatment of persistent tertiary hyperparathyroidism induced by parathyroid adenomas in the aortopulmonary window

    Directory of Open Access Journals (Sweden)

    Elena Alekseevna Ilyicheva

    2014-09-01

    Full Text Available Background. Aortopulmonary window is a rare localization of ectopic parathyroid glands. This localization is the difficulty in diagnosis and surgical treatment, especially in conditions of the heavy somatic pathology that develops with prolonged of kidney replacement therapy. Persistence of tertiary hyperparathyroidism after cervical revision does not give in medical treatment, accompanied by the progression of bone and systemic symptoms of the disease, including death.Materials and Methods. Illustrates a case successful diagnosis and surgical treatment this rare disease. We discuss the treatment and diagnostic tactics. Female patient (age 66 had the experience of peritoneal dialysis for 6 years. She underwent cervical parathyroidectomy. Ectopic mediastinal paratiroma detected by gamma scintigraphy (from 99mTc-MIBI. Determination of the exact tumor location proved to be impossible before the surgery due to bad mental condition of the patient. Localization of adenomas was defined on the surgery after a sternotomy. Results. Operation efficiency proved decrease parathyroid hormone from 2095 pg / ml (before operation to 10 pg / ml (1.5 months after surgery. After surgery, there was a mediastinal hematoma. The patient was discharged 21 days after surgery healed by.Conclusions. The use a sternotomy leads to the removal of the tumor. This access may be used when an unknown location. This access is a forced for tertiary hyperparathyroidism.

  12. Systemic BCG Immunization Induces Persistent Lung Mucosal Multifunctional CD4 TEM Cells which Expand Following Virulent Mycobacterial Challenge

    Science.gov (United States)

    Kaveh, Daryan A.; Bachy, Véronique S.; Hewinson, R. Glyn; Hogarth, Philip J.

    2011-01-01

    To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (TEM) cells in vaccinated mice. These CD4+CD44hiCD62LloCD27− T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or ‘quality of response’ than single cytokine producing cells. These cells are maintained for long periods (>16 months) in BCG protected mice, maintaining a vaccine–specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of TEM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional TEM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific TEM in the lung may represent a new generation of TB vaccines. PMID:21720558

  13. Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

    Science.gov (United States)

    Zimmerman, Matthew C.; Zhang, Hui; Castellanos, Glenda; O’Malley, Jennifer K.; Alvarez-Ramirez, Horacio; Kharbanda, Kusum; Sisson, Joseph H.; Wyatt, Todd A.

    2013-01-01

    Adenosine concentrations are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease, where it balances between tissue repair and excessive airway remodeling. We previously demonstrated that the activation of the adenosine A2A receptor promotes epithelial wound closure. However, the mechanism by which adenosine-mediated wound healing occurs after cigarette smoke exposure has not been investigated. The present study investigates whether cigarette smoke exposure alters adenosine-mediated reparative properties via its ability to induce a shift in the oxidant/antioxidant balance. Using an in vitro wounding model, bronchial epithelial cells were exposed to 5% cigarette smoke extract, were wounded, and were then stimulated with either 10 μM adenosine or the specific A2A receptor agonist, 5′-(N-cyclopropyl)–carboxamido–adenosine (CPCA; 10 μM), and assessed for wound closure. In a subset of experiments, bronchial epithelial cells were infected with adenovirus vectors encoding human superoxide dismutase and/or catalase or control vector. In the presence of 5% smoke extract, significant delay was evident in both adenosine-mediated and CPCA-mediated wound closure. However, cells pretreated with N-acetylcysteine (NAC), a nonspecific antioxidant, reversed smoke extract–mediated inhibition. We found that cells overexpressing mitochondrial catalase repealed the smoke extract inhibition of CPCA-stimulated wound closure, whereas superoxide dismutase overexpression exerted no effect. Kinase experiments revealed that smoke extract significantly reduced the A2A-mediated activation of cyclic adenosine monophosphate–dependent protein kinase. However, pretreatment with NAC reversed this effect. In conclusion, our data suggest that cigarette smoke exposure impairs A2A-stimulated wound repair via a reactive oxygen species–dependent mechanism, thereby providing a better understanding of adenosine signaling that may direct the development of

  14. Hormone-induced luteolysis on physiologically persisting corpora lutea in Eurasian and Iberian lynx (Lynx lynx and Lynx pardinus).

    Science.gov (United States)

    Painer, Johanna; Goeritz, Frank; Dehnhard, Martin; Hildebrandt, Thomas B; Naidenko, Sergey V; Sánchez, Iñigo; Quevedo Muñoz, Miguel A; Jewgenow, Katarina

    2014-09-01

    The Iberian lynx (Lynx pardinus) is the most critically endangered felid. A high reproductive success within the Iberian Lynx Conservation Breeding Program is crucial to maintaining the goal of reintroducing captive born offspring to the wild and thus increasing the population. Lynx follow a unique reproductive strategy with a monoestrous cycle and persisting CLs over many years. These persistent CLs constantly produce progesterone (on average 5 ng/mL) and are hypothesized to hinder a polyestrous cyclicity in lynx. The aim of this study was to evaluate whether artificial luteolysis can be achieved with common luteolytic drugs and if luteolysis would induce a second estrus naturally. We observed a functional regression of lynx CLs after artificial luteolysis with 2.5 μg/kg body weight PGF2α analogue (cloprostenol) administered three times every 16 hours. We could see a similar effect when combining cloprostenol with other drugs like an anti-gestagen (aglepristone) or a dopamin-agonist (prolactin-inhibitor, cabergolin) or by prolonging the cloprostenol administration to a total of 5 days. However, the sample size was too small to draw conclusions about which protocol is superior or if combining different drugs would result in a positive synergism. Neither structural regression of CLs nor subsequent spontaneous estrus induction was induced with any of these treatments. We suggest that a dose of 2.5 μg/kg body weight cloprostenol administered once daily over 3 to 5 days is sufficient for functional luteolysis in lynx. The next step would be to compare the success of estrus induction with or without the preceding artificial luteolysis. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Attentional demands modulate sensorimotor learning induced by persistent exposure to changes in auditory feedback.

    Science.gov (United States)

    Scheerer, Nichole E; Tumber, Anupreet K; Jones, Jeffery A

    2016-02-01

    Hearing one's own voice is important for regulating ongoing speech and for mapping speech sounds onto articulator movements. However, it is currently unknown whether attention mediates changes in the relationship between motor commands and their acoustic output, which are necessary as growth and aging inevitably cause changes to the vocal tract. In this study, participants produced vocalizations while they heard their vocal pitch persistently shifted downward one semitone in both single- and dual-task conditions. During the single-task condition, participants vocalized while passively viewing a visual stream. During the dual-task condition, participants vocalized while also monitoring a visual stream for target letters, forcing participants to divide their attention. Participants' vocal pitch was measured across each vocalization, to index the extent to which their ongoing vocalization was modified as a result of the deviant auditory feedback. Smaller compensatory responses were recorded during the dual-task condition, suggesting that divided attention interfered with the use of auditory feedback for the regulation of ongoing vocalizations. Participants' vocal pitch was also measured at the beginning of each vocalization, before auditory feedback was available, to assess the extent to which the deviant auditory feedback was used to modify subsequent speech motor commands. Smaller changes in vocal pitch at vocalization onset were recorded during the dual-task condition, suggesting that divided attention diminished sensorimotor learning. Together, the results of this study suggest that attention is required for the speech motor control system to make optimal use of auditory feedback for the regulation and planning of speech motor commands. Copyright © 2016 the American Physiological Society.

  16. HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage.

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    Nicholas A Wallace

    Full Text Available The role of the E6 oncoprotein from high-risk members of the α human papillomavirus genus in anogenital cancer has been well established. However, far less is known about the E6 protein from the β human papillomavirus genus (β-HPVs. Some β-HPVs potentially play a role in non-melanoma skin cancer development, although they are not required for tumor maintenance. Instead, they may act as a co-factor that enhances the carcinogenic potential of UV damage. Indeed, the E6 protein from certain β-HPVs (HPV 5 and 8 promotes the degradation of p300, a histone acetyl transferase involved in UV damage repair. Here, we show that the expression of HPV 5 and 8 E6 increases thymine dimer persistence as well as the likelihood of a UVB induced double strand break (DSB. Importantly, we provide a mechanism for the increased DNA damage by showing that both extended thymine dimer persistence as well as elevated DSB levels are dependent on the ability of HPV 8 E6 to promote p300 degradation. We further demonstrate that HPV 5 and 8 E6 expression reduces the mRNA and protein levels of ATR, a PI3 kinase family member that plays a key role in UV damage signaling, but that these levels remain unperturbed in cells expressing a mutated HPV 8 E6 incapable of promoting p300 degradation. We confirm that the degradation of p300 leads to a reduction in ATR protein levels, by showing that ATR levels rebound when a p300 mutant resistant to HPV 8 mediated degradation and HPV 8 E6 are co-transfected. Conversely, we show that ATR protein levels are reduced when p300 is targeted for degradation by siRNA. Moreover, we show the reduced ATR levels in HPV 5 and 8 E6 expressing cells results in delayed ATR activation and an attenuated ability of cells to phosphorylate, and as a result accumulate, p53 in response to UVB exposure, leading to significantly reduced cell cycle arrest. In conclusion, these data demonstrate that β-HPV E6 expression can enhance the carcinogenic potential of

  17. Cyclothiazide-induced persistent increase in respiratory-related activity in vitro.

    Science.gov (United States)

    Babiec, Walter E; Faull, Kym F; Feldman, Jack L

    2012-10-01

    Hypoglossal (XII) motoneurons (MNs) innervate the genioglossus muscle of the tongue, which plays an important role in maintaining upper airway patency, particularly during sleep, and modulating upper airway resistance. Discovering methods for inducing long-term increases in genioglossal motoneuronal excitability to AMPA-mediated drive may help in the development of therapeutics for upper airway motor disorders such as obstructive sleep apnoea. We show that the diuretic, anti-hypertensive, AMPA receptor modulator cyclothiazide (CTZ) induces a profound and long-lasting increase in the amplitude of respiratory-related XII nerve activity in rhythmically active neonatal rat medullary slices. Treatment of the slice with CTZ (90 μM) for 1 h increased the integrated XII ( XII) nerve burst amplitude to 262 ± 23% of pre-treatment control at 1 h post-treatment;much of this increase lasted at least 12 h. The amount of CTZ-induced facilitation (CIF) was dependent upon both CTZ dose and exposure time and was accompanied by a long-lasting increase in endogenous AMPA-mediated drive currents to XII MNs. CIF, however, is not a form of plasticity and does not depend on AMPA or NMDA receptor activation for its induction. Nor does it depend on coincident protein kinase A or C activity. Rather, measurement of mEPSCs along with mass spectrometric analysis of CTZ-treated slices indicates that the cause is prolonged bioavailability of CTZ. These results illustrate a latent residual capacity for potentiating AMPA-mediated inspiratory drive to XII MNs that might be applied to the treatment of upper airway motor deficits.

  18. Pregnancy- and delivery-induced biomechanical changes in rat vagina persist postpartum

    Science.gov (United States)

    Alperin, Marianna; Feola, Andrew; Duerr, Robert; Moalli, Pamela; Abramowitch, Steven

    2010-01-01

    Introduction and hypothesis We sought to define changes in vaginal distensibility (VD) induced by pregnancy and vaginal delivery using a novel in vivo biomechanical testing protocol. Methods Under sedation, a balloon was inserted into the vagina of 27 virgin, pregnant and 4-week postpartum Long–Evans rats and incrementally distended. Pressure–volume curves were generated with slopes characterizing VD (higher slope = less distensible). One-way ANOVA with a Bonferroni post-hoc test were used for statistical analyses. Results Mean pressures at an infusion volume of 1 cc were lower in pregnant and postpartum rats than in virgins (Pvagina related to pregnancy and vaginal delivery. PMID:20424824

  19. Role of adenosine in regulating the heterogeneity of skeletal muscle blood flow during exercise in humans

    DEFF Research Database (Denmark)

    Heinonen, Ilkka; Nesterov, Sergey V; Kemppainen, Jukka

    2007-01-01

    Evidence from both animal and human studies suggests that adenosine plays a role in the regulation of exercise hyperemia in skeletal muscle. We tested whether adenosine also plays a role in the regulation of blood flow (BF) distribution and heterogeneity among and within quadriceps femoris (QF......) muscles during exercise, measured using positron emission tomography. In six healthy young women, BF was measured at rest and then during three incremental low and moderate intermittent isometric one-legged knee-extension exercise intensities without and with theophylline-induced nonselective adenosine...... and with theophylline (P Adenosine receptor blockade did not have any effect on mean bulk BF or BF heterogeneity among the QF muscles, yet blockade increased within-muscle BF heterogeneity in all four QF muscles (P = 0.03). Taken together, these results show that BF becomes less heterogeneous with increasing...

  20. Halobacterial adenosine triphosphatases and the adenosine triphosphatase from Halobacterium saccharovorum

    Science.gov (United States)

    Kristjansson, Hordur; Sadler, Martha H.; Hochstein, Lawrence I.

    1986-01-01

    Membranes prepared from various members of the genus Halobacterium contained a Triton X-l00 activated adenosine triphosphatase. The enzyme from Halobacterium saccharovorum was unstable in solutions of low ionic strength and maximally active in the presence of 3.5 M NaCl. A variety of nucleotide triphosphates was hydrolyzed. MgADP, the product of ATP hydrolysis, was not hydrolyzed and was a competitive inhibitor with respect to MgATP. The enzyme from H. saccharovorum was composed of at least 2 and possibly 4 subunits. The 83-kDa and 60-kDa subunits represented about 90 percent of total protein. The 60-kDa subunit reacted with dicyclohexyl-carbodiimide when inhibition was carried out in an acidic medium. The enzyme from H. saccharovorum, possesses properties of an F(1)F(0) as well as an E(1)E(2) ATPase.

  1. Parent-offspring conflict and the persistence of pregnancy-induced hypertension in modern humans.

    Directory of Open Access Journals (Sweden)

    Birgitte Hollegaard

    Full Text Available Preeclampsia is a major cause of perinatal mortality and disease affecting 5-10% of all pregnancies worldwide, but its etiology remains poorly understood despite considerable research effort. Parent-offspring conflict theory suggests that such hypertensive disorders of pregnancy may have evolved through the ability of fetal genes to increase maternal blood pressure as this enhances general nutrient supply. However, such mechanisms for inducing hypertension in pregnancy would need to incur sufficient offspring health benefits to compensate for the obvious risks for maternal and fetal health towards the end of pregnancy in order to explain why these disorders have not been removed by natural selection in our hunter-gatherer ancestors. We analyzed >750,000 live births in the Danish National Patient Registry and all registered medical diagnoses for up to 30 years after birth. We show that offspring exposed to pregnancy-induced hypertension (PIH in trimester 1 had significantly reduced overall later-life disease risks, but increased risks when PIH exposure started or developed as preeclampsia in later trimesters. Similar patterns were found for first-year mortality. These results suggest that early PIH leading to improved postpartum survival and health represents a balanced compromise between the reproductive interests of parents and offspring, whereas later onset of PIH may reflect an unbalanced parent-offspring conflict at the detriment of maternal and offspring health.

  2. Stem bromelain-induced macrophage apoptosis and activation curtail Mycobacterium tuberculosis persistence.

    Science.gov (United States)

    Mahajan, Sahil; Chandra, Vemika; Dave, Sandeep; Nanduri, Ravikanth; Gupta, Pawan

    2012-08-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis, has a remarkable ability to usurp its host's innate immune response, killing millions of infected people annually. One approach to manage infection is prevention through the use of natural agents. In this regard, stem bromelain (SBM), a pharmacologically active member of the sulfhydryl proteolytic enzyme family, obtained from Ananas comosus and possessing a remarkable ability to induce the innate and acquired immune systems, is important. We evaluated SBM's ability to induce apoptosis and free-radical generation in macrophages. We also studied antimycobacterial properties of SBM and its effect on foamy macrophages. SBM treatment of peritoneal macrophages resulted in the upregulation of proapoptotic proteins and downregulation of antiapoptotic proteins. Additionally, SBM treatment activated macrophages, curtailed the levels of free glutathione, and augmented the production of hydrogen peroxide, superoxide anion, peroxynitrite, and nitric oxide. SBM cleaves CD36 and reduced the formation of foam cells, the hallmark of M. tuberculosis infection. These conditions created an environment for the increased clearance of M. tuberculosis. Together these data provide a mechanism for antimycobacterial activity of SBM and provide important insights for the use of cysteine proteases as immunomodulatory agents.

  3. Persistency of priors-induced bias in decision behavior and the fMRI signal

    Directory of Open Access Journals (Sweden)

    Kathleen eHansen

    2011-03-01

    Full Text Available It is well known that people take advantage of prior knowledge to bias decisions. To investigate this phenomenon behaviorally and in the brain, we acquired fMRI data while human subjects viewed ambiguous abstract shapes and decided whether a shape was of Category A (smoother or B (bumpier. The decision was made in the context of one of two prior knowledge cues, 80/20 and 50/50. The 80/20 cue indicated that upcoming shapes had an 80% probability of being of one category, e.g. B, and a 20% probability of being of the other. The 50/50 cue indicated that upcoming shapes had an equal probability of being of either category. The ideal observer would bias decisions in favor of the indicated alternative at 80/20 and show zero bias at 50/50. We found that subjects did bias their decisions in the predicted direction at 80/20 but did not show zero bias at 50/50. Instead, at 50/50 the subjects retained biases of the same sign as their 80/20 biases, though of diminished magnitude. The signature of a persistent though diminished bias at 50/50 was also evident in fMRI data from frontal and parietal regions previously implicated in decision-making. As a control, we acquired fMRI data from naïve subjects who experienced only the 50/50 stimulus distributions during both the prescan training and the fMRI experiment. The behavioral and fMRI data from the naïve subjects reflected decision biases closer to those of the ideal observer than those of the prior knowledge subjects at 50/50. The results indicate that practice making decisions in the context of non-equal prior probabilities biases decisions made later when prior probabilities are equal. This finding may be related to the anchoring and adjustment strategy described in the psychology, economics and marketing literatures, in which subjects adjust a first approximation response – the anchor – based on additional information, typically applying insufficient adjustment relative to the ideal observer.

  4. Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis.

    Science.gov (United States)

    Guo, R; Nair, S; Zhang, Y; Ren, J

    2017-09-01

    Background &aims:Low levels of adiponectin (APN), an adipose-derived adipokine, are associated with obesity and non-alcoholic steatohepatitis although its role in high-fat diet-induced hepatic injury and steatosis remains unclear. Here we hypothesized that APN deficiency alters fat diet-induced hepatic function. To this end, we examined the effect of APN deficiency on high-fat diet-induced hepatic injury, apoptosis and steatosis. Adult wild type and APN knockout mice were fed a low- or high-fat diet for 20 weeks. Serum levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, hepatic triglycerides, steatosis, pro-inflammatory cytokines, apoptosis and autophagy were examined. High-fat feeding led to elevated body (48.2%) and liver weights (18.8%), increased levels of ALT (87.8%), serum cholesterol (104.4%), hepatic triglycerides (305.6%) and hepatic fat deposition as evidenced by Oil Red O staining, along with a reduced AST/ALT ratio and unchanged AST. Although APN knockout itself did not affect hepatic function and morphology, it reconciled fat diet-induced hepatic injury (Pfat diet intake promoted AMPK phosphorylation, p62 accumulation and apoptosis, including elevated Bax and cleaved Caspase-3 and downregulated Bcl-2, along with suppressed phosphorylation of Akt, STAT3 and JNK, and the autophagy makers Atg7, Beclin-1 and LC3B (Pfat diet intake promotes hepatic steatosis, apoptosis and interrupted autophagy. APN knockout elicits protective effect against hepatic injury possibly associated with autophagy regulation despite persistent hepatic steatosis.

  5. Circulating persistent current and induced magnetic field in a fractal network

    Energy Technology Data Exchange (ETDEWEB)

    Saha, Srilekha [Condensed Matter Physics Division, Saha Institute of Nuclear Physics, Sector-I, Block-AF, Bidhannagar, Kolkata 700 064 (India); Maiti, Santanu K., E-mail: santanu.maiti@isical.ac.in [Physics and Applied Mathematics Unit, Indian Statistical Institute, 203 Barrackpore Trunk Road, Kolkata 700 108 (India); Karmakar, S.N. [Condensed Matter Physics Division, Saha Institute of Nuclear Physics, Sector-I, Block-AF, Bidhannagar, Kolkata 700 064 (India)

    2016-04-29

    We present the overall conductance as well as the circulating currents in individual loops of a Sierpinski gasket (SPG) as we apply bias voltage via the side attached electrodes. SPG being a self-similar structure, its manifestation on loop currents and magnetic fields is examined in various generations of this fractal and it has been observed that for a given configuration of the electrodes, the physical quantities exhibit certain regularity as we go from one generation to another. Also a notable feature is the introduction of anisotropy in hopping causes an increase in magnitude of overall transport current. These features are a subject of interest in this article. - Highlights: • Voltage driven circular current is analyzed in a fractal network. • Current induced magnetic field is strong enough to flip a spin. • Anisotropy in hopping enhances overall transport current.

  6. Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans

    DEFF Research Database (Denmark)

    Astrup, A; Andersen, T; Christensen, N J

    1990-01-01

    in eight obese patients than in matched control subjects (1.7% vs 9.2%, p less than 0.002). The increase in arterial norepinephrine after glucose was also blunted in the obese patients. After a 30-kg weight loss their glucose and lipid profiles were markedly improved but the thermic effect of glucose......A reduced thermic response and an impaired activation of the sympathetic nervous system (SNS) has been reported after oral glucose in human obesity. It is, however, not known whether the reduced SNS activity returns to normal along with weight reduction. The thermic effect of glucose was lower...... was still lower than that of the control subjects (4.2%, p less than 0.001). The glucose-induced arterial norepinephrine response remained diminished in the reduced obese patients whereas the changes in plasma epinephrine were similar in all three groups. The results suggest that a defective SNS may...

  7. Acute Kidney Injury Induced by Systemic Inflammatory Response Syndrome is an Avid and Persistent Sodium-Retaining State

    Directory of Open Access Journals (Sweden)

    Daniel Vitorio

    2014-01-01

    Full Text Available Acute kidney injury (AKI is a frequent complication of the systemic inflammatory response syndrome (SIRS, which is triggered by many conditions in the intensive care unit, including different types of circulatory shock. One under-recognized characteristic of the SIRS-induced AKI is its avidity for sodium retention, with progressive decreases in urinary sodium concentration (NaU and its fractional excretion (FENa. This phenomenon occurs in parallel with increases in serum creatinine, being only transitorily mitigated by diuretic use. In the present case, we report a situation of two consecutive shocks: the first shock is hemorrhagic in origin and then the second shock is a septic one in the same patient. The SIRS and AKI triggered by the first shock were not completely solved when the second shock occurred. This could be viewed as a persistent avid sodium-retaining state, which may be appreciated even during renal replacement therapy (in the absence of complete anuria and that usually solves only after complete AKI and SIRS resolution. We suggest that decreases in NaU and FENa are major characteristics of SIRS-induced AKI, irrespective of the primary cause, and may serve as additional monitoring tools in its development and resolution.

  8. Formation and Stabilization of Environmentally Persistent Free Radicals Induced by the Interaction of Anthracene with Fe(III)-Modified Clays.

    Science.gov (United States)

    Jia, Hanzhong; Nulaji, Gulimire; Gao, Hongwei; Wang, Fu; Zhu, Yunqing; Wang, Chuanyi

    2016-06-21

    Environmentally persistent free radicals (EPFRs) are occasionally detected in Superfund sites but the formation of EPFRs induced by polycyclic aromatic hydrocarbons (PAHs) is not well understood. In the present work, the formation of EPFRs on anthracene-contaminated clay minerals was quantitatively monitored via electron paramagnetic resonance (EPR) spectroscopy, and surface/interface-related environmental influential factors were systematically explored. The obtained results suggest that EPFRs are more readily formed on anthracene-contaminated Fe(III)-montmorillonite than in other tested systems. Depending on the reaction condition, more than one type of organic radicals including anthracene-based radical cations with g-factors of 2.0028-2.0030 and oxygenic carbon-centered radicals featured by g-factors of 2.0032-2.0038 were identified. The formed EPFRs are stabilized by their interaction with interlayer surfaces, and such surface-bound EPFRs exhibit slow decay with 1/e-lifetime of 38.46 days. Transformation pathway and possible mechanism are proposed on the basis of experimental results and quantum mechanical simulations. Overall, the formation of EPFRs involves single-electron-transfer from anthracene to Fe(III) initially, followed by H2O addition on formed aromatic radical cation. Because of their potential exposure in soil and atmosphere, such clay surface-associated EPFRs might induce more serious toxicity than PAHs and exerts significant impacts on human health.

  9. Leishmania infantum Parasites Subvert the Host Inflammatory Response through the Adenosine A2A Receptor to Promote the Establishment of Infection

    OpenAIRE

    Lima, Mikhael H. F.; Sacramento, Lais A.; Gustavo F.S. Quirino; Marcela D Ferreira; Luciana Benevides; Santana, Alynne K. M.; Fernando Q Cunha; Almeida, Roque P; Silva, João S.; Vanessa Carregaro

    2017-01-01

    Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2A, A2B, and A3. Of these, A2AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A2AR signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis...

  10. Homeostatic Control of Synaptic Activity by Endogenous Adenosine is Mediated by Adenosine Kinase

    Science.gov (United States)

    Diógenes, Maria José; Neves-Tomé, Raquel; Fucile, Sergio; Martinello, Katiuscia; Scianni, Maria; Theofilas, Panos; Lopatář, Jan; Ribeiro, Joaquim A.; Maggi, Laura; Frenguelli, Bruno G.; Limatola, Cristina; Boison, Detlev; Sebastião, Ana M.

    2014-01-01

    Extracellular adenosine, a key regulator of neuronal excitability, is metabolized by astrocyte-based enzyme adenosine kinase (ADK). We hypothesized that ADK might be an upstream regulator of adenosine-based homeostatic brain functions by simultaneously affecting several downstream pathways. We therefore studied the relationship between ADK expression, levels of extracellular adenosine, synaptic transmission, intrinsic excitability, and brain-derived neurotrophic factor (BDNF)-dependent synaptic actions in transgenic mice underexpressing or overexpressing ADK. We demonstrate that ADK: 1) Critically influences the basal tone of adenosine, evaluated by microelectrode adenosine biosensors, and its release following stimulation; 2) determines the degree of tonic adenosine-dependent synaptic inhibition, which correlates with differential plasticity at hippocampal synapses with low release probability; 3) modulates the age-dependent effects of BDNF on hippocampal synaptic transmission, an action dependent upon co-activation of adenosine A2A receptors; and 4) influences GABAA receptor-mediated currents in CA3 pyramidal neurons. We conclude that ADK provides important upstream regulation of adenosine-based homeostatic function of the brain and that this mechanism is necessary and permissive to synaptic actions of adenosine acting on multiple pathways. These mechanistic studies support previous therapeutic studies and implicate ADK as a promising therapeutic target for upstream control of multiple neuronal signaling pathways crucial for a variety of neurological disorders. PMID:22997174

  11. Anterior herniation of lumbar disc induces persistent visceral pain: discogenic visceral pain: discogenic visceral pain.

