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Sample records for adenosine induces persistence

  1. Adenosine-induced activation of esophageal nociceptors.

    Ru, F; Surdenikova, L; Brozmanova, M; Kollarik, M

    2011-03-01

    Clinical studies implicate adenosine acting on esophageal nociceptive pathways in the pathogenesis of noncardiac chest pain originating from the esophagus. However, the effect of adenosine on esophageal afferent nerve subtypes is incompletely understood. We addressed the hypothesis that adenosine selectively activates esophageal nociceptors. Whole cell perforated patch-clamp recordings and single-cell RT-PCR analysis were performed on the primary afferent neurons retrogradely labeled from the esophagus in the guinea pig. Extracellular recordings were made from the isolated innervated esophagus. In patch-clamp studies, adenosine evoked activation (inward current) in a majority of putative nociceptive (capsaicin-sensitive) vagal nodose, vagal jugular, and spinal dorsal root ganglia (DRG) neurons innervating the esophagus. Single-cell RT-PCR analysis indicated that the majority of the putative nociceptive (transient receptor potential V1-positive) neurons innervating the esophagus express the adenosine receptors. The neural crest-derived (spinal DRG and vagal jugular) esophageal nociceptors expressed predominantly the adenosine A(1) receptor while the placodes-derived vagal nodose nociceptors expressed the adenosine A(1) and/or A(2A) receptors. Consistent with the studies in the cell bodies, adenosine evoked activation (overt action potential discharge) in esophageal nociceptive nerve terminals. Furthermore, the neural crest-derived jugular nociceptors were activated by the selective A(1) receptor agonist CCPA, and the placodes-derived nodose nociceptors were activated by CCPA and/or the selective adenosine A(2A) receptor CGS-21680. In contrast to esophageal nociceptors, adenosine failed to stimulate the vagal esophageal low-threshold (tension) mechanosensors. We conclude that adenosine selectively activates esophageal nociceptors. Our data indicate that the esophageal neural crest-derived nociceptors can be activated via the adenosine A(1) receptor while the placodes

  2. The role of adenosine receptors and endogenous adenosine in citalopram-induced cardiovascular toxicity

    Kubilay Oransay; Nil Hocaoglu; Mujgan Buyukdeligoz; Yesim Tuncok; Sule Kalkan

    2014-01-01

    Aim: We investigated the role of adenosine in citalopram-induced cardiotoxicity. Materials and Methods: Protocol 1: Rats were randomized into four groups. Sodium cromoglycate was administered to rats. Citalopram was infused after the 5% dextrose, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; A 1 receptor antagonist), 8-(-3-chlorostyryl)-caffeine (CSC; A 2a receptor antagonist), or dimethyl sulfoxide (DMSO) administrations. Protocol 2: First group received 5% dextrose intraperitoneally 1 hour...

  3. Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis.

    Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan; Shao, Hui; Kaplan, Henry J; Sun, Deming

    2016-03-15

    Adenosine is an important regulator of the immune response, and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies showed that adenosine receptor agonists can be anti- or proinflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoimmune uveitis (EAU) induced by immunizing EAU-prone mice with a known uveitogenic peptide, IRBP1-20. Our results showed that the effective time to administer a single dose of ADA to suppress induction of EAU was 8-14 d postimmunization, shortly before EAU expression; however, ADA treatment at other time points exacerbated disease. ADA preferentially inhibited Th17 responses, and this effect was γδ T cell dependent. Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help to improve the design of ADA- and adenosine receptor-targeted therapies. PMID:26856700

  4. Teriparatide Induced Delayed Persistent Hypercalcemia

    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.

  5. Adenosine signaling and the energetic costs of induced immunity.

    Lazzaro, Brian P

    2015-04-01

    Life history theory predicts that trait evolution should be constrained by competing physiological demands on an organism. Immune defense provides a classic example in which immune responses are presumed to be costly and therefore come at the expense of other traits related to fitness. One strategy for mitigating the costs of expensive traits is to render them inducible, such that the cost is paid only when the trait is utilized. In the current issue of PLOS Biology, Bajgar and colleagues elegantly demonstrate the energetic and life history cost of the immune response that Drosophila melanogaster larvae induce after infection by the parasitoid wasp Leptopilina boulardi. These authors show that infection-induced proliferation of defensive blood cells commands a diversion of dietary carbon away from somatic growth and development, with simple sugars instead being shunted to the hematopoetic organ for rapid conversion into the raw energy required for cell proliferation. This metabolic shift results in a 15% delay in the development of the infected larva and is mediated by adenosine signaling between the hematopoietic organ and the central metabolic control organ of the host fly. The adenosine signal thus allows D. melanogaster to rapidly marshal the energy needed for effective defense and to pay the cost of immunity only when infected. PMID:25915419

  6. Adenosine signaling and the energetic costs of induced immunity.

    Brian P Lazzaro

    2015-04-01

    Full Text Available Life history theory predicts that trait evolution should be constrained by competing physiological demands on an organism. Immune defense provides a classic example in which immune responses are presumed to be costly and therefore come at the expense of other traits related to fitness. One strategy for mitigating the costs of expensive traits is to render them inducible, such that the cost is paid only when the trait is utilized. In the current issue of PLOS Biology, Bajgar and colleagues elegantly demonstrate the energetic and life history cost of the immune response that Drosophila melanogaster larvae induce after infection by the parasitoid wasp Leptopilina boulardi. These authors show that infection-induced proliferation of defensive blood cells commands a diversion of dietary carbon away from somatic growth and development, with simple sugars instead being shunted to the hematopoetic organ for rapid conversion into the raw energy required for cell proliferation. This metabolic shift results in a 15% delay in the development of the infected larva and is mediated by adenosine signaling between the hematopoietic organ and the central metabolic control organ of the host fly. The adenosine signal thus allows D. melanogaster to rapidly marshal the energy needed for effective defense and to pay the cost of immunity only when infected.