    Science.gov (United States)

    Tang, Yuan-Zhang; Shannon, Moore-Langston; Lai, Guang-Hui; Li, Xuan-Ying; Li, Na; Ni, Jia-Xiang

    2013-01-01

    Visceral pain is a common cause for seeking medical attention. Afferent fibers innervating viscera project to the central nervous system via sympathetic nerves. The lumbar sympathetic nerve trunk lies in front of the lumbar spine. Thus, it is possible for patients to suffer visceral pain originating from sympathetic nerve irritation induced by anterior herniation of the lumbar disc. This study aimed to evaluate lumbar discogenic visceral pain and its treatment. Twelve consecutive patients with a median age of 56.4 years were enrolled for investigation between June 2012 and December 2012. These patients suffered from long-term abdominal pain unresponsive to current treatment options. Apart from obvious anterior herniation of the lumbar discs and high signal intensity anterior to the herniated disc on magnetic resonance imaging, no significant pathology was noted on gastroscopy, vascular ultrasound, or abdominal computed tomography (CT). To prove that their visceral pain originated from the anteriorly protruding disc, we evaluated whether pain was relieved by sympathetic block at the level of the anteriorly protruding disc. If the block was effective, CT-guided continuous lumbar sympathetic nerve block was finally performed. All patients were positive for pain relief by sympathetic block. Furthermore, the average Visual Analog Scale of visceral pain significantly improved after treatment in all patients (P herniation of the lumbar disc when forming a differential diagnosis for seemingly idiopathic abdominal pain. Continuous lumbar sympathetic nerve block is an effective and safe therapy for patients with discogenic visceral pain.

  12. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM cells which expand following virulent mycobacterial challenge.

    Directory of Open Access Journals (Sweden)

    Daryan A Kaveh

    Full Text Available To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (T(EM cells in vaccinated mice. These CD4+CD44(hiCD62L(loCD27⁻ T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or 'quality of response' than single cytokine producing cells. These cells are maintained for long periods (>16 months in BCG protected mice, maintaining a vaccine-specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of T(EM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional T(EM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific T(EM in the lung may represent a new generation of TB vaccines.

  13. Inhibition of Indoleamine 2,3-Dioxygenase Activity by Levo-1-Methyl Tryptophan Blocks Gamma Interferon-Induced Chlamydia trachomatis Persistence in Human Epithelial Cells ▿

    Science.gov (United States)

    Ibana, Joyce A.; Belland, Robert J.; Zea, Arnold H.; Schust, Danny J.; Nagamatsu, Takeshi; AbdelRahman, Yasser M.; Tate, David J.; Beatty, Wandy L.; Aiyar, Ashok A.; Quayle, Alison J.

    2011-01-01

    Gamma interferon (IFN-γ) induces expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) in human epithelial cells, the permissive cells for the obligate intracellular bacterium Chlamydia trachomatis. IDO1 depletes tryptophan by catabolizing it to kynurenine with consequences for C. trachomatis, which is a tryptophan auxotroph. In vitro studies reveal that tryptophan depletion can result in the formation of persistent (viable but noncultivable) chlamydial forms. Here, we tested the effects of the IDO1 inhibitor, levo-1-methyl-tryptophan (L-1MT), on IFN-γ-induced C. trachomatis persistence. We found that addition of 0.2 mM L-1MT to IFN-γ-exposed infected HeLa cell cultures restricted IDO1 activity at the mid-stage (20 h postinfection [hpi]) of the chlamydial developmental cycle. This delayed tryptophan depletion until the late stage (38 hpi) of the cycle. Parallel morphological and gene expression studies indicated a consequence of the delay was a block in the induction of C. trachomatis persistence by IFN-γ. Furthermore, L-1MT addition allowed C. trachomatis to undergo secondary differentiation, albeit with limited productive multiplication of the bacterium. IFN-γ-induced persistent infections in epithelial cells have been previously reported to be more resistant to doxycycline than normal productive infections in vitro. Pertinent to this observation, we found that L-1MT significantly improved the efficacy of doxycycline in clearing persistent C. trachomatis forms. It has been postulated that persistent forms of C. trachomatis may contribute to chronic chlamydial disease. Our findings suggest that IDO1 inhibitors such as L-1MT might provide a novel means to investigate, and potentially target, persistent chlamydial forms, particularly in conjunction with conventional therapeutics. PMID:21911470

  14. The Formation of Streptococcus mutans Persisters Induced by the Quorum-Sensing Peptide Pheromone Is Affected by the LexA Regulator

    Science.gov (United States)

    Leung, Vincent; Ajdic, Dragana; Koyanagi, Stephanie

    2015-01-01

    The presence of multidrug-tolerant persister cells within microbial populations has been implicated in the resiliency of bacterial survival against antibiotic treatments and is a major contributing factor in chronic infections. The mechanisms by which these phenotypic variants are formed have been linked to stress response pathways in various bacterial species, but many of these mechanisms remain unclear. We have previously shown that in the cariogenic organism Streptococcus mutans, the quorum-sensing peptide CSP (competence-stimulating peptide) pheromone was a stress-inducible alarmone that triggered an increased formation of multidrug-tolerant persisters. In this study, we characterized SMU.2027, a CSP-inducible gene encoding a LexA ortholog. We showed that in addition to exogenous CSP exposure, stressors, including heat shock, oxidative stress, and ofloxacin antibiotic, were capable of triggering expression of lexA in an autoregulatory manner akin to that of LexA-like transcriptional regulators. We demonstrated the role of LexA and its importance in regulating tolerance toward DNA damage in a noncanonical SOS mechanism. We showed its involvement and regulatory role in the formation of persisters induced by the CSP-ComDE quorum-sensing regulatory system. We further identified key genes involved in sugar and amino acid metabolism, the clustered regularly interspaced short palindromic repeat (CRISPR) system, and autolysin from transcriptomic analyses that contribute to the formation of quorum-sensing-induced persister cells. PMID:25583974

  15. 21 CFR 864.7040 - Adenosine triphosphate release assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Adenosine triphosphate release assay. 864.7040... Adenosine triphosphate release assay. (a) Identification. An adenosine triphosphate release assay is a device that measures the release of adenosine triphosphate (ATP) from platelets following aggregation...

  16. Comparison of fractional flow reserve measurements using intracoronary adenosine versus intracoronary sodium nitroprusside infusions in moderately stenotic coronary artery lesions

    Energy Technology Data Exchange (ETDEWEB)

    Safi, Morteza; Namazi, Mohammad Hasan; Fooladi, Esfandiar; Vakili, Hossein; Parsa, Saeed Alipour; Khaheshi, Isa [Cardiovascular Research Center, Modarres hospital, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Abbasi, Mohammad Amin [Department of Internal Medicine, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Movahed, Mohammad Reza, E-mail: rmova@aol.com [CareMore, Arizona, Tucson, AZ (United States); University of Arizona, Sarver Heart Center, Tucson, AZ (United States)

    2016-10-15

    Introduction: The aim of this study was to investigate the efficacy and safety of intracoronary (IC) sodium nitroprusside infusion in comparison to IC adenosine for fractional flow reserve (FFR) measurement in moderately diseased coronary artery lesions for functional assessment. Methods: During a nine month period, a consecutive of 98 patients with suspected or known coronary artery disease with moderate stenosis found during angiography (40% to 70% stenosis), were enrolled in this study. Hyperemia was induced by bolus doses of IC adenosine followed by sodium nitroprusside for FFR measurement. Results: Both IC adenosine and IC sodium nitroprusside induced similar and significant reduction in FFR. There was no statistically difference in FFR values between adenosine vs sodium nitroprusside infusions (mean FFR 84.3 ± 6.3 vs 85.7 ± 6.2, p = 0.1) respectively. Furthermore, comparing different FFR cut-off points between the groups (FFR < 0.75, 0.75–0.8 and > 0.8) showed no significant differences (p value = 0.7). Conclusion: An IC bolus of sodium nitroprusside (0.6 μg/kg) infusion induces a similar degree of hyperemia to IC bolus of 100–300 μg of adenosine. Therefore, IC sodium nitroprusside could be considered as an alternative drug to adenosine for FFR measurement with lower side effect profile. - Highlights: • Intracoronary (IC) sodium nitroprusside was compared with IC adenosine for FFR test. • IC adenosine and IC sodium nitroprusside induced similar reduction in FFR. • Different FFR cut-off points between the groups showed no significant differences. • IC sodium nitroprusside could be considered as an alternative to adenosine for FFR.

  17. Activation of the RAGE/STAT3 Pathway in the Dorsal Root Ganglion Contributes to the Persistent Pain Hypersensitivity Induced by Lumbar Disc Herniation.

    Science.gov (United States)

    Zhang, Xin-Sheng; Li, Xiao; Luo, Hai-Jie; Huang, Zhu-Xi; Liu, Cui-Cui; Wan, Qing; Xu, Shu-Wei; Wu, Shao-Ling; Ke, Song-Jian; Ma, Chao

    2017-07-01

    Clinically, chronic low back pain and sciatica associated with lumbar disc herniation (LDH) is a common musculoskeletal disorder. Due to the unawareness of detailed mechanisms, it is difficult to get an effective therapy. The aim of the present study was to identify the role of the RAGE/STAT3 pathway in the dorsal root ganglion (DRG) on the formation and development of persistent pain hypersensitivity induced by LDH. Controlled animal study. University laboratory. After LDH induced by implantation of autologous nucleus pulposus (NP, harvested from animal tail) on the left L5 nerve root was established, mechanical thresholds and electrophysiological tests were conducted at relevant time points during an observation period of 28 days. Protein levels and localization of RAGE and p-STAT3 were performed by using Western blotting and immunohistochemistry, respectively. LDH induced persistent pain hypersensitivity, increased excitability of DRG neurons, and upregulated the expression of RAGE and p-STAT3 in the DRG. Consecutive injection of both RAGE antagonist FPS-ZM1 (i.t.) and STAT3 activity inhibitor S3I-201 (i.t.) inhibited the enhanced excitability of DRG neurons and mechanical allodynia induced by NP implantation. Furthermore, local knockdown of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3flox/flox mice markedly alleviated NP implantation-induced mechanical allodynia in mice. Importantly, the expression of p-STAT3 was colocalized with that of RAGE in the DRG and inhibition of RAGE with FPS-ZM1 prevented NP implantation-induced STAT3 activation. More underlying mechanism(s) of the role of the RAGE/STAT3 pathway on the formation and development of persistent pain hypersensitivity induced by LDH will be needed to be explored in future research. These findings suggest activation of the RAGE/STAT3 pathway plays a critical role in persistent pain induced by LDH, and this pathway may represent novel therapeutic targets for the treatment of LDH-induced

  18. Impaired Erectile Function in CD73-deficient Mice with Reduced Endogenous Penile Adenosine Production

    Science.gov (United States)

    Wen, Jiaming; Dai, Yingbo; Zhang, Yujin; Zhang, Weiru; Kellems, Rodney E.; Xia, Yang

    2012-01-01

    Introduction Adenosine has been implicated in normal and abnormal penile erection. However, a direct role of endogenous adenosine in erectile physiology and pathology has not been established. Aim To determine the functional role of endogenous adenosine production in erectile function. Methods CD73-deficient mice (CD73−/−) and age-matched wild-type (WT) mice were used. Some WT mice were treated with alpha, beta-methylene adenosine diphosphate (ADP) (APCP), a CD73-specific inhibitor. High-performance liquid chromatography was used to measure adenosine levels in mouse penile tissues. In vivo assessment of intracorporal pressure (ICP) normalized to mean arterial pressure (MAP) in response to electrical stimulation (ES) of the cavernous nerve was used. Main Outcome Measurement The main outcome measures of this study were the in vivo assessment of initiation and maintenance of penile erection in WT mice and mice with deficiency in CD73 (ecto-5′-nucleotidase), a key cell-surface enzyme to produce extracellular adenosine. Results Endogenous adenosine levels were elevated in the erected state induced by ES of cavernous nerve compared to the flaccid state in WT mice but not in CD73−/− mice. At cellular levels, we identified that CD73 was highly expressed in the neuronal, endothelial cells, and vascular smooth muscle cells in mouse penis. Functionally, we found that the ratio of ES-induced ICP to MAP in CD73−/− mice was reduced from 0.48 ± 0.03 to 0.33 ± 0.05 and ES-induced slope was reduced from 0.30 ± 0.13 mm Hg/s to 0.15 ± 0.05 mm Hg/s (both P penile erection. PMID:21595838

  19. Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats.

    Science.gov (United States)

    Cun, Yanping; Tang, Lin; Yan, Jie; He, Chao; Li, Yang; Hu, Zhian; Xia, Jianxia

    2014-10-01

    Orexin neurons within the lateral hypothalamus play a crucial role in the promotion and maintenance of arousal. Studies have strongly suggested that orexin neurons are an important target in endogenous adenosine-regulated sleep homeostasis. Orexin A induces a robust increase in the firing activity of orexin neurons, while adenosine has an inhibitory effect. Whether the excitatory action of orexins in the lateral hypothalamus actually promotes wakefulness and reverses the sleep-producing effect of adenosine in vivo is less clear. In this study, electroencephalographic and electromyographic recordings were used to investigate the effects of orexin A and adenosine on sleep and wakefulness in rats. We found that microinjection of orexin A into the lateral hypothalamus increased wakefulness with a concomitant reduction of sleep during the first 3 h of post-injection recording, and this was completely blocked by a selective antagonist for orexin receptor 1, SB 334867. The enhancement of wakefulness also occurred after application of the excitatory neurotransmitter glutamate in the first 3 h post-injection. However, in the presence of the NMDA receptor antagonist APV, orexin A did not induce any change of sleep and wakefulness in the first 3 h. Further, exogenous application of adenosine into the lateral hypothalamus induced a marked increase of sleep in the first 3-h post-injection. No significant change in sleep and wakefulness was detected after adenosine application followed by orexin A administration into the same brain area. These findings suggest that the sleep-promoting action of adenosine can be reversed by orexin A applied to the lateral hypothalamus, perhaps by exciting glutamatergic input to orexin neurons via the action of orexin receptor 1.

  20. Adenosine receptors as drug targets — what are the challenges?

    Science.gov (United States)

    Chen, Jiang-Fan; Eltzschig, Holger K.; Fredholm, Bertil B.

    2014-01-01

    Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges. PMID:23535933

  1. Adenosine signaling in striatal circuits and alcohol use disorders.

    Science.gov (United States)

    Nam, Hyung Wook; Bruner, Robert C; Choi, Doo-Sup

    2013-09-01

    Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, decreased A2AR function is associated with decreased CREB activity in the DMS, which enhances goal-oriented behaviors and contributes to excessive ethanol drinking in mice. Interestingly, caffeine, the most commonly used psychoactive substance, is known to inhibit both the A1R and A2AR. This dampened adenosine receptor function may mask some of the acute intoxicating effects of ethanol. Furthermore, based on the fact that A2AR activity plays a role in goal-directed behavior, caffeine may also promote ethanol-seeking behavior. The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, which may be responsible for the regulation of inhibitory behavioral control over drug rewarding processes through the indirect pathway of the basal ganglia circuit. Furthermore, the antagonistic interactions between adenosine and dopamine receptors in the striatum also play an integral role in alcoholism and addiction-related disorders. This review focuses on regulation of adenosine signaling in striatal circuits and the possible implication of caffeine in goal-directed behaviors and addiction.

  2. Mast cell adenosine receptors function: a focus on the A3 adenosine receptor and inflammation

    Directory of Open Access Journals (Sweden)

    Noam eRudich

    2012-06-01

    Full Text Available Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease (COPD patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells, as an attractive drug candidate. Four subtypes (A1, A2a, A2b and A3 of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R in mediating hyper responsiveness to adenosine in mast cells, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human mast cells. The relevance of mouse studies to the human is discussed.

  3. Adenosine Deaminase Inhibitor EHNA Exhibits a Potent Anticancer Effect Against Malignant Pleural Mesothelioma

    Directory of Open Access Journals (Sweden)

    Yasuhiro Nakajima

    2015-01-01

    Full Text Available Background/Aims: Malignant pleural mesothelioma (MPM is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA inhibitor EHNA as a target of MPM treatment. Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM- and treatment time (24-48 h-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

  4. Persistence of donor-derived protein in host myeloid cells after induced rejection of engrafted allogeneic bone marrow cells

    Science.gov (United States)

    Saito, Toshiki I.; Fujisaki, Joji; Carlson, Alicia L.; Lin, Charles P.; Sykes, Megan

    2014-01-01

    Objective In recipients of allogeneic hematopoietic stem cell transplantation to treat hematologic malignancies, we have unexpectedly observed anti-tumor effects in association with donor cell rejection in both mice and humans. Host-type CD8 T cells were shown to be required for these anti-tumor effects in the murine model. Since sustained host CD8 T cell activation was observed in the murine bone marrow following the disappearance of donor chimerism in the peripheral blood, we hypothesized that donor antigen presentation in the bone marrow might be prolonged. Materials and Methods To assess this hypothesis, we established mixed chimerism with green fluorescence protein (GFP)-positive allogeneic bone marrow cells, induced rejection of the donor cells by giving recipient leukocyte infusions (RLI), and utilized in vivo microscopy to follow GFP-positive cells. Results After peripheral donor leukocytes disappeared, GFP persisted within host myeloid cells surrounding the blood vessels in the bone marrow, suggesting that the host myeloid cells captured donor-derived GFP protein. Conclusions Since the host-versus-graft reaction promotes the induction of anti-tumor responses in this model, this retention of donor-derived protein may play a role in the efficacy of RLI as an anti-tumor therapy. PMID:20167247

  5. Characterization of persistent follicles induced by prolonged treatment with progesterone in dairy cows: an experimental model for the study of ovarian follicular cysts.

    Science.gov (United States)

    Díaz, Pablo U; Stangaferro, Matías L; Gareis, Natalia C; Silvia, William J; Matiller, Valentina; Salvetti, Natalia R; Rey, Florencia; Barberis, Fabián; Cattaneo, Luciano; Ortega, Hugo H

    2015-10-15

    Cystic ovarian disease (COD) is a major factor contributing to poor reproductive efficiency of lactating dairy cows. The objective of the present study was to analyze the endocrine profile, growth dynamics, and histologic characteristics of persistent ovarian follicles-cysts developing in response to long-term administration of intermediate levels of progesterone. To this end, after synchronization of cows, a low dose of progesterone was administered for 5, 10, and 15 days after the expected day of ovulation in treated cows (groups P5, P10, and P15, respectively), using an intravaginal progesterone-releasing device. A significant increase in diameter was detected on Day 11 of progesterone treatment and thereafter (P cows and affected the basal concentration of LH. The pulse frequency remained high at 5 and 10 days of persistence and declined (P follicular persistence. Changes in the serum levels of estradiol, progesterone, 17-hydroxyprogesterone, and testosterone in serum and follicular fluid were also observed. In serum, estradiol increased gradually from proestrus to Day 10 of follicular persistence (P follicular persistence, 17-hydroxyprogesterone showed a significant decrease at 5 days of follicular persistence in relation to proestrus, and testosterone showed a significant increase (P follicular persistence. Correlation between serum and follicular fluid steroid concentrations was significant for testosterone (P ovarian cysts in COD are similar in many ways to the persistent follicles induced by progesterone, with an analogous hormonal and morphologic context, thus confirming a local role of subluteal levels of progesterone in COD pathogenesis and in the regulatory mechanisms of the ovarian function. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

    Science.gov (United States)

    Hawryluk, J. M.; Ferrari, L. L.; Keating, S. A.

    2012-01-01

    Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPA-mediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A1 receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated. PMID:22357797

  7. Adenosine derived from Staphylococcus aureus-engulfed macrophages functions as a potent stimulant for the induction of inflammatory cytokines in mast cells

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Kim, Chan-Hee; Ryu, Kyoung-Hwa

    2011-01-01

    In this study, we attempted to isolate novel mast cell-stimulating molecules from Staphylococcus aureus. Water-soluble extract of S. aureus cell lysate strongly induced human interleukin- 8 in human mast cell line-1 and mouse interleukin-6 in mouse bone marrow-derived mast cells. The active...... adenosine receptor blocker, verified that purified adenosine can induce interleukin-8 production via adenosine receptors on mast cells. Moreover, adenosine was purified from S. aureusengulfed RAW264.7 cells, a murine macrophage cell line, used to induce phagocytosis of S. aureus. These results show a novel...... view of the source of exogenous adenosine in vivo and provide a mechanistic link between inflammatory disease and bacterial infection....

  8. Acute rejection after kidney transplantation promotes graft fibrosis with elevated adenosine level in rat.

    Directory of Open Access Journals (Sweden)

    Mingliang Li

    Full Text Available Chronic allograft nephropathy is a worldwide issue with the major feature of progressive allograft fibrosis, eventually ending with graft loss. Adenosine has been demonstrated to play an important role in process of fibrosis. Our study aimed to investigate the relationship between adenosine and fibrosis in renal allograft acute rejection in rat.Wistar rats and SD rats were selected as experimental animals. Our study designed two groups. In the allograft transplantation group, kidneys of Wistar rats were orthotopically transplanted into SD rat recipients, the same species but not genetically identical, to induce acute rejection. Kidney transplantations of SD rats to SD rats which were genetically identical were served as the control. We established rat models and detected a series of indicators. All data were analyzed statistically. P<0.05 was considered statistically significant.Compared with the control group, levels of adenosine increased significantly in the allograft transplantation group, in which acute rejection was induced (P<0.05. Progressive allograft fibrosis as well as collagen deposition were observed.These findings suggested that level of adenosine was upregulated in acute rejection after kidney allograft transplantation in rat. Acute rejection may promote renal allograft fibrosis via the adenosine signaling pathways.

  9. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

    Science.gov (United States)

    Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

    2016-01-01

    Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

  10. Subsidence Induced Faulting Hazard Zonation Using Persistent Scatterer Interferometry and Horizontal Gradient Mapping in Mexican Urban Areas

    Science.gov (United States)

    Cabral-Cano, E.; Cigna, F.; Osmanoglu, B.; Dixon, T.; Wdowinski, S.

    2011-12-01

    Subsidence and faulting have affected Mexico city for more than a century and the process is becoming widespread throughout larger urban areas in central Mexico. This process causes substantial damages to the urban infrastructure and housing structures and will certainly become a major factor to be considered when planning urban development, land use zoning and hazard mitigation strategies in the next decades. Subsidence is usually associated with aggressive groundwater extraction rates and a general decrease of aquifer static level that promotes soil consolidation, deformation and ultimately, surface faulting. However, local stratigraphic and structural conditions also play an important role in the development and extension of faults. In all studied cases stratigraphy of the uppermost sediment strata and the structure of the underlying volcanic rocks impose a much different subsidence pattern which is most suitable for imaging through satellite geodetic techniques. We present examples from several cities in central Mexico: a) Mexico-Chalco. Very high rates of subsidence, up to 370 mm/yr are observed within this lacustrine environment surrounded by Pliocene-Quaternary volcanic structures. b) Aguascalientes where rates up to 90 mm/yr in the past decade are observed, is controlled by a stair stepped N-S trending graben that induces nucleation of faults along the edges of contrasting sediment package thicknesses. c) Morelia presents subsidence rates as high as 80 mm/yr. Differential deformation is observed across major basin-bounding E-W trending faults and with higher subsidence rates on their hanging walls, where the thickest sequences of compressible Quaternary sediments crop out. Our subsidence and faulting study in urban areas of central Mexico is based on a horizontal gradient analysis using displacement maps from Persistent Scatterer InSAR that allows definition of areas with high vulnerability to surface faulting. Correlation of the surface subsidence pattern

  11. Intratumoral delivery of CD154 homolog (Ad-ISF35) induces tumor regression: analysis of vector biodistribution, persistence and gene expression.

    Science.gov (United States)

    Melo-Cardenas, J; Urquiza, M; Kipps, T J; Castro, J E

    2012-05-01

    Ad-ISF35 is an adenovirus (Ad) vector that encodes a mouse-human chimeric CD154. Ad-ISF35 induces activation of chronic lymphocytic leukemia (CLL) cells converting them into CLL cells capable of promoting immune recognition and anti-leukemia T-cell activation. Clinical trials in humans treated with Ad-ISF35-transduced leukemia cells or intranodal injection of Ad-ISF35 have shown objective clinical responses. To better understand the biology of Ad-ISF35 and to contribute to its clinical development, we preformed studies to evaluate biodistribution, persistence and toxicity of repeat dose intratumoral administration of Ad-ISF35 in a mouse model. Ad-ISF35 intratumoral administration induced tumor regression in more than 80% of mice bearing A20 tumors. There were no abnormalities in the serum chemistry. Mice receiving Ad-ISF35 presented severe extramedullary hematopoiesis and follicular hyperplasia in the spleen and extramedullary hematopoiesis with lymphoid hyperplasia in lymph nodes. After Ad-ISF35 injection, the vector was found primarily in the injected tumors with a biodistribution pattern that showed a rapid clearance with no evidence of Ad-ISF35 accumulation or persistence in the injected tumor or peripheral organs. Furthermore, pre-existing antibodies against Ad-5 did not abrogate Ad-ISF35 anti-tumor activity. In conclusion, intratumoral administration of Ad-ISF35 induced tumor regression in A20 tumor bearing mice without toxicities and with no evidence of vector accumulation or persistence.

  12. Role of Adenosine Signaling in Penile Erection and Erectile Disorders

    Science.gov (United States)

    Phatarpekar, Prasad V.; Wen, Jiaming; Xia, Yang

    2010-01-01

    Introduction Penile erection is a hemodynamic process, which results from increased flow and retention of blood in the penile organ due to the relaxation of smooth muscle cells. Adenosine, a physiological vasorelaxant, has been shown to be a modulator of penile erection. Aim To summarize the research on the role of adenosine signaling in normal penile erection and erectile disorders. Main Outcome Measures Evidence in the literature on the association between adenosine signaling and normal and abnormal penile erection, i.e., erectile dysfunction (ED) and priapism. Methods The article reviews the literature on the role of endogenous and exogenous adenosine in normal penile erection, as well as in erectile disorders namely, ED and priapism. Results Adenosine has been shown to relax corpus cavernosum from various species including human in both in vivo and in vitro studies. Neuromodulatory role of adenosine in corpus cavernosum has also been demonstrated. Impaired adenosine signaling through A2B receptor causes partial resistance of corpus cavernosum, from men with organic ED, to adenosine-mediated relaxation. Increased level of adenosine has been shown to be a causative factor for priapism. Conclusion Overall, the research reviewed here suggests a general role of exogenous and endogenous adenosine signaling in normal penile erection. From this perspective, it is not surprising that impaired adenosine signaling is associated with ED, and excessive adenosine signaling is associated with priapism. Adenosine signaling represents a potentially important diagnostic and therapeutic target for the treatment of ED and priapism. PMID:19889148

  13. Role of adenosine signaling in penile erection and erectile disorders.

    Science.gov (United States)

    Phatarpekar, Prasad V; Wen, Jiaming; Xia, Yang

    2010-11-01

    Penile erection is a hemodynamic process, which results from increased flow and retention of blood in the penile organ due to the relaxation of smooth muscle cells. Adenosine, a physiological vasorelaxant, has been shown to be a modulator of penile erection. To summarize the research on the role of adenosine signaling in normal penile erection and erectile disorders. Evidence in the literature on the association between adenosine signaling and normal and abnormal penile erection, i.e., erectile dysfunction (ED) and priapism. The article reviews the literature on the role of endogenous and exogenous adenosine in normal penile erection, as well as in erectile disorders namely, ED and priapism. Adenosine has been shown to relax corpus cavernosum from various species including human in both in vivo and in vitro studies. Neuromodulatory role of adenosine in corpus cavernosum has also been demonstrated. Impaired adenosine signaling through A(2B) receptor causes partial resistance of corpus cavernosum, from men with organic ED, to adenosine-mediated relaxation. Increased level of adenosine has been shown to be a causative factor for priapism. Overall, the research reviewed here suggests a general role of exogenous and endogenous adenosine signaling in normal penile erection. From this perspective, it is not surprising that impaired adenosine signaling is associated with ED, and excessive adenosine signaling is associated with priapism. Adenosine signaling represents a potentially important diagnostic and therapeutic target for the treatment of ED and priapism. © 2009 International Society for Sexual Medicine.

  14. Molecular mechanisms underlying bacterial persisters

    DEFF Research Database (Denmark)

    Maisonneuve, Etienne; Gerdes, Kenn

    2014-01-01

    All bacteria form persisters, cells that are multidrug tolerant and therefore able to survive antibiotic treatment. Due to the low frequencies of persisters in growing bacterial cultures and the complex underlying molecular mechanisms, the phenomenon has been challenging to study. However, recent...... technological advances in microfluidics and reporter genes have improved this scenario. Here, we summarize recent progress in the field, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally...... induced persistence. In several different organisms, toxin-antitoxin modules function as effectors of ppGpp-induced persistence....

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

    DEFF Research Database (Denmark)

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

    2006-01-01

    Cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis. It was found in vitro during ischemia that the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, may inhibit synaptic transmission via the A(1...

  16. Pollen-derived adenosine is a necessary cofactor for ragweed allergy.

    Science.gov (United States)

    Wimmer, M; Alessandrini, F; Gilles, S; Frank, U; Oeder, S; Hauser, M; Ring, J; Ferreira, F; Ernst, D; Winkler, J B; Schmitt-Kopplin, P; Ohnmacht, C; Behrendt, H; Schmidt-Weber, C; Traidl-Hoffmann, C; Gutermuth, J

    2015-08-01

    Ragweed (Ambrosia artemisiifolia) is a strong elicitor of allergic airway inflammation with worldwide increasing prevalence. Various components of ragweed pollen are thought to play a role in the development of allergic responses. The aim of this study was to identify critical factors for allergenicity of ragweed pollen in a physiological model of allergic airway inflammation. Aqueous ragweed pollen extract, the low molecular weight fraction or the major allergen Amb a 1 was instilled intranasally on 1-11 consecutive days, and allergic airway inflammation was evaluated by bronchoalveolar lavage, lung histology, serology, gene expression in lung tissue, and measurement of lung function. Pollen-derived adenosine was removed from the extract enzymatically to analyze its role in ragweed-induced allergy. Migration of human neutrophils and eosinophils toward supernatants of ragweed-stimulated bronchial epithelial cells was analyzed. Instillation of ragweed pollen extract, but not of the major allergen or the low molecular weight fraction, induced specific IgG1 , pulmonary infiltration with inflammatory cells, a Th2-associated cytokine signature in pulmonary tissue, and impaired lung function. Adenosine aggravated ragweed-induced allergic lung inflammation. In vitro, human neutrophils and eosinophils migrated toward supernatants of bronchial epithelial cells stimulated with ragweed extract only if adenosine was present. Pollen-derived adenosine is a critical factor in ragweed-pollen-induced allergic airway inflammation. Future studies aim at therapeutic strategies to control these allergen-independent pathways. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Targeting adenosine receptors in the development of cardiovascular therapeutics.

    NARCIS (Netherlands)

    Riksen, N.P.; Rongen, G.A.P.J.M.

    2012-01-01

    Adenosine receptor stimulation has negative inotropic and dromotropic actions, reduces cardiac ischemia-reperfusion injury and remodeling, and prevents cardiac arrhythmias. In the vasculature, adenosine modulates vascular tone, reduces infiltration of inflammatory cells and generation of foam cells,

  18. The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma.

    Science.gov (United States)

    Holgate, Stephen T

    2005-08-01

    Adenosine is a powerful bronchoconstrictor of asthmatic, but not normal, airways. In vitro studies on isolated human mast cells and basophils revealed that adenosine and selective analogues augmented inflammatory mediator release from mast cells by stimulating A(2) receptors. Pharmacological blockade of mast cell mediator release in vivo also attenuated adenosine-induced bronchoconstriction, as did theophylline, by adenosine A(2) receptor antagonism. Further in vitro studies revealed that the asthmatic response to adenosine is likely to be mediated via the A(2B) subtype which is selectively antagonised by enprofylline. Studies in animal models, especially mice, have shown a close synergistic interaction between adenosine, Th2 and airway remodelling responses. The recent description of A(2B) receptors on human airway smooth muscle cells that mediate cytokine and chemokine release and induce differentiation of fibroblasts into myofibroblasts strengthens the view that adenosine maybe more than an inflammatory mediator in asthma but also participates in airway wall remodelling in this disease. These data have provided a firm basis for developing adenosine A(2B) receptor antagonists as a new therapeutic approach to this disease.

  19. The Quintiles Prize Lecture 2004: The identification of the adenosine A2B receptor as a novel therapeutic target in asthma

    Science.gov (United States)

    Holgate, Stephen T

    2005-01-01

    Adenosine is a powerful bronchoconstrictor of asthmatic, but not normal, airways. In vitro studies on isolated human mast cells and basophils revealed that adenosine and selective analogues augmented inflammatory mediator release from mast cells by stimulating A2 receptors. Pharmacological blockade of mast cell mediator release in vivo also attenuated adenosine-induced bronchoconstriction, as did theophylline, by adenosine A2 receptor antagonism. Further in vitro studies revealed that the asthmatic response to adenosine is likely to be mediated via the A2B subtype which is selectively antagonised by enprofylline. Studies in animal models, especially mice, have shown a close synergistic interaction between adenosine, Th2 and airway remodelling responses. The recent description of A2B receptors on human airway smooth muscle cells that mediate cytokine and chemokine release and induce differentiation of fibroblasts into myofibroblasts strengthens the view that adenosine maybe more than an inflammatory mediator in asthma but also participates in airway wall remodelling in this disease. These data have provided a firm basis for developing adenosine A2B receptor antagonists as a new therapeutic approach to this disease. PMID:15980878

  20. Prevalence and significance of electrocardiographic changes and side effect profile of regadenoson compared with adenosine during myocardial perfusion imaging.

    Science.gov (United States)

    Zahid, Maliha; Kapila, Aaysha; Eagan, Cecelia E; Yusko, David A; Miller, Edwin D; Missenda, Cheryl D

    2013-03-01

    Significance of electrocardiogram (EKG) changes associated with regadenoson as well as side effects compared to adenosine in a real world, unselected population is unknown. Three hundred ninety six consecutive patients undergoing either adenosine or regadenoson-based single-isotope (Technetium 99c) nuclear images were evaluated. A standard form documenting side effects was filled immediately following administration. The EKGs and nuclear scans were reviewed in a blinded-fashion. Commonest symptoms reported were flushing (64%), chest pain (36%) and dyspnea (36%). Flushing and chest pain were significantly more common with adenosine (73% vs. 57%, P regadenoson (40% vs. 31%, P = 0.05). Sixty (29%) patients carried a diagnosis of chronic bronchitis or asthma but only 4 (2 with each) required aminophylline. There was no significant correlation between chest pain induced by either agent or ischemia on nuclear imaging. EKG changes occurred infrequently (16% with regadenoson and 10% with adenosine), and had low sensitivity for detecting ischemia (7% for regadenoson and 11% for adenosine). EKG changes with adenosine and regadenoson occur infrequently and have low sensitivity for detecting ischemia. Chest pain is frequently induced by both, and is not predictive of ischemia on nuclear imaging.

  1. Mechanism of protection of adenosine from sulphate radical anion ...

    Indian Academy of Sciences (India)

    The photooxidation of adenosine in presence of peroxydisulphate (PDS) has been studied by spectrophotometrically measuring the absorbance of adenosine at 260 nm. The rates of oxidation of adenosine by sulphate radical anion have been determined in the presence of different concentrations of caffeic acid. Increase in ...

  2. Addition of adenosine to hyperbaric bupivacaine in spinal ...

    African Journals Online (AJOL)

    Background: Systemic administration of adenosine produces anti-nociception. Although literature supports intrathecal adenosine for neuropathic pain, its efficacy in postoperative pain remains unproven. There has been no study on the efficacy of adenosine on postoperative pain when administered with hyperbaric ...

  3. Regulation of Maltodextrin Phosphorylase Synthesis in Escherichia coli by Cyclic Adenosine 3′, 5′-Monophosphate and Glucose1

    Science.gov (United States)

    Chao, Julie; Weathersbee, Carolyn J.

    1974-01-01

    Cyclic adenosine 3′, 5′-monophosphate (AMP) stimulates maltodextrin phosphorylase synthesis in Escherichia coli cells induced with maltose. A maximal effect occurs at 2 to 3 mM cyclic AMP. The action of cyclic AMP is specific, inasmuch as adenosine triphosphate, 3′-AMP, 5′-AMP, adenosine, and dibutyryl cyclic AMP are inactive. Glucose, α-methyl glucoside, 2-deoxyglucose, and pyridoxal 5′-phosphate repress maltodextrin phosphorylase synthesis. This repression is reversed by cyclic AMP. The action of cyclic AMP appears to be at the transcriptional level, since cyclic AMP fails to stimulate phosphorylase production in induced cells in which messenger ribonucleic acid synthesis has been arrested by rifampin or by inducer removal. The two other enzymes involved in the metabolism of maltose, amylomaltase and maltose permease, are also induced in this strain of E. coli and affected by glucose and cyclic AMP in a manner similar to phosphorylase. PMID:4358043

  4. Effects of long-term theophylline exposure on recovery of respiratory function and expression of adenosine A1 mRNA in cervical spinal cord hemisected adult rats.

    Science.gov (United States)

    Nantwi, Kwaku D; Basura, Gregory J; Goshgarian, Harry G

    2003-07-01

    Our lab has previously shown that when administered acutely, the methylxanthine theophylline can activate a latent respiratory motor pathway to restore function to the hemidiaphragm paralyzed by an ipsilateral C2 spinal cord hemisection. The recovery is mediated by the antagonism of CNS adenosine A1 receptors. The objective of the present study was to assess quantitatively recovery after chronic theophylline administration, the effects of weaning from the drug, and the effects of the drug on adenosine A1 receptor mRNA expression in adult rats subjected to a C2 hemisection. Rats subjected to a left C2 hemisection received theophylline orally for 3, 7, 12, or 30 days and were classified as 3D, 7D, 12D, or 30D respectively. Separate groups of 3D animals were weaned from drug administration for 7, 12, and 30 days before assessment of respiratory recovery. Additional groups of 7D and 12D animals were also weaned from drug administration for 7 and 12 days prior to assessment. Sham-operated controls received theophylline vehicle for similar periods. Quantitative assessment of recovered respiratory activity was conducted under standardized electrophysiologic recording conditions approximately 18 h after each drug application period. Serum theophylline analysis was conducted at the end of electrophysiologic recordings. Adenosine A1 receptor mRNA expression in the phrenic nucleus was assessed with in situ hybridization and immunohistochemistry. Chronic theophylline induced a dose-dependent effect on respiratory recovery over a serum theophylline range of 1.2-1.9 microg/ml. Recovery was characterized as respiratory-related activity in the left phrenic nerve and expressed as a percentage of activity in the homolateral nerve in noninjured animals under similar recording conditions. Recovered activity was 34.13 +/- 2.07, 55.89 +/- 2.96, 74.78 +/- 1.93, and 79.12 +/- 1.75% respectively in the 3D, 7D, 12D, and 30D groups. Theophylline-induced recovered activity persisted for as

  5. Structural Mapping of Adenosine Receptor Mutations

    DEFF Research Database (Denmark)

    Jespers, Willem; Schiedel, Anke C; Heitman, Laura H

    2018-01-01

    The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemente...

  6. Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability.

    Directory of Open Access Journals (Sweden)

    Erica Werner

    Full Text Available We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET radiation such as X-rays or high-charge and high-energy (HZE particle high-LET radiation such as (56Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization.

  7. The Role of Adenosine Receptors in Psychostimulant Addiction

    Directory of Open Access Journals (Sweden)

    Inmaculada Ballesteros-Yáñez

    2018-01-01

    Full Text Available Adenosine receptors (AR are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3 receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS, adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A1 and A3 receptors inhibit adenylyl cyclase (AC, through Gi/o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A1/A2A, as well as with other subtypes (e.g., A2A/D2, opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1 and A2A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A1 agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2 heterodimers are

  8. Persistence of mercury-induced motor and sensory neurotoxicity: systematic review of workers previously exposed to mercury vapor.

    Science.gov (United States)

    Fields, Cheryl A; Borak, Jonathan; Louis, Elan D

    2017-11-01

    Elemental mercury (Hg0) is a well-recognized neurotoxicant, but it is uncertain whether and for how long its neurotoxicity persists. Among studies that evaluated previously-exposed workers, only one examined workers during and also years after exposure had ceased. The objective of this review is to create a series of 'synthetic' longitudinal studies to address the question of persistence of Hg0 neurotoxicity in occupationally exposed workers. We systematically reviewed studies describing objective motor and sensory effects in previously-exposed mercury workers. Data from physical examination (PE), neurobehavioral (NB) tests, and electrophysiological studies (EPS) were extracted into structured tables and examined for their consistency and dose-relatedness and then compared with the corresponding results from studies of currently exposed workers. We identified six cohorts that described neurological findings in 1299 workers, examined an average of 4.8-30 years after the cessation of exposure. Historical group mean UHg levels ranged from 23 to >500 μg/L, with UHg levels >6000 μg/L in some individuals. Overall, few findings were significant; most were inconsistent across the previous-exposure studies, and in comparisons between studies of previously and currently exposed workers. The results of this systematic review indicate that Hg0-related neurotoxic effects detectable on PE, NB testing, and EPS are substantially reversed over time. To the extent that such effects do persist, they are reported principally in workers who have had very high-dose exposures. In addition, based on the limited available data, those effects reported to persist have been described as having little or no functional significance.

  9. Comparison of regadenoson and nitroprusside to adenosine for measurement of fractional flow reserve: A systematic review and meta-analysis.

    Science.gov (United States)

    Lee, Justin Z; Singh, Nirmal; Nyotowidjojo, Iwan; Howe, Carol; Low, See-Wei; Nguyen, Thach; Pinto, Duane; Kumar, Gautam; Lee, Kwan S

    2017-07-11

    FFR is useful in defining the physiological significance of intermediate coronary stenosis and requires induction of maximal hyperemia and measurement of pressure proximal and distal to the stenosis. Hyperemia normally is induced by either IV or IC adenosine, a medication associated with short-term side effects. IV regadenoson and IC nitroprusside have been suggested as viable alternatives. This meta-analysis aims to identify all studies comparing use of intravenous (IV) regadenoson or intracoronary (IC) nitroprusside with IV adenosine to determine differences related to the agent utilized for assessment of fractional flow reserve (FFR). We searched PubMed, EMBASE, Web of Science, SCOPUS, ClinicalTrials.gov and the Cochrane Library databases for studies comparing IV regadenoson or IC nitroprusside to IV adenosine for FFR assessment. The main outcome was difference in mean FFR measurement. The main secondary outcomes were composite side-effect profile and reclassification of lesions. Seven studies were included in the analysis, with a total of 375 patients. Compared to IV adenosine, there was no difference in the mean FFR derived from IV regadenoson (p=1.0) or IC nitroprusside (p=0.48). IV regadenoson was associated with 53% lower risk of pooled side effects compared to IV adenosine (p=0.05). IC nitroprusside was associated with 97% lower risk of pooled side effects compared to IV adenosine (pregadenoson and IC nitroprusside produce similar pressure-derived FFR measurements compared to IV adenosine and have a favorable side effect profile. Both can be considered as alternative agents to IV adenosine for FFR measurement. Further clinical validation is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Caloric restriction induces energy-sparing alterations in skeletal muscle contraction, fiber composition and local thyroid hormone metabolism that persist during catch-up fat upon refeeding

    Directory of Open Access Journals (Sweden)

    Paula Bresciani M. De Andrade

    2015-09-01

    Full Text Available Weight regain after caloric restriction results in accelerated fat storage in adipose tissue. This catch-up fat phenomenon is postulated to result partly from suppressed skeletal muscle thermogenesis, but the underlying mechanisms are elusive. We investigated whether the reduced rate of skeletal muscle contraction-relaxation cycle that occurs after caloric restriction persists during weight recovery and could contribute to catch-up fat. Using a rat model of semistarvation-refeeding, in which fat recovery is driven by suppressed thermogenesis, we show that contraction and relaxation of leg muscles are slower after both semistarvation and refeeding. These effects are associated with (i higher expression of muscle deiodinase type 3 (DIO3 which inactivates tri-iodothyronine (T3, and lower expression of T3-activating enzyme, deiodinase type 2 (DIO2, (ii slower net formation of T3 from its T4 precursor in muscles, and (iii accumulation of slow fibers at the expense of fast fibers. These semistarvation-induced changes persisted during recovery and correlated with impaired expression of transcription factors involved in slow-twitch muscle development.We conclude that diminished muscle thermogenesis following caloric restriction results from reduced muscle T3 levels, alteration in muscle-specific transcription factors, and fast-to-slow fiber shift causing slower contractility. Energy-sparing effects persist during weight recovery and likely contribute to catch-up fat.

  11. In growing pigs, chlortetracycline induces a reversible green bone discoloration and a persistent increase of bone mineral density dependent of dosing regimen.

    Science.gov (United States)

    Guillot, Martin; Alexander, Kate; Pomar, Candido; Del Castillo, Jérôme R E

    2011-06-01

    We studied in growing pigs the effects of exposure to dietary chlortetracycline on bone mineral density (BMD) and bone color. Pigs were randomly allocated to a drug-free diet (n=48) or a diet fortified with 800 ppm of chlortetracycline, starting either at 28- or 84-d of age, and for either a 28- or 56-d duration (n=16 pigs/group). The lumbar vertebral discoloration and BMD of randomly chosen pigs were evaluated at 28-d intervals up to 168-d of age. The odds of bone discoloration increased with dosing duration and age at treatment onset, and decreased with the withdrawal time and age at treatment onset interaction (p induced bone discoloration is reversible, and may be prevented with proper dosing regimen design. Moreover, TC induces a persistent increase on BMD that could be detected with quantitative computed tomography. Copyright © 2010. Published by Elsevier India Pvt Ltd.

  12. Adenosine Signaling During Acute and Chronic Disease States

    Science.gov (United States)

    Karmouty-Quintana, Harry; Xia, Yang; Blackburn, Michael R.

    2013-01-01

    Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes such as inflammatory cell regulation, vascular barrier function and tissue fibrosis. PMID:23340998

  13. Delayed persistence of giant-nucleated cells induced by X-ray and proton irradiation in the progeny of replicating normal human f ibroblast cells

    Science.gov (United States)

    Almahwasi, A. A.; Jeynes, J. C.; Merchant, M. J.; Bradley, D. A.; Regan, P. H.

    2017-08-01

    Ionising radiation can induce giant-nucleated cells (GCs) in the progeny of irradiated populations, as demonstrated in various cellular systems. Most in vitro studies have utilised quiescent cancerous or normal cell lines but it is not clear whether radiation-induced GCs persist in the progeny of normal replicated cells. In the current work we show persistent induction of GCs in the progeny of normal human-diploid skin fibroblasts (AG1522). These cells were originally irradiated with a single equivalent clinical dose of 0.2, 1 or 2 Gy of either X-ray or proton irradiation and maintained in an active state for various post-irradiation incubation interval times before they were replated for GC analysis. The results demonstrate that the formation of GCs in the progeny of X-ray or proton irradiated cells was increased in a dose-dependent manner when measured 7 days after irradiation and this finding is in agreement with that reported for the AG1522 cells using other radiation qualities. For the 1 Gy X-ray doses it was found that the GC yield increased continually with time up to 21 days post-irradiation. These results can act as benchmark data for such work and may have important implications for studies aimed at evaluating the efficacy of radiation therapy and in determining the risk of delayed effects particularly when applying protons.

  14. Regadenoson and adenosine are equivalent vasodilators and are superior than dipyridamole- a study of first pass quantitative perfusion cardiovascular magnetic resonance.

    Science.gov (United States)

    Vasu, Sujethra; Bandettini, W Patricia; Hsu, Li-Yueh; Kellman, Peter; Leung, Steve; Mancini, Christine; Shanbhag, Sujata M; Wilson, Joel; Booker, Oscar Julian; Arai, Andrew E

    2013-09-24

    Regadenoson, dipyridamole and adenosine are commonly used vasodilators in myocardial perfusion imaging for the detection of obstructive coronary artery disease. There are few comparative studies of the vasodilator properties of regadenoson, adenosine and dipyridamole in humans. The specific aim of this study was to determine the relative potency of these three vasodilators by quantifying stress and rest myocardial perfusion in humans using cardiovascular magnetic resonance (CMR). Fifteen healthy normal volunteers, with Framingham score less than 1% underwent vasodilator stress testing with regadenoson (400 μg bolus), dipyridamole (0.56 mg/kg) and adenosine (140 μg /kg/min) on separate days. Rest perfusion imaging was performed initially. Twenty minutes later, stress imaging was performed at peak vasodilation, i.e. 70 seconds after regadenoson, 4 minutes after dipyridamole infusion and between 3-4 minutes of the adenosine infusion. Myocardial blood flow (MBF) in ml/min/g and myocardial perfusion reserve (MPR) were quantified using a fully quantitative model constrained deconvolution. Regadenoson produced higher stress MBF than dipyridamole and adenosine (3.58 ± 0.58 vs. 2.81 ± 0.67 vs. 2.78 ± 0.61 ml/min/g, p = 0.0009 and p = 0.0008 respectively). Regadenoson had a much higher heart rate response than adenosine and dipyridamole respectively (95 ± 11 vs. 76 ± 13 vs. 86 ± 12 beats/ minute) When stress MBF was adjusted for heart rate, there were no differences between regadenoson and adenosine (37.8 ± 6 vs. 36.6 ± 4 μl/sec/g, p = NS), but differences between regadenoson and dipyridamole persisted (37.8 ± 6 vs. 32.6 ± 5 μl/sec/g, p = 0.03). The unadjusted MPR was higher with regadenoson (3.11 ± 0.63) when compared with adenosine (2.7 ± 0.61, p = 0.02) and when compared with dipyridamole (2.61 ± 0.57, p = 0.04). Similar to stress MBF, these differences in MPR between regadenoson and adenosine were abolished when adjusted for heart rate (2.04 ± 0.34 vs

  15. Persistent Modelling

    DEFF Research Database (Denmark)

    2012-01-01

    The relationship between representation and the represented is examined here through the notion of persistent modelling. This notion is not novel to the activity of architectural design if it is considered as describing a continued active and iterative engagement with design concerns – an evident...... characteristic of architectural practice. But the persistence in persistent modelling can also be understood to apply in other ways, reflecting and anticipating extended roles for representation. This book identifies three principle areas in which these extensions are becoming apparent within contemporary....... It also provides critical insight into the use of contemporary modelling tools and methods, together with an examination of the implications their use has within the territories of architectural design, realisation and experience....

  16. Persistent Modelling

    DEFF Research Database (Denmark)

    2012-01-01

    The relationship between representation and the represented is examined here through the notion of persistent modelling. This notion is not novel to the activity of architectural design if it is considered as describing a continued active and iterative engagement with design concerns – an evident....... It also provides critical insight into the use of contemporary modelling tools and methods, together with an examination of the implications their use has within the territories of architectural design, realisation and experience....... characteristic of architectural practice. But the persistence in persistent modelling can also be understood to apply in other ways, reflecting and anticipating extended roles for representation. This book identifies three principle areas in which these extensions are becoming apparent within contemporary...

  17. Targeting the small airways with dry powder adenosine: a challenging concept.

    Science.gov (United States)

    van der Wiel, Erica; Lexmond, Anne J; van den Berge, Maarten; Postma, Dirkje S; Hagedoorn, Paul; Frijlink, Henderik W; Farenhorst, Martijn P; de Boer, Anne H; Ten Hacken, Nick H T

    2017-01-01

    Background : Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. Objective : We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. Design : In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min -1 ) and once with a high flow rate (60 l min -1 ). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV 1 reflects the large airways, and FEF 25-75% , R5-R20 and X5 reflect the small airways. Results : The four adenosine tests were not significantly different with respect to the threshold values of FEV 1 ( p  = 0.12), FEF 25-75% ( p  = 0.37), R5-R20 ( p  = 0.60) or X5 ( p  = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. Conclusions : In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.