  7. Adenosine-induced hyperpolarization of the membrane voltage in rat mesangial cells in primary culture.

    Pavenstädt, H. (Hermann); Ruh, J; Greger, R; Schollmeyer, P.

    1994-01-01

    1. The effect of adenosine on membrane voltage and ion currents was studied in rat mesangial cells in primary culture. Membrane voltage was measured with the patch clamp technique in the slow- or fast whole cell configuration. The resting membrane voltage of mesangial cells was -48 +/- 0.5 mV. Adenosine (10(-8)-10(-3) M) induced a sustained and concentration-dependent hyperpolarization of membrane voltage (ED50 approximately 6 x 10(-7) M). Adenosine (10(-5) M) hyperpolarized the membrane volt...

  8. Antagonism by theophylline of respiratory inhibition induced by adenosine.

    Eldridge, F L; Millhorn, D E; Kiley, J P

    1985-11-01

    The effects on respiration of an analogue of adenosine, L-2-N6-(phenylisopropyl)adenosine (PIA), and of the methylxanthine, theophylline, were determined in 19 vagotomized glomectomized cats whose end-tidal PCO2 was kept constant by means of a servo-controlled ventilator. Integrated phrenic nerve activity was used to represent respiratory output. Our results show that PIA, whether given systemically or into the third cerebral ventricle, depressed respiration. Systemically administered theophylline stimulated respiration. Theophylline given intravenously, or into the third ventricle not only reversed the depressive effects of previously administered PIA but caused further increases of respiration above the control level. Prior systemic administration of theophylline blocked both respiratory and hypotensive effects of subsequently administered PIA. Effects of either agent on medullary extracellular fluid pH did not explain the results. We conclude that the adenosine analogue PIA, acts to inhibit neurons in the brain that are involved in the control of respiration and that its effects are blocked by theophylline. We suggest that adenosine acts as a tonic modulator of respiration and that theophylline stimulates breathing by competitive antagonism of adenosine at neuronal receptor sites. PMID:4066573

  9. Susceptibility to seizure-induced sudden death in DBA/2 mice is altered by adenosine.

    Faingold, Carl L; Randall, Marc; Kommajosyula, Srinivasa P

    2016-08-01

    Sudden unexpected death in epilepsy (SUDEP) is rare but is an important public health burden due to the number of patient years lost. Respiratory dysfunction following generalized convulsive seizure is a common sequence of events in witnessed SUDEP cases. The DBA/2 mouse model of SUDEP exhibits generalized convulsive audiogenic seizures (AGSz), which result in seizure-induced respiratory arrest (S-IRA) in ∼75% of these animals, while the remaining DBA/2 mice exhibit AGSz without S-IRA. SUDEP induction may involve actions of adenosine, which is released during generalized seizures in animals and patients and is known to depress respiration. This study examined the effects of systemic administration of agents that alter the actions of adenosine on the incidence of S-IRA in DBA/2 mice. DBA/2 mice that consistently exhibited AGSz without S-IRA showed a significantly increased incidence of S-IRA following treatment with 5-iodotubercidin, which blocks adenosine metabolism. Treatment of DBA/2 mice that consistently exhibited AGSz followed by S-IRA with a non-selective adenosine antagonist, caffeine, or an A2A adenosine receptor subtype-selective antagonist (SCH 442416) significantly reduced S-IRA incidence. By contrast, an A1 adenosine receptor antagonist (DPCPX) was not effective in reducing S-IRA incidence. These findings suggest that preventative approaches for SUDEP should consider agents that reduce the actions of adenosine. PMID:27259068

  10. 2-(1-Hexyn-1-yl)adenosine-induced intraocular hypertension is mediated via K+ channel opening through adenosine A2A receptor in rabbits.

    Konno, Takashi; Uchibori, Takehiro; Nagai, Akihiko; Kogi, Kentaro; Nakahata, Norimichi

    2005-08-22

    The present study was performed to clarify the mechanism of change in intraocular pressure by 2-(1-hexyn-1-yl)adenosine (2-H-Ado), a selective adenosine A2 receptor agonist, in rabbits. 2-H-Ado (0.1%, 50 microl)-induced ocular hypertension (E(max): 7.7 mm Hg) was inhibited by an adenosine A2A receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, ATP-sensitive K+ channel blocker glibenclamide or 5-hydroxydecanoic acid, but not by an adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A2B receptor antagonist alloxazine or a cyclooxygenase inhibitor indomethacin. The outflow facility induced by 2-H-Ado seems to be independent of increase in intraocular pressure or ATP-sensitive K+ channel. In contrast, the recovery rate in intraocular pressure decreased by hypertonic saline was accelerated by 2-H-Ado, and this response was dependent on ATP-sensitive K+ channel. These results suggest that 2-H-Ado-induced ocular hypertension is mediated via K+ channel opening through adenosine A2A receptor, and this is probably due to aqueous formation, but independent of change in outflow facility or prostaglandin production. PMID:16023100

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

    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

  12. Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation

    Frøbert, Ole; Haink, Gesine; Simonsen, Ulf; Gravholt, Claus H; Levin, Max; Deussen, Andreas