  18. Role of adenosine and the orexinergic perifornical hypothalamus in sleep-promoting effects of ethanol.

    Science.gov (United States)

    Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M

    2014-03-01

    Strong clinical and preclinical evidence suggests that acute ethanol promotes sleep. However, very little is known about how and where ethanol acts to promote sleep. We hypothesized that ethanol may induce sleep by increasing extracellular levels of adenosine and inhibiting orexin neurons in the perifornical hypothalamus. Experiments 1 and 2: Within-Subject Design; Experiment 3: Between-Subject Design. N/A. N/A. N/A. Using adult male Sprague-Dawley rats as our animal model, we performed three experiments to test our hypothesis. Our first experiment examined the effect of A1 receptor blockade in the orexinergic perifornical hypothalamus on sleep- promoting effects of ethanol. Bilateral microinjection of the selective A1 receptor antagonist 1,3-dipropyl-8-phenylxanthine (500 μM; 250 nL/side) into orexinergic perifornical hypothalamus significantly reduced nonrapid eye movement sleep with a concomitant increase in wakefulness, suggesting that blockade of adenosine A1 receptor attenuates ethanol-induced sleep promotion. Our second experiment examined adenosine release in the orexinergic perifornical hypothalamus during local ethanol infusion. Local infusion of pharmacologically relevant doses of ethanol significantly and dose-dependently increased adenosine release. Our final experiment used c-Fos immunohistochemistry to examine the effects of ethanol on the activation of orexin neurons. Acute ethanol exposure significantly reduced the number of orexin neurons containing c-Fos, suggesting an inhibition of orexin neurons after ethanol intake. Based on our results, we believe that ethanol promotes sleep by increasing adenosine in the orexinergic perifornical hypothalamus, resulting in A1 receptor-mediated inhibition of orexin neurons.

  19. Persistence theory

    CERN Document Server

    Oudot, Steve Y

    2015-01-01

    Persistence theory emerged in the early 2000s as a new theory in the area of applied and computational topology. This book provides a broad and modern view of the subject, including its algebraic, topological, and algorithmic aspects. It also elaborates on applications in data analysis. The level of detail of the exposition has been set so as to keep a survey style, while providing sufficient insights into the proofs so the reader can understand the mechanisms at work. The book is organized into three parts. The first part is dedicated to the foundations of persistence and emphasizes its conne

  20. [The involvement of adenosine and adenosine deaminase in experimental myocardial infarct].

    Science.gov (United States)

    Stratone, A; Busuioc, A; Roşca, V; Bazgan, L; Popa, M; Hăulică, I

    1989-01-01

    By the ligature of the left coronary artery in the rat anesthetized with nembutal (10 mg/100 i.p.) a significant increase of the 5'-nucleotidase activity (Wooton method) was noticed 10 minutes after the left ventricle infarction (from an average value of 1038.5 +/- 187 mU/g tissue to 1537 +/- 225 mU/g fresh tissue). The adenosine desaminase levels spectrophotometrically determined by Denstedt technique, do not appear significantly modified 10 or 30 minutes after the left ventricle infarction. The chromatographically determined adenosine levels, by HPLC technique, decrease from the average value of 11.63 +/- 1.4 micrograms/mg PT to 8.60 +/- 1.0 micrograms/mg PT 30 minutes after infarction. The observed changes are explained by the conditions of hypoxia in the infarcted ventricle which lead to the raise in adenosine levels by activating the 5'-nucleotidase and their depression by a very fast metabolism of the same substance.

  1. Ultrasonography and hormone profiles of persistent ovarian follicles (cysts) induced with low doses of progesterone in cattle.

    Science.gov (United States)

    Noble, K M; Tebble, J E; Harvey, D; Dobson, H

    2000-11-01

    The aims of this study were to expose dominant ovarian follicles at the end of the oestrous cycle to low progesterone concentrations similar to those that occur during stress, and to examine the effect of a subsequent small increase in progesterone 10 days later. Half a progesterone releasing intravaginal device (0.5 PRID) was administered to 13 heifers from day 15 of the oestrous cycle. In group 1 (n = 7), one 0.5 PRID remained in place until day 40 or until each heifer ovulated. In group 2 (n = 6), the first 0.5 PRID was removed on day 28, and replaced immediately with a second 0.5 PRID. Ultra-sonography and blood collection (10 ml) were conducted each day for 26 days from day 14 and then on alternate days. The largest follicle that emerged during the first 5 days after insertion of the initial 0.5 PRID remained > 10 mm in diameter for 15.3 +/- 1.7 and 11.6 +/- 0.4 days in groups 1 and 2, respectively. This period of dominance, during which no other follicles emerged, was closely correlated with the duration of plasma oestradiol concentrations exceeding 10 pg ml(-1). In four heifers from group 1, the persistent follicle ovulated between days 30 and 37 (sub-group 1a; 0.5 PRID expelled). In three heifers from sub-group 1b (0.5 PRID retained), the dominant follicle secreted oestradiol for 17 +/- 5 days but remained detectable by ultrasonography for a total of 33 +/- 8 days (range 26-52 days). Monitoring continued beyond day 40 in these animals. In group 2, the new 0.5 PRID inserted on day 28 resulted in an increase in plasma progesterone concentration of 0.9 +/- 0.3 ng ml(-1). Simultaneously, oestradiol decreased by 10.1 +/- 3.3 pg ml(-1), and a new follicular wave emerged 5-7 days later. In conclusion, exposure to very low concentrations of progesterone produced persistent follicles that secreted oestradiol for 17 days. This oestradiol production could be disrupted by a second increase of 0.9 ng ml(-1) in peripheral progesterone concentration. In the absence of the

  2. The effect of beta blocker withdrawal on adenosine myocardial perfusion imaging.

    Science.gov (United States)

    Hoffmeister, C; Preuss, R; Weise, R; Burchert, W; Lindner, O

    2014-12-01

    The effect of beta blockers on myocardial blood flow (MBF) under vasodilators has been studied in several SPECT and PET myocardial perfusion imaging (MPI) studies with divergent results. The present study evaluated the effect of a beta blocker withdrawal on quantitative adenosine MBF and on MPI results. Twenty patients with beta blockers and CAD history were studied with quantitative adenosine N-13 ammonia PET. The first study was performed under complete medication and the second after beta blocker withdrawal. The PET studies were independently read with respect to MPI result and clinical decision making. Global MBF showed an increase from 180.2 ± 59.9 to 193.6 ± 60.8 mL·minute(-1)/100 g (P = .02) after beta blocker withdrawal. The segmental perfusion values were closely correlated (R(2) = 0.82) over the entire range of perfusion values. An essentially different interpretation after beta blocker discontinuation was found in two cases (10%). A beta blocker withdrawal induces an increase in adenosine MBF. In the majority of cases, MPI interpretation and decision making are independent of beta blocker intake. If a temporary beta blocker withdrawal before MPI is not possible or was not realized by the patient, it is appropriate to perform adenosine stress testing without loss of the essential MPI result.

  3. Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.

    Science.gov (United States)

    Sandau, Ursula S; Colino-Oliveira, Mariana; Jones, Abbie; Saleumvong, Bounmy; Coffman, Shayla Q; Liu, Long; Miranda-Lourenço, Catarina; Palminha, Cátia; Batalha, Vânia L; Xu, Yiming; Huo, Yuqing; Diógenes, Maria J; Sebastião, Ana M; Boison, Detlev

    2016-11-30

    Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adk(fl/fl) mice. These Adk(Δbrain) mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A1 receptor (A1R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A2A receptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2A receptor activity in Adk(Δbrain) mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency. A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures

  4. Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior.

    Science.gov (United States)

    Kamii, Hironori; Kurosawa, Ryo; Taoka, Naofumi; Shinohara, Fumiya; Minami, Masabumi; Kaneda, Katsuyuki

    2015-05-01

    The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  5. BdlA, DipA and Induced Dispersion Contribute to Acute Virulence and Chronic Persistence of Pseudomonas aeruginosa

    Science.gov (United States)

    Li, Yi; Petrova, Olga E.; Su, Shengchang; Lau, Gee W.; Panmanee, Warunya; Na, Renuka; Hassett, Daniel J.; Davies, David G.; Sauer, Karin

    2014-01-01

    The human pathogen Pseudomonas aeruginosa is capable of causing both acute and chronic infections. Differences in virulence are attributable to the mode of growth: bacteria growing planktonically cause acute infections, while bacteria growing in matrix-enclosed aggregates known as biofilms are associated with chronic, persistent infections. While the contribution of the planktonic and biofilm modes of growth to virulence is now widely accepted, little is known about the role of dispersion in virulence, the active process by which biofilm bacteria switch back to the planktonic mode of growth. Here, we demonstrate that P. aeruginosa dispersed cells display a virulence phenotype distinct from those of planktonic and biofilm cells. While the highest activity of cytotoxic and degradative enzymes capable of breaking down polymeric matrix components was detected in supernatants of planktonic cells, the enzymatic activity of dispersed cell supernatants was similar to that of biofilm supernatants. Supernatants of non-dispersing ΔbdlA biofilms were characterized by a lack of many of the degradative activities. Expression of genes contributing to the virulence of P. aeruginosa was nearly 30-fold reduced in biofilm cells relative to planktonic cells. Gene expression analysis indicated dispersed cells, while dispersing from a biofilm and returning to the single cell lifestyle, to be distinct from both biofilm and planktonic cells, with virulence transcript levels being reduced up to 150-fold compared to planktonic cells. In contrast, virulence gene transcript levels were significantly increased in non-dispersing ΔbdlA and ΔdipA biofilms compared to wild-type planktonic cells. Despite this, bdlA and dipA inactivation, resulting in an inability to disperse in vitro, correlated with reduced pathogenicity and competitiveness in cross-phylum acute virulence models. In contrast, bdlA inactivation rendered P. aeruginosa more persistent upon chronic colonization of the murine lung

  6. Persistent angina

    DEFF Research Database (Denmark)

    Jespersen, Lasse; Abildstrøm, Steen Z; Hvelplund, Anders

    2013-01-01

    AIMS: To evaluate persistent angina in stable angina pectoris with no obstructive coronary artery disease (CAD) compared to obstructive CAD and its relation to long-term anxiety, depression, quality of life (QOL), and physical functioning. METHODS AND RESULTS: We invited 357 patients (men = 191...

  7. Habit persistence

    DEFF Research Database (Denmark)

    Vinther Møller, Stig

    2009-01-01

    This paper uses an iterated GMM approach to estimate and test the consumption based habit persistence model of Campbell and Cochrane (1999) on the US stock market. The empirical evidence shows that the model is able to explain the size premium, but fails to explain the value premium. Further...

  8. Semibiotic Persistence

    Science.gov (United States)

    Prothmann, C.; Zauner, K.-P.

    From observation, we find four different strategies to successfully enable structures to persist over extended periods of time. If functionally relevant features are very large compared to the changes that can be effectuated by entropy, the functional structure itself has a high enough probability to erode only slowly over time. If the functionally relevant features are protected from environmental influence by sacrificial layers that absorb the impinging of the environment, deterioration can be avoided or slowed. Loss of functionality can be delayed, even for complex systems, by keeping alternate options for all required components available. Biological systems also apply information processing to actively counter the impact of entropy by mechanisms such as self-repair. The latter strategy increases the overall persistence of living systems and enables them to maintain a highly complex functional organisation during their lifetime and over generations. In contrast to the other strategies, information processing has only low material overhead. While at present engineered technology is far from achieving the self-repair of evolved systems, the semibiotic combination of biological components with conventionally engineered systems may open a path to long-term persistence of functional devices in harsh environments. We review nature's strategies for persistence, and consider early steps taken in the laboratory to import such capabilities into engineered architectures.

  9. Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations.

    Science.gov (United States)

    Antonioli, Luca; Blandizzi, Corrado; Csóka, Balázs; Pacher, Pál; Haskó, György

    2015-04-01

    Adenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A1, A2A, A2B and A1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of β-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of β cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine-adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications.

  10. Metabolite gene regulation: imidazole and imidazole derivatives which circumvent cyclic adenosine 3',5'-monophosphate in induction of the Escherichia coli L-arabinose operon.

    OpenAIRE

    Kline, E L; Bankaitis, V A; Brown, C S; Montefiori, D. C.

    1980-01-01

    Imidazole, histidine, histamine, histidinol phosphate, urocanic acid, or imidazolepropionic acid were shown to induce the L-arabinose operon in the absence of cyclic adenosine 3',5'-monophosphate. Induction was quantitated by measuring the increased differential rate of synthesis of L-arabinose isomerase in Escherichia coli strains which carried a deletion of the adenyl cyclase gene. The crp gene product (cyclic adenosine 3',5'-monophosphate receptor protein) and the araC gene product (P2) we...

  11. Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis histology, epididymal sperm count and induces sperm DNA fragmentation in mice.

    Science.gov (United States)

    Khezri, Abdolrahman; Lindeman, Birgitte; Krogenæs, Anette K; Berntsen, Hanne F; Zimmer, Karin E; Ropstad, Erik

    2017-08-15

    Persistent organic pollutants (POPs) are widespread throughout the environment and some are suspected to induce reproductive toxicity. As animals and humans are exposed to complex mixtures of POPs, it is reasonable to assess how such mixtures could interact with the reproductive system. Our aim is to investigate how maternal exposure to a mixture of 29 different persistent organic pollutants, formulated to mimic the relative POP levels in the food basket of the Scandinavian population, could alter reproductive endpoints. Female mice were exposed via feed from weaning, during pregnancy and lactation in 3 exposure groups (control (C), low (L) and high (H)). Testicular morphometric endpoints, epididymal sperm concentration and sperm DNA integrity were assessed in adult male offspring. We found that the number of tubules, proportion of tubule compartments and epididymal sperm concentration significantly decreased in both POP exposed groups. Epididymal sperm from both POP exposed groups showed increased DNA fragmentation. It is concluded that maternal exposure to a defined POP mixture relevant to human exposure can affect testicular development, sperm production and sperm chromatin integrity. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Indonesian fire activity and smoke pollution in 2015 show persistent nonlinear sensitivity to El Niño-induced drought

    Science.gov (United States)

    Field, Robert D.; van der Werf, Guido R.; Fanin, Thierry; Fetzer, Eric J.; Fuller, Ryan; Jethva, Hiren; Levy, Robert; Livesey, Nathaniel J.; Luo, Ming; Torres, Omar; Worden, Helen M.

    2016-01-01

    The 2015 fire season and related smoke pollution in Indonesia was more severe than the major 2006 episode, making it the most severe season observed by the NASA Earth Observing System satellites that go back to the early 2000s, namely active fire detections from the Terra and Aqua Moderate Resolution Imaging Spectroradiometers (MODIS), MODIS aerosol optical depth, Terra Measurement of Pollution in the Troposphere (MOPITT) carbon monoxide (CO), Aqua Atmospheric Infrared Sounder (AIRS) CO, Aura Ozone Monitoring Instrument (OMI) aerosol index, and Aura Microwave Limb Sounder (MLS) CO. The MLS CO in the upper troposphere showed a plume of pollution stretching from East Africa to the western Pacific Ocean that persisted for 2 mo. Longer-term records of airport visibility in Sumatra and Kalimantan show that 2015 ranked after 1997 and alongside 1991 and 1994 as among the worst episodes on record. Analysis of yearly dry season rainfall from the Tropical Rainfall Measurement Mission (TRMM) and rain gauges shows that, due to the continued use of fire to clear and prepare land on degraded peat, the Indonesian fire environment continues to have nonlinear sensitivity to dry conditions during prolonged periods with less than 4 mm/d of precipitation, and this sensitivity appears to have increased over Kalimantan. Without significant reforms in land use and the adoption of early warning triggers tied to precipitation forecasts, these intense fire episodes will reoccur during future droughts, usually associated with El Niño events. PMID:27482096

  13. Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment.

    Science.gov (United States)

    Jena, Prasant K; Sheng, Lili; Liu, Hui-Xin; Kalanetra, Karen M; Mirsoian, Annie; Murphy, William J; French, Samuel W; Krishnan, Viswanathan V; Mills, David A; Wan, Yu-Jui Yvonne

    2017-08-01

    Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. Indonesian Fire Activity and Smoke Pollution in 2015 Show Persistent Nonlinear Sensitivity to El Niño-induced Drought

    Science.gov (United States)

    Field, Robert D.; van der Werf, Guido R.; Fanin, Thierry; Fetzer, Eric; Fuller, Ryan; Jethva, Hiren; Levy, Robert; Livesey, Nathaniel; Luo, Ming; Torres, Omar; hide

    2016-01-01

    The 2015 fire season and related smoke pollution in Indonesia was more severe than the major 2006 episode, making it the most severe season observed by the NASA Earth Observing System satellites that go back to the early 2000s, namely active fire detections from the Terra and Aqua Moderate Resolution Imaging Spectroradiometers (MODIS), MODIS aerosol optical depth, Terra Measurement of Pollution in the Troposphere (MOPITT) carbon monoxide (CO), Aqua Atmospheric Infrared Sounder (AIRS) CO, Aura Ozone Monitoring Instrument (OMI) aerosol index, and Aura Microwave Limb Sounder (MLS) CO. The MLS CO in the upper troposphere showed a plume of pollution stretching from East Africa to the western Pacific Ocean that persisted for two months. Longer-term records of airport visibility in Sumatra and Kalimantan show that 2015 ranked after 1997 and alongside 1991 and 1994 as among the worst episodes on record. Analysis of yearly dry season rainfall from the Tropical Rainfall Measurement Mission (TRMM) and rain gauges shows that, due to the continued use of fire to clear and prepare land on degraded peat, the Indonesian fire environment continues to have non-linear sensitivity to dry conditions during prolonged periods with less than 4mmday of precipitation, and this sensitivity appears to have increased over Kalimantan. Without significant reforms in land use and the adoption of early warning triggers tied to precipitation forecasts, these intense fire episodes will re-occur during future droughts, usually associated with El Nio events.

  15. Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia

    Directory of Open Access Journals (Sweden)

    Selena Marini

    2017-08-01

    Full Text Available Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE, accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

  16. Specificity of the stress electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin.

    Science.gov (United States)

    Hart, C Y; Miller, T D; Hodge, D O; Gibbons, R J

    2000-12-01

    In patients taking digoxin, the exercise electrocardiogram has a lower specificity for detecting coronary artery disease. However, the effect of digoxin on adenosine-induced ST-segment depression is unknown. The purpose of this study was to evaluate the specificity of the electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin. Between May 1991 and September 1997, patients (n = 99) taking digoxin who underwent adenosine stress imaging with thallium-201 or technetium-99m sestamibi and coronary angiography within 3 months were retrospectively identified. Exclusion criteria included prior myocardial infarction, coronary artery angioplasty or bypass surgery, left bundle branch block, paced ventricular rhythm, or significant valvular disease. Twelve-lead electrocardiograms were visually interpreted at baseline, during adenosine infusion, and during the recovery period. The stress electrocardiogram was considered positive if there was > or =1 mm additional horizontal or downsloping ST-segment depression or elevation 0.08 seconds after the J-point compared with the baseline tracing. ST-segment depression and/or elevation occurred in 24 of 99 patients. There were only 2 false-positive stress electrocardiograms, yielding a specificity of 87% and positive predictive value of 92%. All 8 patients with > or =2 mm ST segment depression had multivessel disease by coronary angiography. ST-segment depression or elevation during adenosine myocardial perfusion imaging in patients taking digoxin is highly specific for coronary artery disease. Marked (> or =2 mm) ST-segment depression and/or ST-segment elevation is associated with a high likelihood of multivessel disease.

  17. The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain

    Science.gov (United States)

    Matyash, Marina; Zabiegalov, Oleksandr; Wendt, Stefan; Matyash, Vitali

    2017-01-01

    Microglial cells invade the brain as amoeboid precursors and acquire a highly ramified morphology in the postnatal brain. Microglia express all essential purinergic elements such as receptors, nucleoside transporters and ecto-enzymes, including CD39 (NTPDase1) and CD73 (5'-nucleotidase), which sequentially degrade extracellular ATP to adenosine. Here, we show that constitutive deletion of CD39 and CD73 or both caused an inhibition of the microglia ramified phenotype in the brain with a reduction in the length of processes, branching frequency and number of intersections with Sholl spheres. In vitro, unlike wild-type microglia, cd39-/- and cd73-/- microglial cells were less complex and did not respond to ATP with the transformation into a more ramified phenotype. In acute brain slices, wild-type microglia retracted approximately 50% of their processes within 15 min after slicing of the brain, and this phenomenon was augmented in cd39-/- mice; moreover, the elongation of microglial processes towards the source of ATP or towards a laser lesion was observed only in wild-type but not in cd39-/- microglia. An elevation of extracellular adenosine 1) by the inhibition of adenosine transport with dipyridamole, 2) by application of exogenous adenosine or 3) by degradation of endogenous ATP/ADP with apyrase enhanced spontaneous and ATP-induced ramification of cd39-/- microglia in acute brain slices and facilitated the transformation of cd39-/- and cd73-/- microglia into a ramified process-bearing phenotype in vitro. These data indicate that under normal physiological conditions, CD39 and CD73 nucleotidases together with equilibrative nucleoside transporter 1 (ENT1) control the fate of extracellular adenosine and thereby the ramification of microglial processes. PMID:28376099

  18. The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Marina Matyash

    Full Text Available Microglial cells invade the brain as amoeboid precursors and acquire a highly ramified morphology in the postnatal brain. Microglia express all essential purinergic elements such as receptors, nucleoside transporters and ecto-enzymes, including CD39 (NTPDase1 and CD73 (5'-nucleotidase, which sequentially degrade extracellular ATP to adenosine. Here, we show that constitutive deletion of CD39 and CD73 or both caused an inhibition of the microglia ramified phenotype in the brain with a reduction in the length of processes, branching frequency and number of intersections with Sholl spheres. In vitro, unlike wild-type microglia, cd39-/- and cd73-/- microglial cells were less complex and did not respond to ATP with the transformation into a more ramified phenotype. In acute brain slices, wild-type microglia retracted approximately 50% of their processes within 15 min after slicing of the brain, and this phenomenon was augmented in cd39-/- mice; moreover, the elongation of microglial processes towards the source of ATP or towards a laser lesion was observed only in wild-type but not in cd39-/- microglia. An elevation of extracellular adenosine 1 by the inhibition of adenosine transport with dipyridamole, 2 by application of exogenous adenosine or 3 by degradation of endogenous ATP/ADP with apyrase enhanced spontaneous and ATP-induced ramification of cd39-/- microglia in acute brain slices and facilitated the transformation of cd39-/- and cd73-/- microglia into a ramified process-bearing phenotype in vitro. These data indicate that under normal physiological conditions, CD39 and CD73 nucleotidases together with equilibrative nucleoside transporter 1 (ENT1 control the fate of extracellular adenosine and thereby the ramification of microglial processes.

  19. Adenosine, caffeine, and performance: from cognitive neuroscience of sleep to sleep pharmacogenetics.

    Science.gov (United States)

    Urry, Emily; Landolt, Hans-Peter

    2015-01-01

    An intricate interplay between circadian and sleep-wake homeostatic processes regulate cognitive performance on specific tasks, and individual differences in circadian preference and sleep pressure may contribute to individual differences in distinct neurocognitive functions. Attentional performance appears to be particularly sensitive to time of day modulations and the effects of sleep deprivation. Consistent with the notion that the neuromodulator, adenosine , plays an important role in regulating sleep pressure, pharmacologic and genetic data in animals and humans demonstrate that differences in adenosinergic tone affect sleepiness, arousal and vigilant attention in rested and sleep-deprived states. Caffeine--the most often consumed stimulant in the world--blocks adenosine receptors and normally attenuates the consequences of sleep deprivation on arousal, vigilance, and attention. Nevertheless, caffeine cannot substitute for sleep, and is virtually ineffective in mitigating the impact of severe sleep loss on higher-order cognitive functions. Thus, the available evidence suggests that adenosinergic mechanisms, in particular adenosine A2A receptor-mediated signal transduction, contribute to waking-induced impairments of attentional processes, whereas additional mechanisms must be involved in higher-order cognitive consequences of sleep deprivation. Future investigations should further clarify the exact types of cognitive processes affected by inappropriate sleep. This research will aid in the quest to better understand the role of different brain systems (e.g., adenosine and adenosine receptors) in regulating sleep, and sleep-related subjective state, and cognitive processes. Furthermore, it will provide more detail on the underlying mechanisms of the detrimental effects of extended wakefulness, as well as lead to the development of effective, evidence-based countermeasures against the health consequences of circadian misalignment and chronic sleep restriction.

  20. Cell proliferation and survival mechanisms underlying the abnormal persistence of follicular cysts in bovines with cystic ovarian disease induced by ACTH.

    Science.gov (United States)

    Salvetti, Natalia R; Stangaferro, Matías L; Palomar, Martín M; Alfaro, Natalia S; Rey, Florencia; Gimeno, Eduardo J; Ortega, Hugo H

    2010-10-01

    Cystic ovarian disease (COD) is an important cause of infertility that affects cattle. Alterations in the ovarian micro-environment of females with follicular cysts could alter the normal processes of proliferation and programmed cell death in ovarian cells. Thus, the objective in the present study was to evaluate apoptosis and proliferation in induced ovarian cystic follicles in cows to investigate the follicular persistence. Stage of estrous cycle was synchronized in 10 heifers and 5 were then subjected to the induction of COD by administration of ACTH. After the ovariectomy number of in situ apoptotic cells by TUNEL assay, active caspase-3, FAS/FASLG and members of the BCL2 family were compared by immunohistochemistry and multiplex PCR and cell proliferation by evaluation of Ki-67 protein and cyclin D1 and E mRNA. Significantly (pfollicular cysts and related diseases. Copyright © 2010 Elsevier B.V. All rights reserved.

  1. Delayed ischemic electrocortical suppression during rapid repeated cerebral ischemia and kainate-induced seizures in rat

    DEFF Research Database (Denmark)

    Ilie, Andrei; Spulber, Stefan; Avramescu, Sinziana

    2006-01-01

    Global cerebral ischemia induces, within seconds, suppression of spontaneous electrocortical activity, partly due to alterations in synaptic transmission. In vitro studies have found that repeated brief hypoxic episodes prolong the persistence of synaptic transmission due to weakened adenosine...... hydrate anaesthesia. Repeated episodes of 1 min of ischemia were induced by transiently clamping the carotid arteries in a 'four-vessel occlusion' model. We devised an automatic method of T(ES) estimation based on the decay of the root mean square of two-channel electrocorticographic recordings...... in vitro....

  2. Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice.

    Science.gov (United States)

    Pan, Jin; Li, Deguan; Xu, Yanfeng; Zhang, Junling; Wang, Yueying; Chen, Mengyi; Lin, Shuai; Huang, Lan; Chung, Eun Joo; Citrin, Deborah E; Wang, Yingying; Hauer-Jensen, Martin; Zhou, Daohong; Meng, Aimin

    2017-10-01

    Ionizing radiation (IR)-induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiation therapy. The goal of this study was to determine whether clearance of senescent cells with ABT-263, a senolytic drug that can selectively kill senescent cells, can reverse PF. C57BL/6J mice were exposed to a single dose of 17 Gy on the right side of the thorax. Sixteen weeks after IR, they were treated with 2 cycles of vehicle or ABT-263 (50 mg/kg per day for 5 days per cycle) by gavage. The effects of ABT-263 on IR-induced increases in senescent cells; elevation in the expression of selective inflammatory cytokines, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases; and the severity of the tissue injury and fibrosis in the irradiated lungs were evaluated 3 weeks after the last treatment, in comparison with the changes observed in the irradiated lungs before treatment or after vehicle treatment. At 16 weeks after exposure of C57BL/6 mice to a single dose of 17 Gy, thoracic irradiation resulted in persistent PF associated with a significant increase in senescent cells. Treatment of the irradiated mice with ABT-263 after persistent PF had developed reduced senescent cells and reversed the disease. To our knowledge, this is the first study to demonstrate that PF can be reversed by a senolytic drug such as ABT-263 after it becomes a progressive disease. Therefore, ABT-263 has the potential to be developed as a new treatment for PF. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma-Dependent Alterations of Marginal Zone Macrophages in the Spleen.

    Science.gov (United States)

    Machelart, Arnaud; Khadrawi, Abir; Demars, Aurore; Willemart, Kevin; De Trez, Carl; Letesson, Jean-Jacques; Muraille, Eric

    2017-11-01

    The spleen is known as an important filter for blood-borne pathogens that are trapped by specialized macrophages in the marginal zone (MZ): the CD209(+) MZ macrophages (MZMs) and the CD169(+) marginal metallophilic macrophages (MMMs). Acute systemic infection strongly impacts MZ populations and the location of T and B lymphocytes. This phenomenon has been linked to reduced chemokine secretion by stromal cells. Brucella spp. are the causative agent of brucellosis, a widespread zoonotic disease. Here, we used Brucella melitensis infection as a model to investigate the impact of chronic stealth infection on splenic MZ macrophage populations. During the late phase of Brucella infection, we observed a loss of both MZMs and MMMs, with a durable disappearance of MZMs, leading to a reduction of the ability of the spleen to take up soluble antigens, beads, and unrelated bacteria. This effect appears to be selective as every other lymphoid and myeloid population analyzed increased during infection, which was also observed following Brucella abortus and Brucella suis infection. Comparison of wild-type and deficient mice suggested that MZ macrophage population loss is dependent on interferon gamma (IFN-γ) receptor but independent of T cells or tumor necrosis factor alpha receptor 1 (TNF-αR1) signaling pathways and is not correlated to an alteration of CCL19, CCL21, and CXCL13 chemokine mRNA expression. Our results suggest that MZ macrophage populations are particularly sensitive to persistent low-level IFN-γ-mediated inflammation and that Brucella infection could reduce the ability of the spleen to perform certain MZM- and MMM-dependent tasks, such as antigen delivery to lymphocytes and control of systemic infection. Copyright © 2017 American Society for Microbiology.

  4. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

    Energy Technology Data Exchange (ETDEWEB)

    Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna [Department of Health Sciences, University of Genoa, Genoa (Italy); Steele, Vernon E. [National Cancer Institute (NCI), Rockville, MD (United States); De Flora, Silvio, E-mail: sdf@unige.it [Department of Health Sciences, University of Genoa, Genoa (Italy)

    2011-12-01

    Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m{sup 3} of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2 Prime -deoxyguanosine (8-oxodGuo) were measured by {sup 32}P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used.

  5. Persistent efficacy of doramectin injectable against artificially induced infections with Cooperia punctata and Dictyocaulus viviparus in cattle.

    Science.gov (United States)

    Stromberg, B E; Woodward, B W; Courtney, C H; Kunkle, W E; Johnson, E G; Zimmerman, G L; Zimmerman, L A; Marley, S E; Keller, D S; Conder, G A

    1999-06-01

    Three studies were conducted to evaluate the persistent efficacy of doramectin injectable solution against experimental challenges with infective larvae of Cooperia punctata and Dictyocaulus viviparus. In each study, four groups of ten randomly-assigned calves, negative for trichostrongyle-type eggs on fecal examination, were treated subcutaneously in the midline of the neck with saline (1 ml/50 kg) on Day 0 or doramectin (200 microg/kg = 1 ml/50 kg) on Day 0, 7, or 14. Two additional calves from the same pool of animals were randomly assigned as larval-viability monitors and received no treatment. On Days 14-28, approximately 1000 and 50 infective larvae of Cooperia spp. and D. viviparus, respectively, were administered daily by gavage to each animal in Groups T1-T4. On Day 28, the two larval-viability monitor calves were inoculated in a similar manner with a single dose of approximately 30000 and 2000 larvae of Cooperia spp. and D. viviparus, respectively. Equal numbers of calves from each treatment group were killed on Days 42-45, as well as the two viability monitor animals to enumerate worm numbers. A 2% or 5% aliquot of small intestinal contents and washings were examined for worm quantification and identification, while 100% of the lung recoveries were quantified and identified. For each study and across the three studies, geometric mean worm recoveries for each treatment group were calculated from the natural log transformed data (worm count + 1) and were used to estimate percentage reduction. In the three studies, doramectin injectable solution was 97.5% efficacious against lungworms for up to 28 days and was 99.8% efficacious in reducing infection resulting from challenge with infective larvae of C. punctata for at least 28 days post-treatment.

  6. LIGHT induces distinct signals to clear an AAV-expressed persistent antigen in the mouse liver and to induce liver inflammation.

    Directory of Open Access Journals (Sweden)

    Michael L Washburn

    2010-05-01

    Full Text Available Infection with adeno-associated virus (AAV vector with liver tropism leads to persistent expression of foreign antigens in the mouse liver, with no significant liver inflammation or pathology. This provides a model to investigate antigen persistence in the liver and strategies to modulate host immunity to reduce or clear the foreign antigen expressed from AAV vector in the liver.We showed that expressing LIGHT with an adenovirus vector (Ad in mice with established AAV in the liver led to clearance of the AAV. Ad-LIGHT enhanced CD8 effector T cells in the liver, correlated with liver inflammation. LTbetaR-Ig proteins blocked Ad-LIGHT in clearing AAV. Interestingly, in LTbetaR-null mice, Ad-LIGHT still cleared AAV but caused no significant liver inflammation.Our data suggest that LIGHT interaction with the LTbetaR plays a critical role in liver inflammation but is not required for LIGHT-mediated AAV clearance. These findings will shed light on developing novel immuno-therapeutics in treating people chronically infected with hepato-tropic viruses.

  7. Assessment of an innovative antimicrobial surface disinfectant in the operating room environment using adenosine triphosphate bioluminescence assay.

    Science.gov (United States)

    Lewis, Brian D; Spencer, Maureen; Rossi, Peter J; Lee, Cheong J; Brown, Kellie R; Malinowski, Michael; Seabrook, Gary R; Edmiston, Charles E

    2015-03-01

    Terminal cleaning in the operating room is a critical step in preventing the transmission of health care-associated pathogens. The persistent disinfectant activity of a novel isopropyl alcohol/organofunctional silane solution (ISO) was evaluated in 4 operating rooms after terminal cleaning. Adenosine triphosphate bioluminescence documented a significant difference (P contamination on IOS-treated surfaces compared with controls. Further studies are warranted to validate the persistent disinfectant activity of ISO within selective health care settings. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  8. Interferon-γ induced by in vitro re-stimulation of CD4+ T-cells correlates with in vivo FMD vaccine induced protection of cattle against disease and persistent infection.

    Science.gov (United States)

    Oh, Yooni; Fleming, Lucy; Statham, Bob; Hamblin, Pip; Barnett, Paul; Paton, David J; Park, Jong-Hyeon; Joo, Yi Seok; Parida, Satya

    2012-01-01

    The immune defense against FMDV has been correlated to the antibody mediated component. However, there are occasions when some animals with high virus neutralising (VN) antibody are not protected following challenge and some with low neutralising antibody which do not succumb to disease. The importance of cell mediated immunity in clinical protection is less clear and so we investigated the source and production of interferon-gamma (IFN-γ) in re-stimulated whole blood of FMDV immunized cattle and its correlation to vaccine induced protection and FMDV persistence. We were able to show a positive correlation between IFN-γ response and vaccine induced protection as well as reduction of long term persistence of FMD virus. When combining this IFN-γ response in re-stimulated blood with virus neutralizing antibody titer in serum on the day of challenge, a better correlation of vaccine-induced protection with IFN-γ and VN antibody was predicted. Our investigations also showed that CD4+ T-cells are the major proliferating phenotype and IFN-γ producing cells.

  9. A2B adenosine receptor contributes to penile erection via PI3K/AKT signaling cascade-mediated eNOS activation

    Science.gov (United States)

    Wen, Jiaming; Grenz, Almut; Zhang, Yujin; Dai, Yingbo; Kellems, Rodney E.; Blackburn, Michael R.; Eltzschig, Holger K.; Xia, Yang

    2011-01-01

    Normal penile erection is under the control of multiple factors and signaling pathways. Although adenosine signaling is implicated in normal and abnormal penile erection, the exact role and the underlying mechanism for adenosine signaling in penile physiology remain elusive. Here we report that shear stress leads to increased adenosine release from endothelial cells. Subsequently, we determined that ecto-5′-nucleotidase (CD73) is a key enzyme required for the production of elevated adenosine from ATP released by shear-stressed endothelial cells. Mechanistically, we demonstrate that shear stress-mediated elevated adenosine functions through the adenosine A2B receptor (A2BR) to activate the PI3K/AKT signaling cascade and subsequent increased endothelial nitric oxide synthase (eNOS) phosphorylation. These in vitro studies led us to discover further that adenosine was induced during sustained penile erection and contributes to PI3K/AKT activation and subsequent eNOS phosphorylation via A2BR signaling in intact animal. Finally, we demonstrate that lowering adenosine in wild-type mice or genetic deletion of A2BR in mutant mice significantly attenuated PI3K/AKT activation, eNOS phosphorylation, and subsequent impaired penile erection featured with the reduction of ratio of maximal intracavernosal pressure to systemic arterial pressure from 0.49 ± 0.03 to 0.41 ± 0.05 and 0.38 ± 0.04, respectively (both Ppenile erection via PI3K/AKT-dependent eNOS activation. These studies suggest that this signaling pathway may be a novel therapeutic target for erectile disorders.—Wen, J., Grenz, A., Zhang, Y., Dai, Y., Kellems, R. E., Blackburn, M. R., Eltzschig, H. K., Xia, Y. A2B adenosine receptor contributes to penile erection via PI3K/AKT signaling cascade-mediated eNOS activation. PMID:21566208

  10. Partial agonism of theophylline-7-riboside on adenosine receptors

    NARCIS (Netherlands)

    IJzerman, A. P.; van der Wenden, E. M.; von Frijtag Drabbe Künzel, J. K.; Mathôt, R. A.; Danhof, M.; Borea, P. A.; Varani, K.

    1994-01-01

    Theophylline-7-riboside was evaluated as a partial agonist for rat adenosine receptors. Radioligand binding experiments were performed on both A1 and A2a adenosine receptors, using several methodologies to discriminate between agonists and antagonists. Mainly from thermodynamic data it was concluded

  11. Adenosine deaminase activities and fasting blood glucose in obesity ...

    African Journals Online (AJOL)

    Background: A complex relationship seems to exist between adenosine deaminase (ADA) and insulin in obesity. Through its effect on adenosine, the enzyme can modulate the action of insulin and affect blood glucose while the administration of insulin is said to decrease the activities of the enzyme. Aim: To investigate the ...

  12. Endogenous adenosine curtails lipopolysaccharide-stimulated tumour necrosis factor synthesis

    NARCIS (Netherlands)

    Eigler, A; Greten, T F; Sinha, B; Haslberger, C; Sullivan, G W; Endres, S

    Recent studies have demonstrated the inhibitory effect of exogenous adenosine on TNF production. During inflammation endogenous adenosine levels are elevated and may be one of several anti-inflammatory mediators that reduce TNF synthesis. In the present study the authors investigated this role of

  13. Adenosine Deaminase, (ADA) level in leprosy | Ogbu | International ...

    African Journals Online (AJOL)

    Background: Adenosine deaminase (ADA) is involved in and the catabolism of toxic de-oxynucleotides (5) and modulation of insulin action. Although its activities in leprosy have been measured, its characteristics have not been reported. Objective: To determine adenosine deaminase activities in leprosy and possible ...

  14. Motorcycle muffler-induced "pillion burns" of distal leg: a persistent problem of increasing proportions in Indian settings.

    Science.gov (United States)

    Masoodi, Zulqarnain; Ahmad, Imran; Haq, Ansarul

    2013-09-01

    Motorcycles have emerged as a viable mode of transport for millions in the third world. Mufflers (exhaust pipes in some countries) remain a potential "Achilles' tendon" or a designing flaw in the mass-produced, economical motorcycles of the developing world. Owing to the excessive temperature they attain while the hot exhaust gases pass through them and their proximity to the lower limbs while riding a motorcycle, they can lead to burns of varying nature in the lower leg. This is a descriptive retrospective study of muffler-induced lower leg burns treated at our hospital from January 2008 to December 2012. Various parameters including history, exact mode of injury, age, sex, degree and location of burn, treatment modalities, and other relevant circumstantial/logistical factors associated with such injuries were noted; data were tabulated and statistically arranged to gain an insight into this problem. Possible interventions that may help avoid such injuries are also briefly mentioned. Certain findings that are quite distinct to the findings of a few earlier studies carried out on this topic (in the developed world) remain the highlight of our study. The typical muffler-induced burns in the Indian setting occur almost exclusively in the male pillions, most of the times in the right leg in an area near the medial malleolus, and are usually second degree and respond to conservative management. Prompt treatment can circumvent much of the dreaded complications. Preemptive efforts in designing of motorcycles and following traffic regulations at the individual level remain the key to prevention.

  15. EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

    Directory of Open Access Journals (Sweden)

    Honami Takada

    Full Text Available Epstein-Barr virus (EBV has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV. However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

  16. Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet

    Science.gov (United States)

    Asplin, John R.; Culbertson, Christopher D.; Granja, Ignacio; Krieger, Nancy S.; Bushinsky, David A.

    2014-01-01

    Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients. PMID:24573387

  17. EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

    Science.gov (United States)

    Takada, Honami; Imadome, Ken-Ichi; Shibayama, Haruna; Yoshimori, Mayumi; Wang, Ludan; Saitoh, Yasunori; Uota, Shin; Yamaoka, Shoji; Koyama, Takatoshi; Shimizu, Norio; Yamamoto, Kouhei; Fujiwara, Shigeyoshi; Miura, Osamu; Arai, Ayako

    2017-01-01

    Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

  18. Chronic tooth pulp inflammation induces persistent expression of phosphorylated ERK (pERK) and phosphorylated p38 (pp38) in trigeminal subnucleus caudalis

    Science.gov (United States)

    Worsley, M.A.; Allen, C.E.; Billinton, A.; King, A.E.; Boissonade, F.M.

    2014-01-01

    Background Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase are transiently phosphorylated (activated) in the spinal cord and trigeminal nucleus by acute noxious stimuli. Acute stimulation of dental pulp induces short-lived ERK activation in trigeminal subnucleus caudalis (Vc), and p38 inhibition attenuates short-term sensitization in Vc induced by acute pulpal stimulation. We have developed a model to study central changes following chronic inflammation of dental pulp that induces long-term sensitization. Here, we examine the effects of chronic inflammation and acute stimulation on the expression of phosphorylated ERK (pERK), phosphorylated p38 (pp38) and Fos in Vc. Results Chronic inflammation alone induced bilateral expression of pERK and pp38 in Vc, but did not induce Fos expression. Stimulation of both non-inflamed and inflamed pulps significantly increased pERK and pp38 bilaterally; expression was greatest in inflamed, stimulated animals, and was similar following 10-min and 60-min stimulation. Stimulation for 60 min, but not 10 min, induced Fos in ipsilateral Vc; Fos expression was significantly greater in inflamed, stimulated animals. pERK was present in both neurons and astrocytes; pp38 was present in neurons and other non-neuronal, non-astrocytic cell types. Conclusions This study provides the first demonstration that chronic inflammation of tooth pulp induces persistent bilateral activation of ERK and p38 within Vc, and that this activation is further increased by acute stimulation. This altered activity in intracellular signaling is likely to be linked to the sensitization that is seen in our animal model and in patients with pulpitis. Our data indicate that pERK and pp38 are more accurate markers of central change than Fos expression. In our model, localization of pERK and pp38 within specific cell types differs from that seen following acute stimulation. This may indicate specific roles for different cell types in

  19. Serum uncouples elevation of cyclic adenosine monophosphate concentration from cyclic adenosine monophosphate dependent morphological changes exhibited by cultured pituicytes.

    Science.gov (United States)

    Ramsell, K D; Cobbett, P

    1997-04-18

    Cultured pituicytes (neurohypophysial astrocytes) are normally flat amorphous cells when incubated (90 min) in a HEPES balanced salt solution (HBSS) but become stellate when incubated in HBSS supplemented with forskolin. This stellation process is attenuated by serum (0.5% vol/vol). The experiments described here were designed to determine whether serum attenuates stellation by modulation of the intracellular cyclic adenosine monophosphate (cAMP) concentration or some other mechanism. It was observed that the effect of serum on forskolin-induced stellation was not affected by pertussis toxin (100 ng/ml) and that serum also inhibited stellation induced by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX; 100 microM). Further, serum inhibited stellation induced by the membrane permeable cAMP analog 8-bromo cAMP (150 microM). These results indicate that although an increase of intracellular cAMP concentration is necessary for pituicyte stellation, an increase of intracellular cAMP concentration may be decoupled from stellation.

  20. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Pospisil, M.; Hofer, M.; Netikova, J.; Hola, J.; Vacek, A. [Academy of Sciences of the Czech Republic, Inst. of Biophysics, Brno (Czech Republic); Znojil, V.; Vacha, J. [Masaryk Univ., Medical Faculty, Brno (Czech Republic)

    1998-03-01

    The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of {sup 60}Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in combination, were evaluated. The drugs were injected to mice in a 4-d treatment regimen starting on d 3 after irradiation and the haematopoietic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cells, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combination therapy occurred in the post-irradiation recovery phase which is dependent on the repopulation of haematopoietic stem cells. This was indicated by the significant elevation of counts of granulocyte-macrophage progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood. These effects suggest that the repopulation potential of the combination therapy lies in a common multi-lineage cell population. The results of this study implicate the promising possibility to enhance the curative effects of G-CSF under conditions of myelosuppressive state induced by radiation exposure. (au) 43 refs.

  1. Buprenorphine Disrupts Sleep and Decreases Adenosine Levels in Sleep-Regulating Brain Regions of Sprague Dawley Rat

    Science.gov (United States)

    Gauthier, Elizabeth A.; Guzick, Sarah E.; Brummett, Chad M.; Baghdoyan, Helen A.; Lydic, Ralph

    2011-01-01

    Background Buprenorphine, a partial μ opioid receptor agonist and κ opioid receptor antagonist, is an effective analgesic. The effects of buprenorphine on sleep have not been well characterized. This study tested the hypothesis that an antinociceptive dose of buprenorphine decreases sleep and decreases adenosine levels in regions of the basal forebrain and pontine brain stem that regulate sleep. Methods Male Sprague Dawley rats were implanted with intravenous catheters and electrodes for recording states of wakefulness and sleep. Buprenorphine (1 mg/kg) was administered systemically via an indwelling catheter and sleep/wake states were recorded for 24 h. In additional rats buprenorphine was delivered by microdialysis to the pontine reticular formation and substantia innominata of the basal forebrain while simultaneously measuring adenosine. Results An antinociceptive dose of buprenorphine caused a significant increase in wakefulness (25.2%) and a decrease in both nonrapid eye movement sleep (−22.1%) and rapid eye movement sleep (−3.1%). Buprenorphine also increased electroencephalographic delta power during nonrapid eye movement sleep. Coadministration of the sedative/hypnotic eszopiclone diminished the buprenorphine-induced decrease in sleep. Dialysis delivery of buprenorphine significantly decreased adenosine levels in the pontine reticular formation (−14.6%) and substantia innominata (−36.7%). Intravenous administration of buprenorphine significantly decreased (−20%) adenosine in the substantia innominata. Conclusions Buprenorphine significantly increased time spent awake, decreased nonrapid eye movement sleep, and increased latency to sleep onset. These disruptions in sleep architecture were mitigated by coadministration of the nonbenzodiazepine sedative/hypnotic eszopiclone. The buprenorphine-induced decrease in adenosine levels in basal forebrain and pontine reticular formation is consistent with the interpretation that decreasing adenosine in

  2. A High-Affinity Adenosine Kinase from Anopheles Gambiae

    Energy Technology Data Exchange (ETDEWEB)

    M Cassera; M Ho; E Merino; E Burgos; A Rinaldo-Matthis; S Almo; V Schramm

    2011-12-31

    Genome analysis revealed a mosquito orthologue of adenosine kinase in Anopheles gambiae (AgAK; the most important vector for the transmission of Plasmodium falciparum in Africa). P. falciparum are purine auxotrophs and do not express an adenosine kinase but rely on their hosts for purines. AgAK was kinetically characterized and found to have the highest affinity for adenosine (K{sub m} = 8.1 nM) of any known adenosine kinase. AgAK is specific for adenosine at the nucleoside site, but several nucleotide triphosphate phosphoryl donors are tolerated. The AgAK crystal structure with a bound bisubstrate analogue Ap{sub 4}A (2.0 {angstrom} resolution) reveals interactions for adenosine and ATP and the geometry for phosphoryl transfer. The polyphosphate charge is partly neutralized by a bound Mg{sup 2+} ion and an ion pair to a catalytic site Arg. The AgAK structure consists of a large catalytic core in a three-layer {alpha}/{beta}/{alpha} sandwich, and a small cap domain in contact with adenosine. The specificity and tight binding for adenosine arise from hydrogen bond interactions of Asn14, Leu16, Leu40, Leu133, Leu168, Phe168, and Thr171 and the backbone of Ile39 and Phe168 with the adenine ring as well as through hydrogen bond interactions between Asp18, Gly64, and Asn68 and the ribosyl 2'- and 3'-hydroxyl groups. The structure is more similar to that of human adenosine kinase (48% identical) than to that of AK from Toxoplasma gondii (31% identical). With this extraordinary affinity for AgAK, adenosine is efficiently captured and converted to AMP at near the diffusion limit, suggesting an important role for this enzyme in the maintenance of the adenine nucleotide pool. mRNA analysis verifies that AgAK transcripts are produced in the adult insects.

  3. Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain.

    Science.gov (United States)

    Yang, Fan; Yang, Yan; Wang, Yan; Yang, Fei; Li, Chun-Li; Wang, Xiao-Liang; Li, Zhen; Chen, Jun

    2015-10-25

    To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.

  4. Blast exposure causes early and persistent aberrant phospho- and cleaved-tau expression in a murine model of mild blast-induced traumatic brain injury.

    Science.gov (United States)

    Huber, Bertrand R; Meabon, James S; Martin, Tobin J; Mourad, Pierre D; Bennett, Raymond; Kraemer, Brian C; Cernak, Ibolja; Petrie, Eric C; Emery, Michael J; Swenson, Erik R; Mayer, Cynthia; Mehic, Edin; Peskind, Elaine R; Cook, David G

    2013-01-01

    Mild traumatic brain injury (mTBI) is considered the 'signature injury' of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phospho- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes.

  5. Theacrine: A purine alkaloid from Camellia assamica var. kucha with a hypnotic property via the adenosine system.

    Science.gov (United States)

    Qiao, Haoyi; Ye, Xiansheng; Bai, Xiaoyu; He, Jun; Li, Tingli; Zhang, Jia; Zhang, Weiku; Xu, Jiekun

    2017-10-17

    Theacrine (l,3,7,9-tetramethyluric acid), a purine alkaloid from Camellia assamica var. kucha, has diverse pharmacological properties, including sedative and hypnotic activities, anti-inflammatory and analgesic activities, antidepressant effects, and a protective effect against stress-provoked liver damage. The present study aims to investigate the possible mechanism of the hypnotic activity of theacrine. The results revealed that theacrine significantly enhanced pentobarbital-induced sleep at a dose of 3.0mg/kg (i.g.) in mice. Sleep parameter analysis by EEG and EMG showed that theacrine obviously shortened wake time and increased NREM sleep time and that theacrine almost had no effect on REM sleep. Meanwhile, theacrine markedly attenuated caffeine (a nonselective antagonist of adenosine receptor)-induced insomnia. In pretreatment with the adenosine A 1 receptor antagonist DPCPX and the A 2A receptor antagonist SCH 58261, theacrine significantly reversed the decrease in sleeping time in pentobarbital-treated mice. In addition, theacrine also markedly increased the adenosine content in the hippocampus of rats. These results suggested that theacrine might mediate the adenosine system to augment pentobarbital-induced sleep. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Anemone toxin (ATX II)-induced increase in persistent sodium current: effects on the firing properties of rat neocortical pyramidal neurones

    Science.gov (United States)

    Mantegazza, Massimo; Franceschetti, Silvana; Avanzini, Giuliano

    1998-01-01

    The experiments were performed on sensorimotor cortex using current-clamp intracellular recordings in layer V pyramidal neurones and whole-cell voltage-clamp recordings in dissociated pyramidal neurones. The intracellularly recorded neurones were classified on the basis of their firing characteristics as intrinsically bursting (IB) and regular spiking (RS). The RS neurones were further subdivided into adapting (RSAD) or non-adapting (RSNA), depending on the presence or absence of spike frequency adaptation. Since burst firing in neocortical pyramidal neurones has previously been suggested to depend on the persistent fraction of Na+ current (INa,p), pharmacological manipulations with drugs affecting INa inactivation have been employed. ATX II, a toxin derived from Anemonia sulcata, selectively inhibited INa fast inactivation in dissociated neurones. In current-clamp experiments on neocortical slices, ATX II enhanced the naturally occurring burst firing in IB neurones and revealed the ability of RSNA neurones to discharge in bursts, whereas in RSAD neurones it increased firing frequency, without inducing burst discharges. During the ATX II effect, in all the three neuronal subclasses, episodes of a metastable condition occurred, characterized by long-lasting depolarizing shifts, triggered by action potentials, which were attributed to a peak in the toxin-induced inhibition of INa inactivation. The ATX II effect on IB and RSNA neurones was compared with that induced by veratridine and iodoacetamide. Veratridine induced a small increase in the INa and a large shift to the left in the voltage dependence of INa activation. Accordingly, its major effect on firing characteristics was the induction of prolonged tonic discharges, associated with burst facilitation less pronounced than that induced by ATX II. The alkylating agent iodoacetamide was able to induce a selective small increase in the INa,p, with a similar but less pronounced effect than ATX II on firing behaviour

  7. In vivo expansion, persistence, and function of peptide vaccine-induced CD8 T cells occur independently of CD4 T cells.