    2006-01-01

    We tested whether hypoxia-induced coronary artery dilatation could be mediated by an increase in adenosine concentration within the coronary artery wall or by an increase in adenosine sensitivity. Porcine left anterior descendent coronary arteries, precontracted with prostaglandin F2α (10−5m), were mounted in a pressure myograph and microdialysis catheters were inserted into the tunica media. Dialysate adenosine concentrations were analysed by HPLC. Glucose, lactate and pyruvate were measured by an automated spectrophotometric kinetic enzymatic analyser. The exchange fraction of [14C]adenosine over the microdialysis membrane increased from 0.32 ± 0.02 to 0.46 ± 0.02 (n = 4, P < 0.01) during the study period. At baseline, interstitial adenosine was in the region of 10 nm which is significantly less than previously found myocardial concentrations. Hypoxia (PO2 30 mmHg for 60 min, n = 5) increased coronary diameters by 20.0 ± 2.6% (versus continuous oxygenation −3.1 ± 2.4%, n = 6, P < 0.001) but interstitial adenosine concentration fell. Blockade of adenosine deaminase (with erythro-9-(2-hydroxy-3-nonyl-)-adenine, 5 μm), adenosine kinase (with iodotubericidine, 10 μm) and adenosine transport (with n-nitrobenzylthioinosine, 1 μm) increased interstitial adenosine but the increase was unrelated to hypoxia or diameter. A coronary dilatation similar to that during hypoxia could be obtained with 30 μm of adenosine in the organ bath and the resulting interstitial adenosine concentrations (n = 5) were 20 times higher than the adenosine concentration measured during hypoxia. Adenosine concentration–response experiments showed vasodilatation to be more pronounced during hypoxia (n = 9) than during normoxia (n = 9, P < 0.001) and the A2A receptor antagonist ZM241385 (20 nm, n = 5), attenuated hypoxia-induced vasodilatation while the selective A2B receptor antagonist MRS1754 (20 nm, n = 4), had no effect. The lactate/pyruvate ratio was significantly increased in

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

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

    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......-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......) blocked the constriction responses to both adenosine and angiotensin II. In contrast, the adenylate cyclase inhibitor SQ22536 (10 micro M) and the protein kinase A antagonist KT5720 (0.1 and 1 micro M) did not induce significant vasoconstriction of afferent arterioles. It is concluded that the...

  14. Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers.

    Brozmanova, M; Mazurova, L; Ru, F; Tatar, M; Hu, Y; Yu, S; Kollarik, M

    2016-02-01

    Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2A receptor. Here we addressed the hypothesis that stimulation of the adenosine A2A receptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2A receptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10-60 mmHg) in a concentration-dependent fashion (1-100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2A antagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031. Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2A receptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1. PMID:26564719

  15. Involvement of adenosine A2a receptor in intraocular pressure decrease induced by 2-(1-octyn-1-yl)adenosine or 2-(6-cyano-1-hexyn-1-yl)adenosine.

    Konno, Takashi; Murakami, Akira; Uchibori, Takehiro; Nagai, Akihiko; Kogi, Kentaro; Nakahata, Norimichi

    2005-04-01

    The aim of the present study is to clarify the mechanism for the decrease in intraocular pressure by 2-alkynyladenosine derivatives in rabbits. The receptor binding analysis revealed that 2-(1-octyn-1-yl)adenosine (2-O-Ado) and 2-(6-cyano-1-hexyn-1-yl)adenosine (2-CN-Ado) selectively bound to the A(2a) receptor with a high affinity. Ocular hypotensive responses to 2-O-Ado and 2-CN-Ado were inhibited by the adenosine A(2a)-receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), but not by the adenosine A(1)-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or the adenosine A(2b)-receptor antagonist alloxazine. In addition, 2-O-Ado and 2-CN-Ado caused an increase in outflow facility, which was inhibited by CSC, but not by DPCPX or alloxazine. Moreover, 2-O-Ado and 2-CN-Ado increased cAMP in the aqueous humor, and the 2-O-Ado-induced an increase in cAMP was inhibited by CSC. These results suggest that 2-O-Ado and 2-CN-Ado reduced intraocular pressure via an increase in outflow facility. The ocular hypotension may be mainly mediated through the activation of adenosine A(2a) receptor, although a possible involvement of adenosine A(1) receptor cannot be completely ruled out. 2-O-Ado and 2-CN-Ado are useful lead compounds for the treatment of glaucoma. PMID:15821340

  16. Role of nitric oxide in adenosine-induced vasodilation in humans

    Costa, F.; Biaggioni, I.; Robertson, D. (Principal Investigator)

    1998-01-01

    Vasodilation is one of the most prominent effects of adenosine and one of the first to be recognized, but its mechanism of action is not completely understood. In particular, there is conflicting information about the potential contribution of endothelial factors. The purpose of this study was to explore the role of nitric oxide in the vasodilatory effect of adenosine. Forearm blood flow responses to intrabrachial adenosine infusion (125 microg/min) were assessed with venous occlusion plethysmography during intrabrachial infusion of saline or the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (12.5 mg/min). Intrabrachial infusions of acetylcholine (50 microg/min) and nitroprusside (3 microg/min) were used as a positive and negative control, respectively. These doses were chosen to produce comparable levels of vasodilation. In a separate study, a second saline infusion was administered instead of L-NMMA to rule out time-related effects. As expected, pretreatment with L-NMMA reduced acetylcholine-induced vasodilation; 50 microg/min acetylcholine increased forearm blood flow by 150+/-43% and 51+/-12% during saline and L-NMMA infusion, respectively (P<.01, n=6). In contrast, L-NMMA did not affect the increase in forearm blood flow produced by 3 microg/min nitroprusside (165+/-30% and 248+/-41% during saline and L-NMMA, respectively) or adenosine (173+/-48% and 270+/-75% during saline and L-NMMA, respectively). On the basis of our observations, we conclude that adenosine-induced vasodilation is not mediated by nitric oxide in the human forearm.

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

    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

  18. Adenosine modulates hypoxia-induced responses in rat PC12 cells via the A2A receptor.

    Kobayashi, S; Conforti, L; Pun, R Y; Millhorn, D E

    1998-04-01

    1. The present study was undertaken to determine the role of adenosine in mediating the cellular responses to hypoxia in rat phaeochromocytoma (PC12) cells, an oxygen-sensitive clonal cell line. 2. Reverse transcriptase polymerase chain reaction studies revealed that PC12 cells express adenosine deaminase (the first catalysing enzyme of adenosine degradation) and the A2A and A2B adenosine receptors, but not the A1 or A3 adenosine receptors. 3. Whole-cell current- and voltage-clamp experiments showed that adenosine attenuated the hypoxia-induced membrane depolarization. The hypoxia-induced suppression of the voltage-sensitive potassium current (IK(V)) was markedly reduced by adenosine. Furthermore, extracellularly applied adenosine increased the peak amplitudes of IK(V) in a concentration-dependent manner. This increase was blocked by pretreatment not only with a non-specific adenosine receptor antagonist, 8-phenyltheophylline (8-PT), but also with a selective A2A receptor antagonist, ZM241385. 4. Ca2+ imaging studies using fura-2 acetoxymethyl ester (fura-2 AM) revealed that the increase in intracellular free Ca2+ during hypoxic exposure was attenuated significantly by adenosine. Voltage-clamp studies showed that adenosine inhibited the voltage-dependent Ca2+ currents (ICa) in a concentration-dependent fashion. This inhibition was also abolished by both 8-PT and ZM241385. 5. The modulation of both IK(V) and ICa by adenosine was prevented by intracellular application of an inhibitor of protein kinase A (PKA), PKA inhibitor fragment (6-22) amide. In addition, the effect of adenosine on either IK(V) or ICa was absent in PKA-deficient PC12 cells. 6. These results indicate that the modulatory effects of adenosine on the hypoxia-induced membrane responses of PC12 cells are likely to be mediated via activation of the A2A receptor, and that the PKA pathway is required for these modulatory actions. We propose that this modulation serves to regulate membrane excitability in

  19. Role of adenosine receptor agonists in pharmacological modulation of myelosuppression induced by ionizing radiation

    Hofer, Michal; Pospíšil, Milan; Holá, Jiřina; Vacek, Antonín; Štreitová, Denisa

    Buenos Aires, 2008. s. 1-7. [IRPA 12 - 12th International Congress of the International Radiation Protection Association - Strengthening Radiation Protection Worldwide. 19.10.2008-24.10.2008, Buenos Aires] R&D Projects: GA ČR(CZ) GA305/06/0015; GA ČR(CZ) GA305/08/0158 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : adenosine receptors * hematopoiesis * radiation-induced myelosuppression Subject RIV: BO - Biophysics

  20. Outcome of Patients With Adenosine-Induced ST Segment Depression and Normal Myocardial Perfusion

    The aim of the present study was to determine the outcome of patients with normal MPS and adenosine-induced ST segment depression. A total of 1867 patients underwent adenosine Tc99m-tetrofosmin MPS in nuclear medicine unit in Saudi German Hospital, Saudi Arabia, between January 2004 and May 2008. Their ECGs were checked for ST segment depression during adenosine infusion. All patients with ≥ 1 mm horizontal or down-sloping ST segment depression or≥ 1.5 mm up-sloping ST segment depression were included in the study. Fifty-six patients met our inclusion criteria, of which 45 (80%) were females. During the follow-up period, a total of 15 of patients ended up doing coronary angiography, either for high clinical suspicion or following a second positive MPS performed 6-18 months after the first study. Seven of them were positive for coronary artery disease and were subsequently treated with revascularization procedure, and 8 returned either normal angiography or non-obstructive coronary artery disease. Male diabetic smoking patients were more prevalent and underwent revascularization. The patients were followed up for a mean of 22.8 ±7.8 months. No cardiac deaths or myocardial infarctions were reported. It could be concluded that adenosine-induced ST segment depression in patients with normal myocardial perfusion was a benign finding and did not increase the very low risk of cardiac events in those patients. However, male smokers and/or diabetics might need further investigation. This suggestion needs further evaluation

  1. Differential modulation of ATP-induced calcium signalling by A1 and A2 adenosine receptors in cultured cortical astrocytes

    Alloisio, Susanna; Cugnoli, Carlo; Ferroni, Stefano; Nobile, Mario

    2004-01-01

    Despite the accumulating evidence that under various pathological conditions the extracellular elevation of adenine-based nucleotides and nucleosides plays a key role in the control of astroglial reactivity, how these signalling molecules interact in the regulation of astrocyte function is still largely elusive.The action of the nucleoside adenosine in the modulation of the intracellular calcium signalling ([Ca2+]i) elicited by adenosine 5′-triphosphate (ATP)-induced activation of P2 purinoce...

  2. Adenosine inhibitory effect on enhanced growth of aortic smooth muscle cells from streptozotocin-induced diabetic rats.

    Parés-Herbuté, N.; Hillaire-Buys, D.; Etienne, P.; Gross, R.; Loubatières-Mariani, M. M.; MONNIER, L.

    1996-01-01

    1. There is evidence to suggest that adenosine may regulate arterial smooth muscle cell (SMC) growth and proliferation, which is a key event in atherogenesis. This regulation may be mediated via adenylate cyclase. As diabetes is a known risk factor for atherosclerosis, we investigated the growth of aortic SMC from diabetic rats in primary culture and their sensitivity to adenosine and to adenylate cyclase activity. 2. Diabetes was induced with streptozotocin (STZ, 66 mg kg-1, i.p.) Aortic SMC...

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

    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

  4. Persistent ion beam induced conductivity in zinc oxide nanowires

    Johannes, Andreas; Niepelt, Raphael; Gnauck, Martin; Ronning, Carsten

    2015-01-01

    We report persistently increased conduction in ZnO nanowires irradiated by ion beam with various ion energies and species. This effect is shown to be related to the already known persistent photo conduction in ZnO and dubbed persistent ion beam induced conduction. Both effects show similar excitation efficiency, decay rates, and chemical sensitivity. Persistent ion beam induced conduction will potentially allow countable (i.e., single dopant) implantation in ZnO nanostructures and other mater...