    Science.gov (United States)

    Assudani, Deepak; Cho, Hyun-Il; DeVito, Nicholas; Bradley, Norma; Celis, Esteban

    2008-12-01

    Significant efforts are being devoted toward the development of effective therapeutic vaccines against cancer. Specifically, well-characterized subunit vaccines, which are designed to generate antitumor cytotoxic CD8 T-cell responses. Because CD4 T cells participate at various stages of CD8 T-cell responses, it is important to study the role of CD4 T cells in the induction and persistence of antitumor CD8 T-cell responses by these vaccines. Recent evidence points to the requirement of CD4 T cells for the long-term persistence of memory CD8 T cells, which in the case of cancer immunotherapy would be critical for the prevention of tumor recurrences. The purpose of the present study was to assess whether CD4 T cells are necessary for the generation and maintenance of antigen-specific CD8 T cells induced by subunit (peptide or DNA) vaccines. We have used a vaccination strategy that combines synthetic peptides representing CD8 T-cell epitopes, a costimulatory anti-CD40 antibody and a Toll-like receptor agonist (TriVax) to generate large numbers of antigen-specific CD8 T-cell responses. Our results show that the rate of decline (clonal contraction) of the antigen-specific CD8 T cells and their functional state is not affected by the presence or absence of CD4 T cells throughout the immune response generated by TriVax. We believe that these results bear importance for the design of effective vaccination strategies against cancer.

  8. In Vivo Expansion, Persistence and Function of Peptide Vaccine-Induced CD8 T Cells Occurs Independently of CD4 T Cells

    Science.gov (United States)

    Assudani, Deepak; Cho, Hyun-Il; DeVito, Nicholas; Bradley, Norma; Celis, Esteban

    2008-01-01

    Significant efforts are being devoted towards the development of effective therapeutic vaccines against cancer. Specifically, well-characterized subunit vaccines, which are designed to generate anti-tumor cytotoxic CD8 T cell responses. Since CD4 T cells participate at various stages of CD8 T cell responses, it is important to study the role of CD4 T cells in the induction and persistence of anti-tumor CD8 T cell responses by these vaccines. Recent evidence points to the requirement of CD4 T cells for the long-term persistence of memory CD8 T cells, which in the case of cancer immunotherapy would be critical for the prevention of tumor recurrences. The purpose of the present study was to assess whether CD4 T cells are necessary for the generation and maintenance of antigen-specific CD8 T cells induced by subunit (peptide or DNA) vaccines. We have utilized a vaccination strategy that combines synthetic peptides representing CD8 T cell epitopes, a costimulatory anti-CD40 antibody and a Toll-like receptor agonist (TriVax) to generate large numbers of antigen-specific CD8 T cell responses. Our results show that the rate of decline (clonal contraction) of the antigen-specific CD8 T cells and their functional state is not affected by the presence or absence of CD4 T cells throughout the immune response generated by TriVax. We believe that these results bear importance for the design of effective vaccination strategies against cancer. PMID:19047170

  9. Anti-hyperalgesic activity of the aqueous and methanol extracts of the leaves of Pittosporum mannii Hook on CFA-induced persistent inflammatory pain.

    Science.gov (United States)

    Wandji, Bibiane Aimée; Bomba, Francis Desire Tatsinkou; Nkeng-Efouet, Pepin Alango; Piegang, Basile Nganmegne; Kamanyi, Albert; Nguelefack, Télesphore Benoît

    2017-08-29

    Previous study showed that aqueous (AEPM) and methanol (MEPM) extracts from the leaves of Pittosporum mannii have analgesic effects in acute pain models. The present study evaluates the acute and chronic anti-hypernociceptive and anti-inflammatory effects of AEPM and MEPM in a model of persistent inflammatory pain. The third day after induction of inflammatory pain by subplantar injection of 100 µL of CFA in Wistar rats, AEPM and MEPM were administered orally (75, 150 and 300 mg/kg/day) and their anti-hyperalgesic and anti-inflammatory effects were follow in acute (1-24 h) and chronic (for 14 days) treatments. At the end of the chronic treatment, oxidative stress and liver parameters were assessed. Effects of plant extracts were also evaluated on nociception induced by Phorbol 12-Myristate 13-Acetate (PMA) and 8-bromo 3',5'-cAMP (8-Br-cAMP) in mice. AEPM and MEPM significantly reversed the mechanical hyperalgesia caused by CFA in acute and chronic treatment. Moreover, AEPM and MEPM also significantly reduced the nociception caused by PMA (60%) and 8-Br-cAMP (87%). Nevertheless, AEPM and MEPM failed to inhibit the paw edema caused by CFA. Plant extracts significantly reduced the nitric oxide content in the spinal cord and the plasmatic concentration of alanine aminotransferase. MEPM also significantly increased the glutathione content in the spinal cord. AEPM and MEPM given orally are effective in inhibiting mechanical hyperalgesia in persistent inflammatory pain caused by CFA. Their mechanisms of action seem to involve an interaction with PKC, PKA and nitric oxide pathways. These extracts might be devoid of hepatotoxic effects.

  10. Intracellular Adenosine Triphosphate Deprivation through Lanthanide-Doped Nanoparticles.

    Science.gov (United States)

    Tian, Jing; Zeng, Xiao; Xie, Xiaoji; Han, Sanyang; Liew, Oi-Wah; Chen, Yei-Tsung; Wang, Lianhui; Liu, Xiaogang

    2015-05-27

    Growing interest in lanthanide-doped nanoparticles for biological and medical uses has brought particular attention to their safety concerns. However, the intrinsic toxicity of this new class of optical nanomaterials in biological systems has not been fully evaluated. In this work, we systematically evaluate the long-term cytotoxicity of lanthanide-doped nanoparticles (NaGdF4 and NaYF4) to HeLa cells by monitoring cell viability (mitochondrial activity), adenosine triphosphate (ATP) level, and cell membrane integrity (lactate dehydrogenase release), respectively. Importantly, we find that ligand-free lanthanide-doped nanoparticles induce intracellular ATP deprivation of HeLa cells, resulting in a significant decrease in cell viability after exposure for 7 days. We attribute the particle-induced cell death to two distinct cell death pathways, autophagy and apoptosis, which are primarily mediated via the interaction between the nanoparticle and the phosphate group of cellular ATP. The understanding gained from the investigation of cytotoxicity associated with lanthanide-doped nanoparticles provides keen insights into the safe use of these nanoparticles in biological systems.

  11. Excessive penile norepinephrine level underlies impaired erectile function in adenosine A1 receptor deficient mice.

    Science.gov (United States)

    Ning, Chen; Qi, Lin; Wen, Jiaming; Zhang, Yujin; Zhang, Weiru; Wang, Wei; Blackburn, Michael; Kellems, Rodney; Xia, Yang

    2012-10-01

    Penile erection is a complex neurovascular physiological event controlled by multiple factors and signaling pathways. A considerable amount of evidence indicates that adenosine plays a significant role in cavernosal smooth muscle relaxation. However, the specific role of adenosine and its receptors in erectile physiology and pathology is not fully understood. To determine the role of the adenosine A1 receptor (ADORA1) in penile erection. Adenosine A1 receptor deficient (Adora1-/-) mice and aged-matched wild-type (WT) mice were utilized. We evaluated the in vivo erectile function by measuring the intracavernosal pressure (ICP) in response to cavernous nerve stimulation (CNS). Enzyme-linked immunosorbent assay was used to measure the norepinephrine (NE) plasma concentration in the corpus cavernosum and systemic circulation. We also evaluated the myosin light chain phosphorylation (p-MLC) in penile tissue pre- and post-CNS. The main outcome measurement of this research was the evaluation of in vivo erectile response to CNS by measuring the ICP in Adora1-/- mice and WT mice and to identify the localization and specific neuron types of ADORA1 expression by dual immunostaining and immunofluorescence co-localization. In vivo, both the ratio of CNS-induced Maximum ICP to mean arterial pressure and CNS-induced slope in Adora1-/- mice were significantly lower than WT mice. At the cellular level in penile tissue, we determined that ADORA1 was highly abundant in neuronal cells. During penile erection, Adora1-/- mice exhibited a higher level of NE plasma concentration in the penis than WT mice. And WT mice had a significantly greater reduction in p-MLC compared to Adora1-/- mice. Our results show that ADORA1 is enriched on neuron cells where it functions to control NE release. Activation of this receptor during penile erection results in reduced NE release and reduced cavernosal smooth muscle contraction, therefore facilitating penile erection. © 2012 International Society for

  12. Persistent Modelling

    DEFF Research Database (Denmark)

    2012-01-01

    The relationship between representation and the represented is examined here through the notion of persistent modelling. This notion is not novel to the activity of architectural design if it is considered as describing a continued active and iterative engagement with design concerns – an evident....... It also provides critical insight into the use of contemporary modelling tools and methods, together with an examination of the implications their use has within the territories of architectural design, realisation and experience....... on this subject, this book makes essential reading for anyone considering new ways of thinking about architecture. In drawing upon both historical and contemporary perspectives this book provides evidence of the ways in which relations between representation and the represented continue to be reconsidered...

  13. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Zhumur Ghosh

    Full Text Available Human induced pluripotent stem cells (hiPSCs generated by de-differentiation of adult somatic cells offer potential solutions for the ethical issues surrounding human embryonic stem cells (hESCs, as well as their immunologic rejection after cellular transplantation. However, although hiPSCs have been described as "embryonic stem cell-like", these cells have a distinct gene expression pattern compared to hESCs, making incomplete reprogramming a potential pitfall. It is unclear to what degree the difference in tissue of origin may contribute to these gene expression differences. To answer these important questions, a careful transcriptional profiling analysis is necessary to investigate the exact reprogramming state of hiPSCs, as well as analysis of the impression, if any, of the tissue of origin on the resulting hiPSCs. In this study, we compare the gene profiles of hiPSCs derived from fetal fibroblasts, neonatal fibroblasts, adipose stem cells, and keratinocytes to their corresponding donor cells and hESCs. Our analysis elucidates the overall degree of reprogramming within each hiPSC line, as well as the "distance" between each hiPSC line and its donor cell. We further identify genes that have a similar mode of regulation in hiPSCs and their corresponding donor cells compared to hESCs, allowing us to specify core sets of donor genes that continue to be expressed in each hiPSC line. We report that residual gene expression of the donor cell type contributes significantly to the differences among hiPSCs and hESCs, and adds to the incompleteness in reprogramming. Specifically, our analysis reveals that fetal fibroblast-derived hiPSCs are closer to hESCs, followed by adipose, neonatal fibroblast, and keratinocyte-derived hiPSCs.

  14. Persistence of Th17/Tc17 Cell Expression upon Smoking Cessation in Mice with Cigarette Smoke-Induced Emphysema

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    Min-Chao Duan

    2013-01-01

    Full Text Available Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD, a disease caused predominantly by cigarette smoking. Smoking cessation is the only intervention in the management of COPD. However, even after cessation, the airway inflammation may be present. In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation. Morphological changes were evaluated by mean linear intercepts (Lm and destructive index (DI. The frequencies of CD8+IL-17+(Tc17 and CD4+IL-17+(Th17 cells, the mRNA levels of ROR gamma and IL-17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed. Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation. In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions. More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17. These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema. Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema.

  15. Coronary vasodilator reserve persists despite tachycardia and myocardial ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Bristow, J.D.; McFalls, E.O.; Anselone, C.G.; Pantely, G.A. (Oregon Health Sciences Univ., Portland (USA))

    1987-08-01

    During myocardial ischemia, the authors tested whether coronary blood flow measured with radioactive microspheres labeled with {sup 141}Ce, {sup 51}Cr, {sup 103}Ru, and {sup 95}Nb would increase in response to tachycardia thereby employing known coronary flow reserve. The authors instrumented the left anterior descending (LAD) coronary circulation in anesthetized pigs and performed three sets of experiments while coronary pressure was controlled and several heart rate increases were produced. (1) Pacing-induced tachycardia at normal LAD pressure was characterized by increased LAD flow and myocardial oxygen consumption, without production of lactate. (2) Tachycardia at a mean LAD pressure of 38 mmHg was associated with a lower, fixed coronary flow and oxygen consumption. Lactate was produced at all rates and local myocardial function declined progressively. (3) Coronary flow at low LAD pressure doubled during tachycardia when intracoronary adenosine was added. The increase to the subepicardium was >100%, whereas subendocardial flow changed little. There is persistent coronary flow reserve during moderately severe myocardial ischemia, even when metabolic demand is increased by tachycardia. This reserve, however, is predominantly subepicardial.

  16. Exposure of insect cells to ionising radiation in vivo induces persistent phosphorylation of a H2AX homologue (H2AvB).

    Science.gov (United States)

    Siddiqui, Mohammad S; Filomeni, Erika; François, Maxime; Collins, Samuel R; Cooper, Tamara; Glatz, Richard V; Taylor, Phillip W; Fenech, Michael; Leifert, Wayne R

    2013-09-01

    The response of eukaryotic cells to ionising radiation (IR)-induced double-strand DNA breaks is highly conserved and involves a DNA repair mechanism characterised by the early phosphorylation of histone protein H2AX (producing the active form γH2AX). Although the expression of an induced γH2AX variant has been detected in Drosophila melanogaster, the expression and radiation response of a γH2AX homologue has not been reported in economically important fruit flies. We use Bactrocera tryoni (Diptera: Tephritidae, Queensland fruit fly or 'Q-fly') to investigate this response with a view to developing molecular assays to detect/quantify exposure of fruit flies to IR and consequent DNA damage. Deep sequencing confirmed the presence of a H2AX homologue that we have termed H2AvB (i.e. variant Bactrocera) and has an identical sequence to a histone reported from the human disease vector Glossina morsitans. A linear dose-response of γH2AvB (0-400 Gy IR) was observed in whole Q-fly pupal lysates 24h post-IR and was detected at doses as low as 20 Gy. γH2AvB signal peaked at ~20min after IR exposure and at 24h post-IR the signal remained elevated but declined significantly by 5 days. Persistent and dose-dependent γH2AvB signal could be detected and quantified either by western blot or by laser scanning cytometry up to 17 days post-IR exposure in histone extracts or isolated nuclei from adult Q-flies (irradiated as pupae). We conclude that IR exposure in Q-fly leads to persistent γH2AvB signals (over a period of days) that can easily be detected by western blot or quantitative immunofluorescence techniques. These approaches have potential as the basis for assays for detection and quantification of prior IR exposure in pest fruit flies.

  17. Regulation of aggregate size and pattern by adenosine and caffeine in cellular slime molds

    Science.gov (United States)

    2012-01-01

    Background Multicellularity in cellular slime molds is achieved by aggregation of several hundreds to thousands of cells. In the model slime mold Dictyostelium discoideum, adenosine is known to increase the aggregate size and its antagonist caffeine reduces the aggregate size. However, it is not clear if the actions of adenosine and caffeine are evolutionarily conserved among other slime molds known to use structurally unrelated chemoattractants. We have examined how the known factors affecting aggregate size are modulated by adenosine and caffeine. Result Adenosine and caffeine induced the formation of large and small aggregates respectively, in evolutionarily distinct slime molds known to use diverse chemoattractants for their aggregation. Due to its genetic tractability, we chose D. discoideum to further investigate the factors affecting aggregate size. The changes in aggregate size are caused by the effect of the compounds on several parameters such as cell number and size, cell-cell adhesion, cAMP signal relay and cell counting mechanisms. While some of the effects of these two compounds are opposite to each other, interestingly, both compounds increase the intracellular glucose level and strengthen cell-cell adhesion. These compounds also inhibit the synthesis of cAMP phosphodiesterase (PdsA), weakening the relay of extracellular cAMP signal. Adenosine as well as caffeine rescue mutants impaired in stream formation (pde4- and pdiA-) and colony size (smlA- and ctnA-) and restore their parental aggregate size. Conclusion Adenosine increased the cell division timings thereby making large number of cells available for aggregation and also it marginally increased the cell size contributing to large aggregate size. Reduced cell division rates and decreased cell size in the presence of caffeine makes the aggregates smaller than controls. Both the compounds altered the speed of the chemotactic amoebae causing a variation in aggregate size. Our data strongly suggests

  18. Regulation of aggregate size and pattern by adenosine and caffeine in cellular slime molds

    Directory of Open Access Journals (Sweden)

    Jaiswal Pundrik

    2012-01-01

    Full Text Available Abstract Background Multicellularity in cellular slime molds is achieved by aggregation of several hundreds to thousands of cells. In the model slime mold Dictyostelium discoideum, adenosine is known to increase the aggregate size and its antagonist caffeine reduces the aggregate size. However, it is not clear if the actions of adenosine and caffeine are evolutionarily conserved among other slime molds known to use structurally unrelated chemoattractants. We have examined how the known factors affecting aggregate size are modulated by adenosine and caffeine. Result Adenosine and caffeine induced the formation of large and small aggregates respectively, in evolutionarily distinct slime molds known to use diverse chemoattractants for their aggregation. Due to its genetic tractability, we chose D. discoideum to further investigate the factors affecting aggregate size. The changes in aggregate size are caused by the effect of the compounds on several parameters such as cell number and size, cell-cell adhesion, cAMP signal relay and cell counting mechanisms. While some of the effects of these two compounds are opposite to each other, interestingly, both compounds increase the intracellular glucose level and strengthen cell-cell adhesion. These compounds also inhibit the synthesis of cAMP phosphodiesterase (PdsA, weakening the relay of extracellular cAMP signal. Adenosine as well as caffeine rescue mutants impaired in stream formation (pde4- and pdiA- and colony size (smlA- and ctnA- and restore their parental aggregate size. Conclusion Adenosine increased the cell division timings thereby making large number of cells available for aggregation and also it marginally increased the cell size contributing to large aggregate size. Reduced cell division rates and decreased cell size in the presence of caffeine makes the aggregates smaller than controls. Both the compounds altered the speed of the chemotactic amoebae causing a variation in aggregate size

  19. Persistent Hiccups Following Stapedectomy

    Directory of Open Access Journals (Sweden)

    Aidonis I

    2010-10-01

    Full Text Available Objective: We report a case of a 37 year-old man who developed persistent hiccups after elective stapedectomy. Method and Results: The diagnostic approach is discussed as well as the non-pharmacologic and pharmacologic treatments and overall management. The aim is to stress that there is a variety of potential factors that can induce hiccups perioperatively and in cases like this a step by step approach must be taken. Conclusion: Persistent hiccups are very rare following stapedectomy, control of them is crucial for the successful outcome. The trigger may be more than one factors and the good response to treatment may be due to dealing successfully with more than one thing.

  20. Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression

    Science.gov (United States)

    Ning, Chen; Wen, Jiaming; Zhang, Yujin; Dai, Yingbo; Wang, Wei; Zhang, Weiru; Qi, Lin; Grenz, Almut; Eltzschig, Holger K.; Blackburn, Michael R.; Kellems, Rodney E.; Xia, Yang

    2014-01-01

    Priapism is featured with prolonged and painful penile erection and is prevalent among males with sickle cell disease (SCD). The disorder is a dangerous urological and hematological emergency since it is associated with ischemic tissue damage and erectile disability. Here we report that phosphodiesterase-5 (PDE5) gene expression and PDE activity is significantly reduced in penile tissues of two independent priapic models: SCD mice and adenosine deaminase (ADA)-deficient mice. Moreover, using ADA enzyme therapy to reduce adenosine or a specific antagonist to block A2B adenosine receptor (ADORA2B) signaling, we successfully attenuated priapism in both ADA−/− and SCD mice by restoring penile PDE5 gene expression to normal levels. This finding led us to further discover that excess adenosine signaling via ADORA2B activation directly reduces PDE5 gene expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. Overall, we reveal that excess adenosine-mediated ADORA2B signaling underlies reduced penile PDE activity by decreasing PDE5 gene expression in a HIF-1α-dependent manner and provide new insight for the pathogenesis of priapism and novel therapies for the disease.—Ning, C., Wen, J., Zhang, Y., Dai, Y., Wang, W., Zhang, W., Qi, L., Grenz, A., Eltzschig, H. K., Blackburn, M. R., Kellems, R. E., Xia, Y. Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression. PMID:24614760

  1. Semi-automated extraction of Deviation Indexes (DI from satellite Persistent Scatterers time series: tests on sedimentary volcanism and tectonically-induced motions

    Directory of Open Access Journals (Sweden)

    F. Cigna

    2012-11-01

    Full Text Available We develop a methodology based on satellite Persistent Scatterers (PS time series and aimed to calculate two indexes which are capable to depict the deviation from a deformation model defined a priori. Through a simple mathematical approach, these indexes reproduce the visual process of identification of trend deviations that is usually performed manually by the radar-interpreter, and guide the prioritization of further interpretation for those areas recording significant variations within their motion history. First tests on semi-automated extraction of the Deviation Indexes (DI from RADARSAT-1 PS data available over Southern Italy allowed the quantification of tectonically-induced land motions which occurred in February 2005 within the town of Naro, and also the clear recognition of the precursors to mud volcano eruptions which occurred in August 2008 in the village of St. Barbara. For these areas, the information level brought by the DI increases and adds onto that of other PS parameters, such as yearly velocity, standard deviation and coherence. Factors exerting influence on the DI are critically tackled within the discussions, together with the analysis of the potentials of these indexes for monitoring and warning activities of geohazards.

  2. Revaccination with a 23-Valent Pneumococcal Polysaccharide Vaccine Induces Elevated and Persistent Functional Antibody Responses in Adults Aged ⩾65 Years

    National Research Council Canada - National Science Library

    Susan B. Manoff; Charles Liss; Michael J. Caulfield; Rocio D. Marchese; Jeffrey Silber; John Boslego; Sandra Romero-Steiner; Gowrisankar Rajam; Nina E. Glass; Cynthia G. Whitney; George M. Carlone

    2010-01-01

    .... We compared revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23) with primary vaccination for eliciting initial and persistent functional antibody responses. Methods. Subjects aged...

  3. Adenosine Preconditioning versus Ischemic Preconditioning in Patients undergoing Off-Pump Coronary Artery Bypass (OPCAB

    Directory of Open Access Journals (Sweden)

    SeyedKhalil Forouzannia

    2015-10-01

    Full Text Available Background: During off-pump coronary artery bypass (OPCAB, the heart is subjected to ischemic and reperfusion injury. Preconditioning is a mechanism that permits the heart to tolerate myocardial ischemia. The aim of this study was to compare the effects of Adenosine preconditioning with ischemic preconditioning on the global ejection fraction (EF in patients undergoing OPCAB.Methods: In this single-blind, randomized controlled trial, sixty patients undergoing OPCAB were allocated into three equally-numbered groups through simple randomization: Adenosine group, ischemic group, and control group. The patients in the Adenosine group received an infusion of Adenosine. In the ischemic group, ischemic preconditioning was induced by the temporary occlusion of the left anterior descending coronary artery twice for a 2-minute period, followed by 3-minute reperfusion before bypass grafting of the first coronary vessel. The control group received an intravenous infusion of 0.9% saline. Blood samples at different times were sent for the measurement of creatine kinase isoenzyme MB (CK-MB and cardiac troponin I (cTnI. We also recorded electrocardiographic indices and clinical parameters, including postoperative use of inotropic drugs and preoperative and postoperative EF.Results: History of myocardial infarction, hyperlipidemia, diabetes mellitus, kidney disease, preoperative arrhythmias, and utilization of postoperative inotrope was the same between the three groups. The incidence of postoperative arrhythmias was not significant between the three groups. Also, there were no significant differences in preoperative and postoperative EF and the serum levels of enzymes (cTnI and CK-MB between the groups.Conclusion: Based on the findings of this study, there was no significant difference in the postoperative EF between the groups. Although the incidence of arrhythmias was higher in the ischemic preconditioning group than in the other groups, the difference

  4. Adenosine reduces reactive oxygen species and interleukin-8 production by Trichomonas vaginalis-stimulated neutrophils.

    Science.gov (United States)

    Frasson, Amanda Piccoli; Menezes, Camila Braz; Goelzer, Gustavo Krumel; Gnoatto, Simone Cristina Baggio; Garcia, Solange Cristina; Tasca, Tiana

    2017-12-01

    Trichomonas vaginalis is a flagellated protozoan that affects the human urogenital tract causing 276.4 million new infections a year. The parasite elicits a vaginal mucosal infiltration of immune cells, especially neutrophils which are considered to be primarily responsible for cytological change observed at the infection site as well as the major contributor in the inflammatory response against the parasite. Extracellular nucleotides and their nucleosides are signaling compounds involved in several biological processes, including inflammation and immune responses. Once in the extracellular space, the nucleotides and nucleosides can directly activate the purinergic receptors. Herein, we investigated the involvement of purinergic signaling on the production of reactive oxygen species (ROS) and cytokines by T. vaginalis-stimulated neutrophils. Parasites were able to induce an increase in ROS and IL-8 levels while they did not promote IL-6 secretion or neutrophil elastase activity. Adenine and guanine nucleotides or nucleosides were not able to modulate ROS and cytokine production; however, when T. vaginalis-stimulated neutrophils were incubated with adenosine and adenosine deaminase inhibitor, the levels of ROS and IL-8 were significantly reduced. These immunosuppressive effects were probably a response to the higher bioavailability of adenosine found in the supernatant as result of inhibition of enzyme activity. The involvement of P1 receptors was investigated by immunofluorescence and A1 receptor was the most abundant. Our data show that the influence of purinergic signaling, specifically those effects associated with adenosine accumulation, on the modulation of production of proinflammatory mediators by T. vaginalis-stimulated neutrophils contribute to the understanding of immunological aspects of trichomoniasis.

  5. Expression of Drosophila adenosine deaminase in immune cells during inflammatory response.

    Directory of Open Access Journals (Sweden)

    Milena Novakova

    Full Text Available Extra-cellular adenosine is an important regulator of inflammatory responses. It is generated from released ATP by a cascade of ectoenzymes and degraded by adenosine deaminase (ADA. There are two types of enzymes with ADA activity: ADA1 and ADGF/ADA2. ADA2 activity originates from macrophages and dendritic cells and is associated with inflammatory responses in humans and rats. Drosophila possesses a family of six ADGF proteins with ADGF-A being the main regulator of extra-cellular adenosine during larval stages. Herein we present the generation of a GFP reporter for ADGF-A expression by a precise replacement of the ADGF-A coding sequence with GFP using homologous recombination. We show that the reporter is specifically expressed in aggregating hemocytes (Drosophila immune cells forming melanotic capsules; a characteristic of inflammatory response. Our vital reporter thus confirms ADA expression in sites of inflammation in vivo and demonstrates that the requirement for ADA activity during inflammatory response is evolutionary conserved from insects to vertebrates. Our results also suggest that ADA activity is achieved specifically within sites of inflammation by an uncharacterized post-transcriptional regulation based mechanism. Utilizing various mutants that induce melanotic capsule formation and also a real immune challenge provided by parasitic wasps, we show that the acute expression of the ADGF-A protein is not driven by one specific signaling cascade but is rather associated with the behavior of immune cells during the general inflammatory response. Connecting the exclusive expression of ADGF-A within sites of inflammation, as presented here, with the release of energy stores when the ADGF-A activity is absent, suggests that extra-cellular adenosine may function as a signal for energy allocation during immune response and that ADGF-A/ADA2 expression in such sites of inflammation may regulate this role.