  5. Staurosporine-induced apoptosis in astrocytes is prevented by A1 adenosine receptor activation.

    D'Alimonte, Iolanda; Ballerini, Patrizia; Nargi, Eleonora; Buccella, Silvana; Giuliani, Patricia; Di Iorio, Patrizia; Caciagli, Francesco; Ciccarelli, Renata

    2007-05-11

    Astrocyte apoptosis occurs in acute and chronic pathological processes at the central nervous system and the prevention of astrocyte death may represent an efficacious intervention in protecting neurons against degeneration. Our research shows that rat astrocyte exposure to 100 nM staurosporine for 3h caused apoptotic death accompanied by caspase-3, p38 mitogen-ed protein kinase (MAPK) and glycogen synthase kinase-3beta (GSK3beta) activation. N(6)-chlorocyclopentyladenosine (CCPA, 2.5-75 nM), a selective agonist of A(1) adenosine receptors, added to the cultures 1h prior to staurosporine, induced a dose-dependent anti-apoptotic effect, which was inhibited by the A(1) receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine. CCPA also caused a dose- and time-dependent phosphorylation/activation of Akt, a downstream effector of cell survival promoting phosphatidylinositol 3-kinase (PI3K) pathway, which in turn led to inhibition of staurosporine-induced GSK3beta and p38 MAPK activity. Accordingly, the anti-apoptotic effect of CCPA was abolished by culture pre-treatment with LY294002, a selective PI3K inhibitor, pointing out the prevailing role played by PI3K pathway in the protective effect exerted by A(1) receptor activation. Since an abnormal p38 and GSK3beta activity is implicated in acute (stroke) and chronic (Alzheimer's disease) neurodegenerative diseases, the results of the present study provide a hint to better understand adenosine relevance in these disorders. PMID:17400382

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

    Høier, Birgitte; Olsen, Karina; Nyberg, Michael Permin; Bangsbo, Jens; Hellsten, Ylva

    2010-01-01

    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...

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

    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)

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

    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·kg-1·min-1) in 8 WHHL rabbits (13.8±0.5 months) with 13N-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·min-1·g-1) did not differ significantly between control and WHHL groups both at baseline (3.67±0.72 vs 4.26±1.12 ml·min-1·g-1, p=NS) and with adenosine (7.92±2.00 vs 9.27±2.91 ml·min-1·g-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)

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

    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.

  10. Adenosine A1 receptors in contrast media-induced renal dysfunction in the normal rat

    Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. In this study we investigated the effects of injection of the non-ionic low-osmolar CM iopromide with and without pretreatment with the selective adenosine A1-receptor antagonist DPCPX. The effects were evaluated on regional renal blood flow, outer medullary oxygen tension (PO2) and urine output in normal anaesthetised rats. A laser-Doppler technique was used for recording haemodynamic changes while oxygen microelectrodes were used for oxygen measurements. The A1-receptor antagonist per se elevated glomerular filtration rate (+44%), cortical blood flow (+15%) and urine output (threefold) while reducing outer medullary PO2 (-24%). Administration of CM reduced outer medullary blood flow (OMBF; -26%) and PO2 (-80%) but did not affect cortical blood flow. Urine output increased 28-fold by CM while arterial blood pressure was reduced. The CM-mediated effect on haemodynamics, PO2, urine output and blood pressure was unaffected by the A1-receptor antagonist. Adenosine A1-receptors are not important mediators of the depression of outer medullary blood flow and PO2 caused by the CM iopromide in the normal rat; however, A1-receptors are tonically active to regulate renal haemodynamics, PO2 and urine production during normal physiological conditions. (orig.)

  11. Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery

    Eltzschig, Holger K.

    2013-01-01

    The gastrointestinal mucosa has proven to be an interesting tissue in which to investigate disease-related metabolism. In this review, we outline some of the evidence that implicates hypoxia-mediated adenosine signaling as an important signature within both healthy and diseased mucosa. Studies derived from cultured cell systems, animal models, and human patients have revealed that hypoxia is a significant component of the inflammatory microenvironment. These studies have revealed a prominent role for hypoxia-induced factor (HIF) and hypoxia signaling at several steps along the adenine nucleotide metabolism and adenosine receptor signaling pathways. Likewise, studies to date in animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes. Ongoing studies to define potential similarities with and differences between innate and adaptive immune responses will continue to teach us important lessons about the complexity of the gastrointestinal tract. Such information has provided new insights into disease pathogenesis and, importantly, will provide insights into new therapeutic targets. PMID:21942704

  12. Metabolic changes of cultured DRG neurons induced by adenosine using confocal microscopy imaging

    Zheng, Liqin; Huang, Yimei; Chen, Jiangxu; Wang, Yuhua; Yang, Hongqin; Zhang, Yanding; Xie, Shusen

    2012-12-01

    Adenosine exerts multiple effects on pain transmission in the peripheral nervous system. This study was performed to use confocal microscopy to evaluate whether adenosine could affect dorsal root ganglia (DRG) neurons in vitro and test which adenosine receptor mediates the effect of adenosine on DRG neurons. After adding adenosine with different concentration, we compared the metabolic changes by the real time imaging of calcium and mitochondria membrane potential using confocal microscopy. The results showed that the effect of 500 μM adenosine on the metabolic changes of DRG neurons was more significant than others. Furthermore, four different adenosine receptor antagonists were used to study which receptor mediated the influences of adenosine on the cultured DRG neurons. All adenosine receptor antagonists especially A1 receptor antagonist (DPCPX) had effect on the Ca2+ and mitochondria membrane potential dynamics of DRG neurons. The above studies demonstrated that the effect of adenosine which may be involved in the signal transmission on the sensory neurons was dose-dependent, and all the four adenosine receptors especially the A1R may mediate the transmission.

  13. Mixed Inhibition of Adenosine Deaminase Activity by 1,3-Dinitrobenzene: A Model for Understanding Cell-Selective Neurotoxicity in Chemically-Induced Energy Deprivation Syndromes in Brain

    Wang, Yipei; Liu, Xin; Schneider, Brandon; Zverina, Elaina A.; Russ, Kristen; Wijeyesakere, Sanjeeva J.; Fierke, Carol A.; Richardson., Rudy J.; Philbert, Martin A.

    2011-01-01

    Astrocytes are acutely sensitive to 1,3-dinitrobenzene (1,3-DNB) while adjacent neurons are relatively unaffected, consistent with other chemically-induced energy deprivation syndromes. Previous studies have investigated the role of astrocytes in protecting neurons from hypoxia and chemical injury via adenosine release. Adenosine is considered neuroprotective, but it is rapidly removed by extracellular deaminases such as adenosine deaminase (ADA). The present study tested the hypothesis that ...

  14. The dopamine-induced coronary vasoconstrictor response is potentiated by adenosine administration in the dog heart.

    Kollár, A; Kékesi, V; Juhász-Nagy, A

    1989-09-01

    The ineffectiveness of beta-adrenergic blockade in abolishing adenosine-induced coronary vasodilation was utilized to demonstrate that dopamine (DA) is capable of eliciting very strong coronary vasoconstrictor actions in vivo. In 2 separate groups of dogs anesthetized with pentobarbital, responses to DA were assessed either by flowmeter recordings or by computer-aided infrared thermography, which senses coronary blood flow-dependent heat emission from the epicardium. In untreated controls, submaximal DA infusions (16 micrograms.kg-1.min-1 iv) elicited a coronary vasodilator response. The thermographic equivalent of this hemodynamic action was an increased epicardial temperature. Pretreatment with oxprenolol (0.5 mg.kg-1 iv) preserved both basic heart activity and cardiac heat emission at levels which were comparable to the control state, but prevented DA mediated excitation of cardiac and coronary beta-adrenoceptors. In this state, DA infusion constricted the coronary arteries and tended to decrease heart emission. However, both types of effects were moderate, and only the hemodynamic effect was statistically significant. If DA was given after the coronary bed had been dilated submaximally by adenosine (30 micrograms.kg-1.min-1 infused into the left heart), the flow-reducing effect of DA became a dramatic phenomenon, and the DA-induced epicardial cooling was significantly potentiated. The results show that after eliminating conventional beta-effects, DA affects the coronary arteries through vasoconstrictor mechanisms. This finding suggests that the DA-induced constriction is limited in undilated coronary arteries by the metabolic autoregulatory capacity of the vessels. PMID:2614933

  15. Adenosine induces cell cycle arrest and apoptosis via cyclinD1/Cdk4 and Bcl-2/Bax pathways in human ovarian cancer cell line OVCAR-3.

    Shirali, Saeid; Aghaei, Mahmoud; Shabani, Mahdi; Fathi, Mojtaba; Sohrabi, Majid; Moeinifard, Marzieh

    2013-04-01

    Adenosine is a regulatory molecule with widespread physiological effects in almost every cells and acts as a potent regulator of cell growth. Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via caspase activation and Bcl-2/Bax pathway. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the OVCAR-3 human ovarian cancer cells. MTT viability, BrdU and cell counting assays were used to study the cell proliferation effect of adenosine in presence of adenosine deaminase inhibitor and the nucleoside transporter inhibitor. Cell cycle analysis, propidium iodide and annexin V staining, caspase-3 activity assay, cyclinD1, Cdk4, Bcl-2 and Bax protein expressions were assessed to detect apoptosis. Adenosine significantly inhibited cell proliferation in a concentration-dependent manner in OVCAR-3 cell line. Adenosine induced cell cycle arrest in G0/G1 phase via Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by Annexin V-FITC staining and increased sub-G1 population. Moreover, down-regulation of Bcl-2 protein expression, up-regulation of Bax protein expression and activation of caspase-3 were observed in response to adenosine treatment. The results of this study suggest that extracellular adenosine induced G1 cell cycle arrest and apoptosis in ovarian cancer cells via cyclinD1/ Cdk4 and Bcl-2/Bax pathways and caspase-3 activation. These data might suggest that adenosine could be used as an agent for the treatment of ovarian cancer. PMID:23345014

  16. Interactions of adenosine, prostaglandins and nitric oxide in hypoxia-induced vasodilatation: in vivo and in vitro studies

    Ray, Clare J; Abbas, Mark R; Coney, Andrew M; Marshall, Janice M

    2002-01-01

    Adenosine, prostaglandins (PG) and nitric oxide (NO) have all been implicated in hypoxia-evoked vasodilatation. We investigated whether their actions are interdependent. In anaesthetised rats, the PG synthesis inhibitors diclofenac or indomethacin reduced muscle vasodilatation evoked by systemic hypoxia or adenosine, but not that evoked by iloprost, a stable analogue of prostacyclin (PGI2), or by an NO donor. After diclofenac, the A1 receptor agonist CCPA evoked no vasodilatation: we previously showed that A1, but not A2A, receptors mediate the hypoxia-induced muscle vasodilatation. Further, in freshly excised rat aorta, adenosine evoked a release of NO, detected with an NO-sensitive electrode, that was abolished by NO synthesis inhibition, or endothelium removal, and reduced by ≈50 % by the A1 antagonist DPCPX, the remainder being attenuated by the A2A antagonist ZM241385. Diclofenac reduced adenosine-evoked NO release by ≈50 % under control conditions, abolished that evoked in the presence of ZM241385, but did not affect that evoked in the presence of DPCPX. Adenosine-evoked NO release was also abolished by the adenyl cyclase inhibitor 2′,5′-dideoxyadenosine, while dose-dependent NO release was evoked by iloprost. Finally, stimulation of A1, but not A2A, receptors caused a release of PGI2 from rat aorta, assessed by radioimmunoassay of its stable metabolite, 6-keto PGF1α, that was abolished by diclofenac. These results suggest that during systemic hypoxia, adenosine acts on endothelial A1 receptors to increase PG synthesis, thereby generating cAMP, which increases the synthesis and release of NO and causes muscle vasodilatation. This pathway may be important in other situations involving these autocoids. PMID:12356892

  17. Effect of adenosine receptors on 3, 4 methylene dioxy methamphetamine induced hyperthermic, neuroinflammatory and neurotoxic effects in mouse brain

    Khairnar, Amit S.