  6. Adenosine A2B receptor blockade slows growth of bladder and breast tumors.

    Science.gov (United States)

    Cekic, Caglar; Sag, Duygu; Li, Yuesheng; Theodorescu, Dan; Strieter, Robert M; Linden, Joel

    2012-01-01

    The accumulation of high levels of adenosine in tumors activates A(2A) and A(2B) receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of adenosine A(2A) receptors (A(2A)ARs) has been reported to activate antitumor T cells, stimulate dendritic cell (DC) function, and inhibit angiogenesis. In this study, we evaluated the effects of intermittent intratumor injection of a nonselective adenosine receptor antagonist, aminophylline (AMO; theophylline ethylenediamine) and, for the first time to our knowledge, a selective A(2B)AR antagonist, ATL801. AMO and ATL801 slowed the growth of MB49 bladder and 4T1 breast tumors in syngeneic mice and reduced by 85% metastasizes of breast cancer cells from mammary fat to lung. Based on experiments with A(2A)AR(-/-) or adenosine A(2B) receptor(-/-) mice, the effect of AMO injection was unexpectedly attributed to A(2B)AR and not to A(2A)AR blockade. AMO and ATL801 significantly increased tumor levels of IFN-γ and the IFN-inducible chemokine CXCL10, which is a ligand for CXCR3. This was associated with an increase in activated tumor-infiltrating CXCR3(+) T cells and a decrease in endothelial cell precursors within tumors. Tumor growth inhibition by AMO or ATL801 was eliminated in CXCR3(-/-) mice and RAG1(-/-) mice that lack mature T cells. In RAG1(-/-) mice, A(2B)AR deletion enhanced CD86 expression on CD11b(-) DCs. Bone marrow chimera experiments demonstrated that CXCR3 and A(2B)AR expression on bone marrow cells is required for the antitumor effects of AMO. The data suggest that blockade of A(2B)ARs enhances DC activation and CXCR3-dependent antitumor responses.

  7. Inhibition of uptake of adenosine into human blood platelets

    NARCIS (Netherlands)

    Lips, J.P.M.; Sixma, J.J.; Trieschnigg, A.C.

    1980-01-01

    Adenosine transport into human blood platelets is mediated by two independent systems with different affinities. Both systems transport only purine nucleosides and no pyrimidine nucleosides. In experiments with differently substituted purine nucleosides, purines and analogues, differences in carrier

  8. Adenosin deaminasa como molecula coestimuladora y marcador de inmunidad celular

    National Research Council Canada - National Science Library

    Perez-Aguilar, Mary Carmen; Goncalves, Loredana; Ibarra, Alba; Bonfante-Cabarcas, Rafael

    2010-01-01

    La adenosin deaminasa (ADA), es una enzima del metabolismo de las purinas que ha sido objeto de mucho interes debido a que el defecto congenito de esta enzima causa el sindrome de inmunodeficiencia combinada severa...

  9. Addition of adenosine to hyperbaric bupivacaine in spinal ...

    African Journals Online (AJOL)

    2011-04-17

    effects, ... efficacy of adenosine on postoperative pain when administered with hyperbaric bupivacaine. The aim of our present study ... lower back, or ingestion of methylxanthine-containing food or beverages within 12 hours of ...

  10. Adenosine-deaminase (ADA activity in Psoriasis (A Preliminary Study

    Directory of Open Access Journals (Sweden)

    S D Chaudhry

    1988-01-01

    Full Text Available Study of adenosine-deaminase activity ′in 23 patients hav-mg psoriasis compared with an equal number of healthy controls revealed significantly high ADA-activity in the psotiatic patients.

  11. Vasoconstrictor and vasodilator effects of adenosine in the kidney

    DEFF Research Database (Denmark)

    Hansen, Pernille B; Schnermann, Jurgen

    2003-01-01

    Adenosine is an ATP breakdown product that in most vessels causes vasodilatation and that contributes to the metabolic control of organ perfusion, i.e., to the match between oxygen demand and oxygen delivery. In the renal vasculature, in contrast, adenosine can produce vasoconstriction, a response...... that has been suggested to be an organ-specific version of metabolic control designed to restrict organ perfusion when transport work increases. However, the vasoconstriction elicited by an intravenous infusion of adenosine is only short lasting, being replaced within 1-2 min by vasodilatation. It appears...... that the steady-state response to the increase of plasma adenosine levels above normal resulting from the infusion is global renal vasorelaxation that is the result of A2AR activation in most parts of the renal vasculature, including larger renal arteries, juxtamedullary afferent arterioles, efferent arterioles...

  12. Ethanol induces apoptotic death of developing beta-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-beta1-linked apoptotic signaling.

    Science.gov (United States)

    Chen, Cui Ping; Kuhn, Peter; Chaturvedi, Kirti; Boyadjieva, Nadka; Sarkar, Dipak K

    2006-03-01

    The mechanism by which ethanol induces beta-endorphin (beta-EP) neuronal death during the developmental period was determined using fetal rat hypothalamic cells in primary cultures. The addition of ethanol to hypothalamic cell cultures stimulated apoptotic cell death of beta-EP neurons by increasing caspase-3 activity. Ethanol lowered the levels of adenylyl cyclase (AC)7 mRNA, AC8 mRNA, and/or cAMP in hypothalamic cells, whereas a cAMP analog blocked the apoptotic action of ethanol on beta-EP neurons. The AC inhibitor dideoxyadenosine (DDA) increased cell apoptosis and reduced the number of beta-EP neurons, and it potentiated the apoptotic action of ethanol on these neurons. beta-EP neurons in hypothalamic cultures showed immunoreactivity to transforming growth factor-beta1 (TGF-beta1) protein. Ethanol and DDA increased TGF-beta1 production and/or release from hypothalamic cells. A cAMP analog blocked the activation by ethanol of TGF-beta1 in these cells. TGF-beta1 increased apoptosis of beta-EP neurons, but it did not potentiate the action of ethanol or DDA actions on these neurons. TGF-beta1 neutralizing antibody blocked the apoptotic action of ethanol on beta-EP neurons. Determination of TGF-beta1-controlled cell apoptosis regulatory gene levels in hypothalamic cell cultures and in isolated beta-EP neurons indicated that ethanol, TGF-beta1, and DDA similarly alter the expression of these genes in these cells. These data suggest that ethanol increases beta-EP neuronal death during the developmental period by cellular mechanisms involving, at least partly, the suppression of cAMP production and activation of TGF-beta1-linked apoptotic signaling.

  13. Cell Type-Specific Effects of Adenosine on Cortical Neurons

    Science.gov (United States)

    van Aerde, Karlijn I.; Qi, Guanxiao; Feldmeyer, Dirk

    2015-01-01

    The neuromodulator adenosine is widely considered to be a key regulator of sleep homeostasis and an indicator of sleep need. Although the effect of adenosine on subcortical areas has been previously described, the effects on cortical neurons have not been addressed systematically to date. To that purpose, we performed in vitro whole-cell patch-clamp recordings and biocytin staining of pyramidal neurons and interneurons throughout all layers of rat prefrontal and somatosensory cortex, followed by morphological analysis. We found that adenosine, via the A1 receptor, exerts differential effects depending on neuronal cell type and laminar location. Interneurons and pyramidal neurons in layer 2 and a subpopulation of layer 3 pyramidal neurons that displayed regular spiking were insensitive to adenosine application, whereas other pyramidal cells in layers 3–6 were hyperpolarized (range 1.2–10.8 mV). Broad tufted pyramidal neurons with little spike adaptation showed a small adenosine response, whereas slender tufted pyramidal neurons with substantial adaptation showed a bigger response. These studies of the action of adenosine at the postsynaptic level may contribute to the understanding of the changes in cortical circuit functioning that take place between sleep and awakening. PMID:24108800

  14. Low-dose adenosine stress echocardiography: Detection of myocardial viability

    Directory of Open Access Journals (Sweden)

    Nedeljkovic Milan

    2003-06-01

    Full Text Available Abstract Objective The aim of this study was to evaluate the diagnostic potential of low-dose adenosine stress echocardiography in detection of myocardial viability. Background Vasodilation through low dose dipyridamole infusion may recruit contractile reserve by increasing coronary flow or by increasing levels of endogenous adenosine. Methods Forty-three patients with resting dyssynergy, due to previous myocardial infarction, underwent low-dose adenosine (80, 100, 110 mcg/kg/min in 3 minutes intervals echocardiography test. Gold standard for myocardial viability was improvement in systolic thickening of dyssinergic segments of ≥ 1 grade at follow-up. Coronary angiography was done in 41 pts. Twenty-seven patients were revascularized and 16 were medically treated. Echocardiographic follow up data (12 ± 2 months were available in 24 revascularized patients. Results Wall motion score index improved from rest 1.55 ± 0.30 to 1.33 ± 0.26 at low-dose adenosine (p Conclusion Low-dose adenosine stress echocardiography test has high diagnostic potential for detection of myocardial viability in the group of patients with left ventricle dysfunction due to previous myocardial infarction. Low dose adenosine stress echocardiography may be adequate alternative to low-dose dobutamine test for evaluation of myocardial viability.

  15. Monitoring landslide-induced deformation with TerraSAR-X Persistent Scatterer Interferometry (PSI): Gimigliano case study in Calabria Region (Italy)

    Science.gov (United States)

    Bianchini, S.; Cigna, F.; Del Ventisette, C.; Moretti, S.; Casagli, N.

    2012-04-01

    Landslide phenomena represent a major geological hazard worldwide, threatening human lives and settlements, especially in urban areas where the potential socio-economic losses and damages are stronger because of the higher value of the element at risk exposure and vulnerability. The impact of these natural disasters in highly populated and vulnerable areas can be reduced or prevented by performing a proper detection of such ground movements, in order to support an appropriate urban planning. Mapping and monitoring of active landslides and vulnerable slopes can greatly benefit from radar satellite data analysis, due to the great cost-benefits ratio, non-invasiveness and high precision of remote sensing techniques. This work illustrates the potential of Persistent Scatterer Interferometry (PSI) using X-band SAR (Synthetic Aperture Radar) data for a detailed detection and characterization of landslide ground displacements at local scale. PSI analysis is a powerful tool for mapping and monitoring slow surface displacements, just particularly in built-up and urbanized areas where many radar benchmarks (the PS, Persistent Scatterers) are retrieved. We exploit X-band radar data acquired from the German satellite TerraSAR-X on Gimigliano site located in Calabria Region (Italy). The use of TerraSAR-X imagery significantly improves the level of detail of the analysis and extends the applicability of space-borne SAR interferometry to faster ground movements, due to higher spatial resolutions (up to 1 m), higher PS targets density and shorter repeat cycles (11 days) of X-band satellites with respect to the medium resolution SAR sensors, such as ERS1/2, ENVISAT and RADARSAT1/2. 27 SAR scenes were acquired over a 116.9 Km2 extended area from the satellite TerraSAR-X in Spotlight mode, along descending orbits, with a look angle of 34°, from November 2010 to October 2011. The images were processed by e-GEOS with the Persistent Scatterers Pairs (PSP) technique, providing the

  16. Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury.

    Science.gov (United States)

    Hasan, Djo; Blankman, Paul; Nieman, Gary F

    2017-09-01

    Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

  17. The 1976C>T polymorphism in the adenosine A2A receptor gene does not affect the vasodilator response to adenosine in humans in vivo

    NARCIS (Netherlands)

    Riksen, N.P.; Franke, B.; Broek, P. van den; Smits, P.; Rongen, G.A.

    2007-01-01

    The 1976C>T polymorphism in the adenosine A2A receptor gene (ADORA2A) modulates the psychological response to administration of the adenosine receptor antagonist caffeine. We quantified the vascular response to adenosine and caffeine to determine the relevance of this variant allele in the

  18. Single bolus intravenous regadenoson injection versus central venous infusion of adenosine for maximum coronary hyperaemia in fractional flow reserve measurement.

    Science.gov (United States)

    van Nunen, Lokien X; Lenders, Guy D; Schampaert, Stéphanie; van 't Veer, Marcel; Wijnbergen, Inge; Brueren, Guus R G; Tonino, Pim A L; Pijls, Nico H J

    2015-12-01

    The aim of this study was to compare the hyperaemic effect of a single bolus regadenoson injection to a central venous adenosine infusion for inducing hyperaemia in the measurement of fractional flow reserve (FFR). One hundred patients scheduled for FFR measurement were enrolled. FFR was first measured by IV adenosine (140 µg/kg/min), thereafter by IV bolus regadenoson injection (400 µg), followed by another measurement by IV adenosine and bolus injection of regadenoson. The regadenoson injections were randomised to central or peripheral intravenous. Hyperaemic response and duration of steady state maximum hyperaemia were studied, central versus peripheral venous regadenoson injections were compared, and safety and reproducibility of repeated injections were investigated. Mean age was 66±8 years, 75% of the patients were male. The target stenosis was located in the LM, LAD, LCX, and RCA in 7%, 54%, 20% and 19%, respectively. There was no difference in FFR measured by adenosine or by regadenoson (ΔFFR=0.00±0.01, r=0.994, pregadenoson was variable (10-600 s). No serious side effects of either drug were observed. Maximum coronary hyperaemia can be achieved easily, rapidly, and safely by one single intravenous bolus of regadenoson administered either centrally or peripherally. Repeated regadenoson injections are safe. The hyperaemic plateau is variable. Clinical Trial Registration: http://clinicaltrials.gov/ct2/ show/study/NCT01809743?term=NCT01809743&rank=1 (ClinicalTrials.gov Identifier: NCT01809743).

  19. Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

    Directory of Open Access Journals (Sweden)

    Sama Adnan

    2016-12-01

    Full Text Available Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

  20. Early-life stress induces persistent alterationsin 5-HT1Areceptor and serotonin transporter mRNA expression in the adultrat brain.

    Directory of Open Access Journals (Sweden)

    Javier A. Bravo

    2014-04-01

    Full Text Available Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT mRNA expression in brain areas involved in the control of emotions, memory and fear as well as in regions controlling the central serotonergic tone.To test this, Sprague-Dawley rats were subjected to MS for 3h daily during post-natal days 2-12. As control, age matched rats were not separated (NS from their dams. When animals reached adulthood (11-13 weeks brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN and SERT in the DRN was analyzed through in-situ hybridisation.Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats.These results suggest that early-life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood.

  1. Neurobehavioral deficits and brain oxidative stress induced by chronic low dose exposure of persistent organic pollutants mixture in adult female rat.

    Science.gov (United States)

    Lahouel, Asma; Kebieche, Mohamed; Lakroun, Zohra; Rouabhi, Rachid; Fetoui, Hamadi; Chtourou, Yassine; Djamila, Zama; Soulimani, Rachid

    2016-10-01

    Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6 μg/kg), chlorpyrifos (5.2 μg/kg), naphthalene (0.023 μg/kg) and benzopyrane (0.002 μg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats.

  2. Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist.

    Science.gov (United States)

    Eastwood, Paul; Esteve, Cristina; González, Jacob; Fonquerna, Silvia; Aiguadé, Josep; Carranco, Inés; Doménech, Teresa; Aparici, Mònica; Miralpeix, Montserrat; Albertí, Joan; Córdoba, Mónica; Fernández, Raquel; Pont, Mercè; Godessart, Núria; Prats, Neus; Loza, María Isabel; Cadavid, María Isabel; Nueda, Arsenio; Vidal, Bernat

    2011-03-10

    The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.

  3. Skeletal muscle expresses the extracellular cyclic AMP–adenosine pathway

    Science.gov (United States)

    Chiavegatti, T; Costa, V L; Araújo, M S; Godinho, R O

    2007-01-01

    Background and purpose: cAMP is a key intracellular signalling molecule that regulates multiple processes of the vertebrate skeletal muscle. We have shown that cAMP can be actively pumped out from the skeletal muscle cell. Since in other tissues, cAMP efflux had been associated with extracellular generation of adenosine, in the present study we have assessed the fate of interstitial cAMP and the existence of an extracellular cAMP-adenosine signalling pathway in skeletal muscle. Experimental approach: cAMP efflux and/or its extracellular degradation were analysed by incubating rat cultured skeletal muscle with exogenous cAMP, forskolin or isoprenaline. cAMP and its metabolites were quantified by radioassay or HPLC, respectively. Key results: Incubation of cells with exogenous cAMP was followed by interstitial accumulation of 5′-AMP and adenosine, a phenomenon inhibited by selective inhibitors of ecto-phosphodiesterase (DPSPX) and ecto-nucleotidase (AMPCP). Activation of adenylyl cyclase (AC) in cultured cells with forskolin or isoprenaline increased cAMP efflux and extracellular generation of 5′-AMP and adenosine. Extracellular cAMP-adenosine pathway was also observed after direct and receptor-dependent stimulation of AC in rat extensor muscle ex vivo. These events were attenuated by probenecid, an inhibitor of ATP binding cassette family transporters. Conclusions and implications: Our results show the existence of an extracellular biochemical cascade that converts cAMP into adenosine. The functional relevance of this extracellular signalling system may involve a feedback modulation of cellular response initiated by several G protein-coupled receptor ligands, amplifying cAMP influence to a paracrine mode, through its metabolite, adenosine. PMID:18157164

  4. Partial Adenosine A1 Agonist in Heart Failure.

    Science.gov (United States)

    Dinh, Wilfried; Albrecht-Küpper, Barbara; Gheorghiade, Mihai; Voors, Adriaan A; van der Laan, Michael; Sabbah, Hani N

    2017-01-01

    Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.

  5. Role of adipokinetic hormone and adenosine in the anti-stress response in Drosophila melanogaster.

    Science.gov (United States)

    Zemanová, Milada; Stašková, Tereza; Kodrík, Dalibor

    2016-01-01

    The role of adipokinetic hormone (AKH) and adenosine in the anti-stress response was studied in Drosophila melanogaster larvae and adults carrying a mutation in the Akh gene (Akh(1)), the adenosine receptor gene (AdoR(1)), or in both of these genes (Akh(1) AdoR(1) double mutant). Stress was induced by starvation or by the addition of an oxidative stressor paraquat (PQ) to food. Mortality tests revealed that the Akh(1) mutant was the most resistant to starvation, while the AdoR(1) mutant was the most sensitive. Conversely, the Akh(1) AdoR(1) double mutant was more sensitive to PQ toxicity than either of the single mutants. Administration of PQ significantly increased the Drome-AKH level in w(1118) and AdoR(1) larvae; however, this was not accompanied by a simultaneous increase in Akh gene expression. In contrast, PQ significantly increased the expression of the glutathione S-transferase D1 (GstD1) gene. The presence of both a functional adenosine receptor and AKH seem to be important for the proper control of GstD1 gene expression under oxidative stress, however, the latter appears to play more dominant role. On the other hand, differences in glutathione S-transferase (GST) activity among the strains, and between untreated and PQ-treated groups were minimal. In addition, the glutathione level was significantly lower in all untreated AKH- or AdoR-deficient mutant flies as compared with the untreated control w(1118) flies and further declined following treatment with PQ. All oxidative stress characteristics modified by mutations in Akh gene were restored or even improved by 'rescue' mutation in flies which ectopically express Akh. Thus, the results of the present study demonstrate the important roles of AKH and adenosine in the anti-stress response elicited by PQ in a D. melanogaster model, and provide the first evidence for the involvement of adenosine in the anti-oxidative stress response in insects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Respiratory gating in cardiac PET: Effects of adenosine and dipyridamole.

    Science.gov (United States)

    Lassen, Martin Lyngby; Rasmussen, Thomas; Christensen, Thomas E; Kjær, Andreas; Hasbak, Philip

    2017-12-01

    Respiratory motion due to breathing during cardiac positron emission tomography (PET) results in spatial blurring and erroneous tracer quantification. Respiratory gating might represent a solution by dividing the PET coincidence dataset into smaller respiratory phase subsets. The aim of our study was to compare the resulting imaging quality by the use of a time-based respiratory gating system in two groups administered either adenosine or dipyridamole as the pharmacological stress agent. Forty-eight patients were randomized to adenosine or dipyridamole cardiac stress 82RB-PET. Respiratory rates and depths were measured by a respiratory gating system in addition to registering actual respiratory rates. Patients undergoing adenosine stress showed a decrease in measured respiratory rate from initial to later scan phase measurements [12.4 (±5.7) vs 5.6 (±4.7) min-1, P respiratory gating compared to dipyridamole (47% vs 71%, P = .12). As a result, imaging quality was superior in the dipyridamole group compared to adenosine. If respiratory gating is considered for use in cardiac PET, a dipyridamole stress protocol is recommended as it, compared to adenosine, causes a more uniform respiration and results in a higher frequency of successful respiratory gating and thereby superior imaging quality.

  7. [Hypocretins and adenosine in the regulation of sleep].

    Science.gov (United States)

    Salín-Pascual, R J

    To review the recent discovery of hypocretins (orexins) and their link to the pathophysiology of narcolepsy and the role of adenosine in the integration of brain metabolism and sleep. The importance of the functions carried out by the hypothalamus in the regulation of sleep and the waking state has been consolidated by the discovery of hypocretins and the role played by cerebral adenosine. Hypocretins are two peptides made up of 33 and 28 amino acids whose neurons are located predominantly in the lateral hypothalamus and surrounding regions. In the Doberman canine narcolepsy model, in which this disease is presented with an autosomal recessive pattern, a mutation was detected in one of the receptors involved in the hypocretin system, namely the hypocretin-2 receptor. Failures in the hypocretin system have been confirmed as a key factor in narcolepsy by other findings in laboratory animals and humans. Adenosine, on the other hand, is accumulated during the waking state as a result of neuronal metabolism and this in turn is related to drowsiness. Sleep episodes lower the levels of this substance in the brain. Adenosine receptor antagonists increase wakefulness (e.g. caffeine), while the agonists promote slow-wave sleep. Hypocretins and adenosine from the hypothalamus perform functions involving the regulation of sleep and wakefulness. Understanding these two systems can have repercussions on clinical problems such as insomnia, hypersomnia and other neuropsychiatric disorders.

  8. Regioselective 1-N-Alkylation and Rearrangement of Adenosine Derivatives.

    Science.gov (United States)

    Oslovsky, Vladimir E; Drenichev, Mikhail S; Mikhailov, Sergey N

    2015-01-01

    Several methods for the preparation of some N(6)-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The proposed methods seem to be effective for the preparation of natural N(6)-isopentenyl- and N(6)-benzyladenosines, which are known to possess pronounced biological activities. Direct 1-N-alkylation of 2',3',5'-tri-O-acetyladenosine and 3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides in N,N-dimethylformamide (DMF) in the presence of BaCO3 and KI gave 1-N-substituted derivatives with quantitative yields, whereas 1-N-alkylation of adenosine was accompanied by significant O-alkylation. Moreover, the reaction of trimethylsilyl derivatives of N(6)-acetyl-2',3',5'-tri-O-acetyladenosine and N(6)-acetyl-3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides leads to the formation of the stable 1-N-substituted adenosines. Dimroth rearrangement of 1-N-substituted adenosines in aqueous ammonia yields pure N(6)-substituted adenosines.

  9. High salt diet exacerbates vascular contraction in the absence of adenosine A₂A receptor.

    Science.gov (United States)

    Pradhan, Isha; Zeldin, Darryl C; Ledent, Catherine; Mustafa, Jamal S; Falck, John R; Nayeem, Mohammed A

    2014-05-01

    High salt (4% NaCl, HS) diet modulates adenosine-induced vascular response through adenosine A(2A) receptor (A(2A)AR). Evidence suggests that A(2A)AR stimulates cyp450-epoxygenases, leading to epoxyeicosatrienoic acids (EETs) generation. The aim of this study was to understand the vascular reactivity to HS and underlying signaling mechanism in the presence or absence of A(2A)AR. Therefore, we hypothesized that HS enhances adenosine-induced relaxation through EETs in A(2A)AR⁺/⁺, but exaggerates contraction in A(2A)AR⁻/⁻. Organ bath and Western blot experiments were conducted in HS and normal salt (NS, 0.18% NaCl)-fed A(2A)AR⁺/⁺ and A(2A)AR⁻/⁻ mice aorta. HS produced concentration-dependent relaxation to non-selective adenosine analog, NECA in A(2A)AR⁺/⁺, whereas contraction was observed in A(2A)AR⁻/⁻ mice and this was attenuated by A₁AR antagonist (DPCPX). CGS 21680 (selective A(2A)AR agonist) enhanced relaxation in HS-A(2A)AR⁺/⁺ versus NS-A(2A)AR⁺/⁺, which was blocked by EETs antagonist (14,15-EEZE). Compared with NS, HS significantly upregulated the expression of vasodilators A(2A)AR and cyp2c29, whereas vasoconstrictors A₁AR and cyp4a in A(2A)AR⁺/⁺ were downregulated. In A(2A)AR⁻/⁻ mice, however, HS significantly downregulated the expression of cyp2c29, whereas A₁AR and cyp4a were upregulated compared with A(2A)AR⁺/⁺ mice. Hence, our data suggest that in A(2A)AR⁺/⁺, HS enhances A(2A)AR-induced relaxation through increased cyp-expoxygenases-derived EETs and decreased A₁AR levels, whereas in A(2A)AR⁻/⁻, HS exaggerates contraction through decreased cyp-epoxygenases and increased A₁AR levels.