    2010-01-01

    Previous studies of ours and other groups in mice have shown that 3, 4 Methylenedioxymethamphetamine (MDMA, ecstasy) produces neurotoxic damage to dopaminergic neurons and neuroinflammation and caffeine, an adenosine A1/A2A antagonist enhances glial activation induced by MDMA, suggesting potential facilitation of neurodegenerative processes. In the present study we want to investigate effect of caffeine on MDMA induced dopaminergic neurotoxicity in adult mice, whereas selective A1 ( DPCPX ) a...

  18. SOS response induces persistence to fluoroquinolones in Escherichia coli.

    Tobias Dörr

    2009-12-01

    Full Text Available Bacteria can survive antibiotic treatment without acquiring heritable antibiotic resistance. We investigated persistence to the fluoroquinolone ciprofloxacin in Escherichia coli. Our data show that a majority of persisters to ciprofloxacin were formed upon exposure to the antibiotic, in a manner dependent on the SOS gene network. These findings reveal an active and inducible mechanism of persister formation mediated by the SOS response, challenging the prevailing view that persisters are pre-existing and formed purely by stochastic means. SOS-induced persistence is a novel mechanism by which cells can counteract DNA damage and promote survival to fluoroquinolones. This unique survival mechanism may be an important factor influencing the outcome of antibiotic therapy in vivo.

  19. Inhibition of adenosine diphosphate-induced platelet aggregation by alpha-lipoic acid and dihydroquercetin in vitro

    Ivan S Ivanov; Sidehmenova, Anastasia V.; Vera I Smol′yakova; Chernysheva, Galina A.; Plotnikov, Mark B.

    2014-01-01

    Objectives: To investigate the antiplatelet activity of alpha-lipoic acid (α-LA) and dihydroquercetin (DHQ). Materials and Methods: Antiplatelet activity of the α-LA and DHQ was evaluated in rich platelet plasma of rat. The platelet aggregation was induced by adenosine diphosphate (ADP) in concentration of 4 Χ 10 -5 Μ. Results: α-LA and DHQ inhibited platelet aggregation in concentration-dependent manner. The antiplatelet activity of α-LA was more pronounced than DHQ. DHQ also increas...

  20. Diastolic Dysfunction Induced by a High-Fat Diet Is Associated with Mitochondrial Abnormality and Adenosine Triphosphate Levels in Rats

    Kang, Ki-Woon; Kim, Ok-Soon; Chin, Jung Yeon; Kim, Won Ho; Park, Sang Hyun; Choi, Yu Jeong; Shin, Jong Ho; Jung, Kyung Tae; Lim, Do-Seon; Lee, Seong-Kyu

    2015-01-01

    Background Obesity is well-known as a risk factor for heart failure, including diastolic dysfunction. However, this mechanism in high-fat diet (HFD)-induced obese rats remain controversial. The purpose of this study was to investigate whether cardiac dysfunction develops when rats are fed with a HFD for 10 weeks; additionally, we sought to investigate the association between mitochondrial abnormalities, adenosine triphosphate (ATP) levels and cardiac dysfunction. Methods We examined myocardia...

  1. Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice.

    Moscoso-Castro, Maria; Gracia-Rubio, Irene; Ciruela, Francisco; Valverde, Olga

    2016-07-01

    Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2AR) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2AR knockout (KO) mice with complete and specific inactivation of A2AR, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2AR KO animals. Hyperlocomotion induced by d-amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2AR KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia. PMID:27133030

  2. Disinhibition of hippocampal CA3 neurons induced by suppression of an adenosine A1 receptor-mediated inhibitory tonus: Pre- and postsynaptic components

    Alzheimer, Christian; Sutor, Bernd; Ten Bruggencate, Gerrit

    1993-01-01

    Intracellular recordings were performed on hippocampal CA3 neuronsin vitro to investigate the inhibitory tonus generated by endogenously produced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine at concentrations up to 100 nM induced both spontaneous and stimulus-evoked epileptiform burst discharges. Once induced, the 1,3-dipropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparently irreve...

  3. Measuring the dynamics of cyclic adenosine monophosphate level in living cells induced by low-level laser irradiation using bioluminescence resonance energy transfer

    Huang, Yimei; Zheng, Liqin; Yang, Hongqin; Chen, Jiangxu; Wang, Yuhua; Li, Hui; Xie, Shusen; Zeng, Haishan

    2015-05-01

    Several studies demonstrated that the cyclic adenosine monophosphate (cAMP), an important second messenger, is involved in the mechanism of low-level laser irradiation (LLLI) treatment. However, most of these studies obtained the cAMP level in cell culture extracts or supernatant. In this study, the cAMP level in living cells was measured with bioluminescence resonance energy transfer (BRET). The effect of LLLI on cAMP level in living cells with adenosine receptors blocked was explored to identify the role of adenosine receptors in LLLI. The results showed that LLLI increased the cAMP level. Moreover, the rise of cAMP level was light dose dependent but wavelength independent for 658-, 785-, and 830-nm laser light. The results also exhibited that the adenosine receptors, a class of G protein-coupled receptor (GPCR), modulated the increase of cAMP level induced by LLLI. The cAMP level increased more significantly when the A3 adenosine receptors (A3R) were blocked by A3R antagonist compared with A1 adenosine receptor or A2a adenosine receptor blocked in HEK293T cells after LLLI, which was in good agreement with the adenosine receptors' expressions. All these results suggested that measuring the cAMP level with BRET could be a useful technique to study the role of GPCRs in living cells under LLLI.