  10. Caffeine intake inverts the effect of adenosine on myocardial perfusion during stress as measured by T1 mapping.

    Science.gov (United States)

    Kuijpers, Dirkjan; Prakken, Niek H; Vliegenthart, Rozemarijn; van Dijkman, Paul R M; van der Harst, Pim; Oudkerk, Matthijs

    2016-10-01

    Caffeine intake before adenosine stress myocardial perfusion imaging may cause false negative findings. We hypothesized that the antagonistic effect of caffeine can be measured by T1 relaxation times in rest and adenosine stress cardiac magnetic resonance imaging (CMR), as T1 mapping techniques are sensitive to changes in myocardial blood volume. We prospectively analyzed 105 consecutive patients with adenosine stress perfusion CMR on a 1.5-T MRI system. Rest and stress T1 mapping was performed using Modified Look-Locker Inversion recovery. T1 reactivity was defined as difference in T1rest and T1stress (∆T1). Fifteen patients drank coffee within 4 h of CMR (8H caffeine group). Comparison was made to patients without self-reported coffee intake: 50 with normal CMR (control group), 18 with myocardial ischemia, and 12 with myocardial infarction. The national review board approved the study; all patients gave written informed consent. The T1 of -7.8 % (T1rest 975 ± 42 ms, T1stress 898 ± 51 ms, p 8H caffeine group showed reduced T1 reactivity (1.8 %; T1rest 979 ms, T1stress 997 ms) compared to the controls (4.3 %; T1rest 977 ± 40 ms, T1stress 1018 ± 40 ms), p infarcted myocardium showed minimal T1 reactivity (0.2 and 0.3 %, respectively). Caffeine intake inverts the adenosine effect during stress perfusion CMR as measured by T1 mapping. T1 reactivity can assess the adequacy of adenosine-induced stress in perfusion CMR.

  11. No role of interstitial adenosine in insulin-mediated vasodilation

    DEFF Research Database (Denmark)

    Dela, F; Stallknecht, B

    1999-01-01

    The mechanisms behind the vasodilatory effect of insulin are not fully understood, but nitric oxide plays an important role. We have investigated the possibility that insulin mediates vasodilatation in the human skeletal muscle via an increase in extracellular adenosine concentrations. In eight...... healthy subjects (H) and in four subjects with a complete, high (C5-C6/7) spinal cord injury (SCI) a hyperinsulinaemic (480 mU min-1 kg-1), isoglycaemic clamp was performed. SCI subjects were included as it has been proposed that adenosine and adenine nucleotides may be released from nerve endings...... in the skeletal muscle. Adenosine concentrations in the extracellular fluid (ECF) of skeletal muscle in the thigh were measured by means of the microdialysis technique. Leg blood flow (LBF) was measured by termodilution. In response to insulin infusion, LBF always increased (P

  12. Comparison of Effects on Gene Expression Activity of Low-Molecular-Weight Lychee Fruit Polyphenol (Oligonol®), Adenosine, and Minoxidil in Human Dermal Papilla Cells

    OpenAIRE

    Koji Wakame; Akifumi Nakata; Keisuke Sato; Yoshihiro Mihara; Jun Takanari; Atuya Sato; Ken-ichi Komatsu

    2017-01-01

    Background: Oligonol® (OLG) is a functional food product and ingredient for cosmetics derived from a lychee fruit polyphenol. It has been reported to act on the skin as an anti-inflammatory and prevent UVB-induced skin damage. Aim: In this study, with the aim of exploring new functionalities of OLG on the scalp, we investigated the effect of OLG on human dermal papilla cells by comparing with adenosine and minoxidil at the genetic level. Method: OLG, adenosine, and minoxidil were appl...

  13. Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration.

    Science.gov (United States)

    Galvao, Joana; Elvas, Filipe; Martins, Tiago; Cordeiro, M Francesca; Ambrósio, António Francisco; Santiago, Ana Raquel

    2015-11-01

    Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3R) in neuroprotection is controversial, A3R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3R activation against retinal neurodegeneration. The A3R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL(+)-cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL(+)-cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL(+)-cells/mm(2) in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL(+) cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V(+)-cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo. Activation of A3R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Inhibition of adenosine kinase attenuates acute lung injury

    Science.gov (United States)

    Köhler, David; Streißenberger, Ariane; Morote-García, Julio C.; Granja, Tiago F.; Schneider, Mariella; Straub, Andreas; Boison, Detlev; Rosenberger, Peter

    2015-01-01

    Objective Extracellular adenosine has tissue protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase (ADK). Based on evidence of the role of ADK in regulating adenosine levels during hypoxia, we evaluated the effect of ADK on lung injury. Furthermore, we tested the influence of a pharmacological approach to blocking ADK on the extent of lung injury. Design Prospective experimental animal study. Setting University based research laboratory. Subjects In vitro cell lines, wildtype (Wt) and ADK+/− mice. Methods We tested the expression of ADK during inflammatory stimulation in vitro and in a model of lipopolysaccharide (LPS) inhalation in vivo. Studies using the ADK promoter were performed in vitro. Wt and ADK+/− mice were subjected to LPS inhalation. Pharmacological inhibition of ADK was performed in vitro, and its effect on adenosine uptake was evaluated. The pharmacological inhibition was also performed in vivo, and the effect on lung injury was assessed. Measurements and Results We observed the repression of ADK by pro-inflammatory cytokines and found a significant influence of NF-κB on regulation of the ADK promoter. Mice with endogenous ADK repression (ADK+/−) showed reduced infiltration of leukocytes into the alveolar space, decreased total protein and myeloperoxidase levels, and lower cytokine levels in the alveolar lavage fluid. The inhibition of ADK by 5-iodotubercidine increased the extracellular adenosine levels in vitro, diminished the transmigration of neutrophils and improved the epithelial barrier function. The inhibition of ADK in vivo showed protective properties, reducing the extent of pulmonary inflammation during lung injury. Conclusions Taken together, these data show that ADK is a valuable target for reducing the inflammatory changes associated with lung injury and should be pursued as a therapeutic option. PMID:26491864

  15. Metabolite gene regulation: imidazole and imidazole derivatives which circumvent cyclic adenosine 3',5'-monophosphate in induction of the Escherichia coli L-arabinose operon.

    Science.gov (United States)

    Kline, E L; Bankaitis, V A; Brown, C S; Montefiori, D C

    1980-02-01

    Imidazole, histidine, histamine, histidinol phosphate, urocanic acid, or imidazolepropionic acid were shown to induce the L-arabinose operon in the absence of cyclic adenosine 3',5'-monophosphate. Induction was quantitated by measuring the increased differential rate of synthesis of L-arabinose isomerase in Escherichia coli strains which carried a deletion of the adenyl cyclase gene. The crp gene product (cyclic adenosine 3',5'-monophosphate receptor protein) and the araC gene product (P2) were essential for induction of the L-arabinose operon by imidazole and its derivatives. These compounds were unable to circumvent the cyclic adenosine 3',5'-monophosphate in the induction of the lactose or the maltose operons. The L-arabinose regulon was catabolite repressed upon the addition of glucose to a strain carrying an adenyl cyclase deletion growing in the presence of L-arabinose with imidazole. These results demonstrated that several imidazole derivatives may be involved in metabolite gene regulation (23).

  16. Diadenosine diphosphate (Ap₂A) delays neutrophil apoptosis via the adenosine A2A receptor and cAMP/PKA pathway.

    Science.gov (United States)

    Pliyev, Boris K; Dimitrieva, Tatyana V; Savchenko, Valery G

    2014-10-01

    Diadenosine polyphosphates have been shown to inhibit neutrophil apoptosis, but mechanisms of the antiapoptotic effect are not known. Diadenosine diphosphate (Ap2A) is the simplest naturally occurring diadenosine polyphosphate, and its effect on neutrophil apoptosis has not previously been investigated. Here we report that Ap2A delays spontaneous apoptosis of human neutrophils, and the effect is reversed by the adenosine A2A receptor antagonists SCH442416 and ZM241385. Ap2A induced an elevation of intracellular cAMP and the elevation was blocked by the adenosine A2A receptor antagonists. The antiapoptotic effect of Ap2A was abrogated by 2',5'-dideoxyadenosine, an inhibitor of adenylyl cyclase, and Rp-8-Br-cAMPS, an inhibitor of type I cAMP-dependent protein kinase A (PKA). Together, these results demonstrate that Ap2A delays neutrophil apoptosis via the adenosine A2A receptor and cAMP/PKA signaling axis.

  17. Inert Reassessment Document for Adenosine - CAS No. 58-61-7

    Science.gov (United States)

    Adenosine is classified as a 4B inert ingredient. Based on the reasonable certainty of no harm safety finding and the existing 40 CFR 180.920 use limiation, the List 4B classification for adenosine is affirmed.

  18. In vivo evidence against a role for adenosine in the exercise pressor reflex in humans.

    NARCIS (Netherlands)

    Riksen, N.P.; Ginneken, E.E.M. van; Broek, P.H.H. van den; Smits, P.; Rongen, G.A.

    2005-01-01

    The pressor response to exercise is of great importance in both physiology and pathophysiology. Whether endogenous adenosine is a trigger for this reflex remains controversial. Muscle interstitial adenosine concentration can be determined by microdialysis. However, there are indications that local

  19. Comparison of the novel vasodilator uridine triphosphate and adenosine for the measurement of fractional flow reserve

    DEFF Research Database (Denmark)

    Sivertsen, Jacob; Jensen, Jan; Galatius, Søren

    2014-01-01

    AIM: Examination of the fractional flow reserve (FFR) responses of intravenous (IV) adenosine with increasing doses of intracoronary (IC) adenosine versus IC uridine triphosphate (UTP) in patients with coronary artery disease. METHODS AND RESULTS: We measured FFR in 25 patients during continuous IV...... and IC infusion (using a microcatheter in the coronary ostium). Standard IV adenosine infusion (140 μg/kg/min) was compared to 8 equimolar incremental doses of IC UTP and IC adenosine (20, 40, 60, 80, 160, 240, 320 and 640 μg/min) in a randomized order. Across all doses, ΔFFR[IC UTP - IC adenosine......] was -0.038 ± 0.008, Padenosine (FFR[IV adenosine] = 0.72 ± 0.05; P=.02) and IC adenosine (FFR[IC adenosine] = 0.68 ± 0.05; P=.03). Furthermore, UTP had significantly fewer side effects compared...

  20. Characterization and treatment of persistent hepatocellular secretory failure

    NARCIS (Netherlands)

    van Dijk, Remco; Kremer, Andreas E.; Smit, Wouter; van den Elzen, Bram; van Gulik, Thomas; Gouma, Dirk; Lameris, Johan S.; Bikker, Hennie; Enemuo, Valentine; Stokkers, Pieter C. F.; Feist, Mark; Bosma, Piter; Jansen, Peter L. M.; Beuers, Ulrich

    2015-01-01

    Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure

  1. Central adenosinergic system involvement in ethanol-induced motor incoordination in mice

    Energy Technology Data Exchange (ETDEWEB)

    Dar, M.S. (East Carolina Univ., Greenville, NC (USA))

    1990-12-01

    To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of (3H)R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered (3H)R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.

  2. Development of coronary vasospasm during adenosine-stress myocardial perfusion CT imaging

    Energy Technology Data Exchange (ETDEWEB)

    Nam, Jeong Gu; Choi, Seong Hoon; Kang, Byeong Seong; Bang, Min Aeo; Kwon, Woon Jeong [Dept. of Radiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (Korea, Republic of)

    2015-06-15

    Adenosine is a short-acting coronary vasodilator, and it is widely used during pharmacological stress myocardial perfusion imaging. It has a well-established safety profile, and most of its side effects are known to be mild and transient. Until now, coronary vasospasm has been rarely reported as a side effect of adenosine during or after adenosine stress test. This study reports a case of coronary vasospasm which was documented on stress myocardial perfusion CT imaging during adenosine stress test.

  3. Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity

    Directory of Open Access Journals (Sweden)

    Moidunny Shamsudheen

    2012-08-01

    Full Text Available Abstract Background Neuroprotective and neurotrophic properties of leukemia inhibitory factor (LIF have been widely reported. In the central nervous system (CNS, astrocytes are the major source for LIF, expression of which is enhanced following disturbances leading to neuronal damage. How astrocytic LIF expression is regulated, however, has remained an unanswered question. Since neuronal stress is associated with production of extracellular adenosine, we investigated whether LIF expression in astrocytes was mediated through adenosine receptor signaling. Methods Mouse cortical neuronal and astrocyte cultures from wild-type and adenosine A2B receptor knock-out animals, as well as adenosine receptor agonists/antagonists and various enzymatic inhibitors, were used to study LIF expression and release in astrocytes. When needed, a one-way analysis of variance (ANOVA followed by Bonferroni post-hoc test was used for statistical analysis. Results We show here that glutamate-stressed cortical neurons induce LIF expression through activation of adenosine A2B receptor subtype in cultured astrocytes and require signaling of protein kinase C (PKC, mitogen-activated protein kinases (MAPKs: p38 and ERK1/2, and the nuclear transcription factor (NF-κB. Moreover, LIF concentration in the supernatant in response to 5′-N-ethylcarboxamide (NECA stimulation was directly correlated to de novo protein synthesis, suggesting that LIF release did not occur through a regulated release pathway. Immunocytochemistry experiments show that LIF-containing vesicles co-localize with clathrin and Rab11, but not with pHogrin, Chromogranin (CgA and CgB, suggesting that LIF might be secreted through recycling endosomes. We further show that pre-treatment with supernatants from NECA-treated astrocytes increased survival of cultured cortical neurons against glutamate, which was absent when the supernatants were pre-treated with an anti-LIF neutralizing antibody. Conclusions

  4. Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety.

    Science.gov (United States)

    Gao, Zhan-Guo; Jeong, Lak Shin; Moon, Hyung Ryong; Kim, Hea Ok; Choi, Won Jun; Shin, Dae Hong; Elhalem, Eleonora; Comin, Maria J; Melman, Neli; Mamedova, Liaman; Gross, Ariel S; Rodriguez, Juan B; Jacobson, Kenneth A

    2004-03-01

    We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A3 AR expressed in CHO cells. Both 2'- and 3'-hydroxyl groups in the ribose moiety contribute to A3 AR binding and activation, with 2'-OH being more essential. Thus, the 2'-fluoro substitution eliminated both binding and activation, while a 3'-fluoro substitution led to only a partial reduction of potency and efficacy at the A3 AR. A 5'-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3'-fluoro derivatives. The 4'-thio substitution, which generally enhanced A3 AR potency and selectivity, resulted in 5'-CH2OH analogues (10 and 12) which were partial agonists of the A3 AR. Interestingly, the shifting of the N6-(3-iodobenzyl)adenine moiety from the 1'- to 4'-position had a minor influence on A3 AR selectivity, but transformed 15 into a potent antagonist (16) (Ki = 4.3 nM). Compound 16 antagonized human A3 AR agonist-induced inhibition of cyclic AMP with a K(B) value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A3 ARs.

  5. Captopril-induced acute renal artery thrombosis and persistent anuria in a patient with documented pre-existing renal artery stenosis and renal failure.

    Science.gov (United States)

    Williams, P. S.; Hendy, M. S.; Ackrill, P.

    1984-01-01

    We describe an elderly man, with pre-existing renal failure and atheromatous renal artery stenosis, who developed persistent anuria due to renal artery thrombosis after acute hypotension following captopril administration. Caution should be used when captopril is first administered to patients with impaired renal function in whom renal artery stenosis is known or suspected. Images Fig. 1 PMID:6382225

  6. The mouse brain adenosine A(1) receptor : functional expression and pharmacology

    NARCIS (Netherlands)

    Wittendorp, MC; Kunzel, JVD; Ijzerman, AP; Boddeke, HWGM; Biber, K

    2004-01-01

    The adenosinergic system is involved in many important physiological functions. Adenosine exerts its extracellular effects through four types of G-protein-coupled receptors: A(1), A(2A), A(2B) and A(3). Adenosine acts as an important regulator of metabolic processes. In the brain adenosine mediates

  7. The role of glial adenosine receptors in neural resilience and the neurobiology of mood disorders

    NARCIS (Netherlands)

    Calker, D; Biber, K

    2005-01-01

    Adenosine receptors were classified into A(1)- and A(2)-receptors in the laboratory of Bernd Hamprecht more than 25 years ago. Adenosine receptors are instrumental to the neurotrophic effects of glia cells. Both microglia and astrocytes release after stimulation via adenosine receptors factors that

  8. Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia.

    Science.gov (United States)

    Espinosa, Janaína; Rocha, Andreia; Nunes, Fernanda; Costa, Marcelo S; Schein, Vanessa; Kazlauckas, Vanessa; Kalinine, Eduardo; Souza, Diogo O; Cunha, Rodrigo A; Porciúncula, Lisiane O

    2013-01-01

    Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.

  9. Concomitant Immunity Induced by Persistent Leishmania major Does Not Preclude Secondary Re-Infection: Implications for Genetic Exchange, Diversity and Vaccination.

    Directory of Open Access Journals (Sweden)

    Michael A Mandell

    2016-06-01

    Full Text Available Many microbes have evolved the ability to co-exist for long periods of time within other species in the absence of overt pathology. Evolutionary biologists have proposed benefits to the microbe from 'asymptomatic persistent infections', most commonly invoking increased likelihood of transmission by longer-lived hosts. Typically asymptomatic persistent infections arise from strong containment by the immune system, accompanied by protective immunity; such 'vaccination' from overt disease in the presence of a non-sterilizing immune response is termed premunition or concomitant immunity. Here we consider another potential benefit of persistence and concomitant immunity to the parasite: the 'exclusion' of competing super-infecting strains, which would favor transmission of the original infecting organism.To investigate this in the protozoan parasite Leishmania major, a superb model for the study of asymptomatic persistence, we used isogenic lines of comparable virulence bearing independent selectable markers. One was then used to infect genetically resistant mice, yielding infections which healed and progressed to asymptomatic persistent infection; these mice were then super-infected with the second marked line. As anticipated, super-infection yielded minimal pathology, showing that protective immunity against disease pathology had been established. The relative abundance of the primary and super-infecting secondary parasites was then assessed by plating on selective media. The data show clearly that super-infecting parasites were able to colonize the immune host effectively, achieving numbers comparable to and sometimes greater than that of the primary parasite.We conclude that induction of protective immunity does not guarantee the Leishmania parasite exclusive occupation of the infected host. This finding has important consequences to the maintenance and generation of parasite diversity in the natural Leishmania infectious cycle alternating

  10. Concomitant Immunity Induced by Persistent Leishmania major Does Not Preclude Secondary Re-Infection: Implications for Genetic Exchange, Diversity and Vaccination.

    Science.gov (United States)

    Mandell, Michael A; Beverley, Stephen M

    2016-06-01

    Many microbes have evolved the ability to co-exist for long periods of time within other species in the absence of overt pathology. Evolutionary biologists have proposed benefits to the microbe from 'asymptomatic persistent infections', most commonly invoking increased likelihood of transmission by longer-lived hosts. Typically asymptomatic persistent infections arise from strong containment by the immune system, accompanied by protective immunity; such 'vaccination' from overt disease in the presence of a non-sterilizing immune response is termed premunition or concomitant immunity. Here we consider another potential benefit of persistence and concomitant immunity to the parasite: the 'exclusion' of competing super-infecting strains, which would favor transmission of the original infecting organism. To investigate this in the protozoan parasite Leishmania major, a superb model for the study of asymptomatic persistence, we used isogenic lines of comparable virulence bearing independent selectable markers. One was then used to infect genetically resistant mice, yielding infections which healed and progressed to asymptomatic persistent infection; these mice were then super-infected with the second marked line. As anticipated, super-infection yielded minimal pathology, showing that protective immunity against disease pathology had been established. The relative abundance of the primary and super-infecting secondary parasites was then assessed by plating on selective media. The data show clearly that super-infecting parasites were able to colonize the immune host effectively, achieving numbers comparable to and sometimes greater than that of the primary parasite. We conclude that induction of protective immunity does not guarantee the Leishmania parasite exclusive occupation of the infected host. This finding has important consequences to the maintenance and generation of parasite diversity in the natural Leishmania infectious cycle alternating between mammalian and

  11. Gene expression profiles in adenosine-treated human mast cells ...

    African Journals Online (AJOL)

    The role of mast cells in allergic diseases and innate immunity has been widely researched and much is known about the expression profiles of immune-related genes in mast cells after bacterial challenges. However, little is known about the gene expression profiles of mast cells in response to adenosine. Herein, we ...

  12. Plasma Adenosine Deaminase Enzyme Reduces with Treatment of ...

    African Journals Online (AJOL)

    olayemitoyin

    Plasma Adenosine Deaminase Enzyme Reduces with Treatment of Pulmonary Tuberculosis in Nigerian Patients: Indication for. Diagnosis and Treatment Monitoring. Ige O.a, Edem V.F.b and Arinola O.G.b,*. aDepartment of Medicine, University of Ibadan, Ibadan, Nigeria b Department of Chemical Pathology,. University of ...

  13. Short Term Glucose Load and Serum Adenosine Deaminase Activity ...

    African Journals Online (AJOL)

    Adenosine deaminase (ADA), an enzyme that is involved in nucleic acid metabolism has been reported to show raised serum activity in diabetic patients. As part of a preliminary study to assess ADA activity in diabetic and non-diabetic Nigerians, ADA was measured in fasting and 2 hour post-prandial (PP) sera from the ...

  14. Quantitative effect and regulatory function of cyclic adenosine 5 ...

    Indian Academy of Sciences (India)

    Cyclic adenosine 5′-phosphate (cAMP) is a global regulator of gene expression in Escherichia coli. Despite decades of intensive study, the quantitative effect and regulatory function of cAMP remain the subjects of considerable debate. Here, we analyse the data in the literature to show that: In carbon-limited cultures ...

  15. Validity of serum Adenosine deaminase in diagnosis of tuberculosis ...

    African Journals Online (AJOL)

    Introduction: Tuberculosis is one of the most important infectious causes of death worldwide. Ziehl-Neelsen staining of sputum has high specificity in tuberculosis endemic countries, but modest sensitivity which varies among laboratories. This study was set up to investigate the diagnostic value of serum Adenosine ...

  16. Adenosine Deaminase Activity in Diabetic and Obese Patients ...

    African Journals Online (AJOL)

    Adenosine deaminase (ADA) commonly associated with severe combined immunodeficiency disease believed to be an important enzyme for the modulation of bioactivity of insulin. The clinical significance in Metabolic Diseases patients in South Eastern Nigeria was studied. Body Mass Index (BMI), Fating Blood Glucose, ...

  17. Contributory role of adenosine deaminase in metabolic syndrome

    African Journals Online (AJOL)

    olayemitoyin

    levels) is one of the complications of diabetes mellitus, and that ADA plays an important role in the in the modulation of carbohydrate metabolism and glucose regulation (Onyeanusi et al, 2003). Table 4 shows the correlation and comparison of the Glycated Hemoglobin (GHbAic) with the. Adenosine Deaminase (ADA) in the ...

  18. Contributory role of adenosine deaminase in metabolic syndrome ...

    African Journals Online (AJOL)

    Adenosine deaminase (ADA) is an enzyme of purine metabolism commonly associated with severe combined immunodeficiency disease and believed to modulate bioactivity of insulin. Its contributory role in patients with metabolic syndrome (having features such as obesity, insulin resistance, fasting hyperglycaemia, lipid ...

  19. Contributory role of adenosine deaminase in metabolic syndrome

    African Journals Online (AJOL)

    olayemitoyin

    Summary: Adenosine deaminase (ADA) is an enzyme of purine metabolism commonly associated with severe combined immunodeficiency disease and believed to modulate bioactivity of insulin. Its contributory role in patients with metabolic syndrome (having features such as obesity, insulin resistance, fasting ...

  20. High pleural fluid adenosine deaminase levels: A valuable tool for ...

    African Journals Online (AJOL)

    High pleural fluid adenosine deaminase levels: A valuable tool for rapid diagnosis of pleural TB in a middle-income country with a high TB/HIV burden. ... Following queries from clinicians concerning the likely high false-positive (FP) rate of FADA from our laboratory, we performed a retrospective audit of all high FADA ...

  1. Adenosine involvement on bronchial reactivity modulation by diesel exhaust

    NARCIS (Netherlands)

    Cojocaru, Elena; Dumitriu, Irina Luciana; Gurzu, B; Margineanu, Ioana; Dinca, Maria; Costuleanu, M; Slătineanu, Simona Mihaela; Scutaru, Brigitte; Petrescu, Gh

    2009-01-01

    UNLABELLED: In recent decades, epidemiologic investigations have suggested a strong relationship between air pollution and an increase in the prevalence of allergic rhinitis and asthma. AIM: To investigate the possible involvement of adenosine (AD) in bronchomotor effects of diesel exhaust (DE).

  2. Adenosine receptor modulation of seizure susceptibility in rats

    Energy Technology Data Exchange (ETDEWEB)

    Szot, P.

    1987-01-01

    Adenosine is considered to be a neuromodulator or cotransmitter in the periphery and CNS. This neuromodulatory action of adenosine may be observed as an anticonvulsant effect. Dose-response curves for R-phenylisopropyladenosine (PIA), cycohexyladenosine (CHA), 2-chloroadenosine (2-ClAdo), N-ethylcarboxamidoadenosine (NECA) and S-PIA were generated against PTZ seizure thresholds in the rat. The rank order of potency for adenosine agonists to elevate PTZ seizure threshold was R-PIA > 2-ClAdo > NECA > CHA > S-PIA. R-PIA was approximately 80-fold more potent than S-PIA. This 80-fold difference in potency between the diasteriomers of PIA was consistent with an A{sub 1} adenoise receptor-mediated response. The anticonvulsant action of 2-ClAdo was reversed by pretreatment with theoplylline. Chronic administration of theophylline significantly increased the specific binding of {sup 3}H-cyclohexyladenosine in membranes of the cerebral cortex and cerebellum of the rat. Chronic exposure to theophylline produced a significant increase in the densities of both the high- and low-affinity forms of A{sub 1} adenosine receptors in the cerebral cortex.

  3. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

    OpenAIRE

    Jie eFeng; Wanliang eShi; Shuo eZhang; David eSullivan; Paul eAuwaerter; Ying eZhang

    2016-01-01

    Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effectiv...

  4. Small-Animal PET Study of Adenosine A(1) Receptors in Rat Brain : Blocking Receptors and Raising Extracellular Adenosine

    NARCIS (Netherlands)

    Paul, Soumen; Khanapur, Shivashankar; Rybczynska, Anna A.; Kwizera, Chantal; Sijbesma, Jurgen W. A.; Ishiwata, Kiichi; Willemsen, Antoon T. M.; Elsinga, Philip H.; Dierckx, Rudi A. J. O.; van Waarde, Aren

    2011-01-01

    Activation of adenosine A(1) receptors (A(1)R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A(1)R can be visualized using 8-dicyclopropylmethyl-1-C-11-methyl-3-propyl-xanthine (C-11-MPDX) and PET. This study aims to test whether C-11-MPDX

  5. Feed-Forward Inhibition of CD73 and Upregulation of Adenosine Deaminase Contribute to the Loss of Adenosine Neuromodulation in Postinflammatory Ileitis

    Science.gov (United States)

    Magalhães-Cardoso, Maria Teresa; Ferreirinha, Fátima; Dias, Ana Sofia; Pelletier, Julie

    2014-01-01

    Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the “purinome” may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on A2A excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5′-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from rele