  4. Mitochondrial Damage and Apoptosis Induced by Adenosine Deaminase Inhibition and Deoxyadenosine in Human Neuroblastoma Cell Lines.

    Garcia-Gil, Mercedes; Tozzi, Maria Grazia; Balestri, Francesco; Colombaioni, Laura; Camici, Marcella

    2016-07-01

    The treatment with deoxycoformycin, a strong adenosine deaminase inhibitor, in combination with deoxyadenosine, causes apoptotic cell death of two human neuroblastoma cell lines, SH-SY5Y and LAN5. Herein we demonstrate that, in SH-SY5Y cells, this combination rapidly decreases mitochondrial reactive oxygen species and, in parallel, increases mitochondrial mass, while, later, induces nuclear fragmentation, and activation of caspase-8, -9, and -3. In previous papers we have shown that a human astrocytoma cell line, subjected to the same treatment, undergoes apoptotic death as well. Therefore, both astrocytoma and neuroblastoma cell lines undergo apoptotic death following the combined treatment with deoxycoformycin and deoxyadenosine, but several differences have been found in the mode of action, possibly reflecting a different functional and metabolic profile of the two cell lines. Overall this work indicates that the neuroblastoma cell lines, like the line of astrocytic origin, are very sensitive to purine metabolism perturbation thus suggesting new therapeutic approaches to nervous system tumors. J. Cell. Biochem. 117: 1671-1679, 2016. © 2015 Wiley Periodicals, Inc. PMID:26659614

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

    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. PMID:27316329

  6. Detection of adenosine triphosphate through polymerization-induced aggregation of actin-conjugated gold/silver nanorods

    Liao, Yu-Ju; Shiang, Yen-Chun; Chen, Li-Yi; Hsu, Chia-Lun; Huang, Chih-Ching; Chang, Huan-Tsung

    2013-11-01

    We have developed a simple and selective nanosensor for the optical detection of adenosine triphosphate (ATP) using globular actin-conjugated gold/silver nanorods (G-actin-Au/Ag NRs). By simply mixing G-actin and Au/Ag NRs (length ˜56 nm and diameter ˜12 nm), G-actin-Au/Ag NRs were prepared which were stable in physiological solutions (25 mM Tris-HCl, 150 mM NaCl, 5.0 mM KCl, 3.0 mM MgCl2 and 1.0 mM CaCl2; pH 7.4). Introduction of ATP into the G-actin-Au/Ag NR solutions in the presence of excess G-actin induced the formation of filamentous actin-conjugated Au/Ag NR aggregates through ATP-induced polymerization of G-actin. When compared to G-actin-modified spherical Au nanoparticles having a size of 13 nm or 56 nm, G-actin-Au/Ag NRs provided better sensitivity for ATP, mainly because the longitudinal surface plasmon absorbance of the Au/Ag NR has a more sensitive response to aggregation. This G-actin-Au/Ag NR probe provided high sensitivity (limit of detection 25 nM) for ATP with remarkable selectivity (>10-fold) over other adenine nucleotides (adenosine, adenosine monophosphate and adenosine diphosphate) and nucleoside triphosphates (guanosine triphosphate, cytidine triphosphate and uridine triphosphate). It also allowed the determination of ATP concentrations in plasma samples without conducting tedious sample pretreatments; the only necessary step was simple dilution. Our experimental results are in good agreement with those obtained from a commercial luciferin-luciferase bioluminescence assay. Our simple, sensitive and selective approach appears to have a practical potential for the clinical diagnosis of diseases (e.g. cystic fibrosis) associated with changes in ATP concentrations.

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

    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...... The observations are consistent with the view that energy requiring processes are involved in ionophore-induced histamine release from rat mast cells although part of the ATP reduction in the aerobic experiments may be due to an uncoupling effect of calcium on the oxidative phosphorylation....

  8. Theophylline and adenosine modulate the inflammatory functions of the human neutrophil by exerting an opposing influence on the stimulus-induced increase in intracellular calcium

    Based on evidence that endogenously-produced adenosine inhibited neutrophil responses, the influence of methylxanthine bronchodilators on neutrophil responses stimulated in vitro by n-formyl-methionyl-leucyl-phenylalanine (fMLP) was examined. At concentrations between 10/sup /minus/5/ M and 10/sup /minus/4/ M, theophylline potentiated lysosomal enzyme release by 30 to 50%, superoxide anion formation by 30 to 60%, and neutrophil aggregation. Theophylline at concentrations >10/sup /minus/4/ M inhibited the same responses by >90%. Adenosine deaminase mimicked, whereas adenosine reversed the theophylline potentiation. A potential role for calcium in the modulation of the neutrophil responses by theophylline and adenosine was explored. Theophylline enhanced by >150% the fMLP-stimulated increase in cytoplasmic calcium concentration ([Ca2+]/sub i/) at time points between 5 and 90 sec as measured by Fura-2. Adenosine deaminase induced a comparable enhancement, whereas 3 /times/ 10/sup /minus/7/ M adenosine and 10/sup /minus/7/ M N-ethylcarboxamideadenosine decreased the [Ca2+]/sub i/ in fMLP-stimulated neutrophils. Extracellular calcium was not required for the opposing influences of theophylline and adenosine and neither compound altered fMLP-stimulated 45Ca uptake at the early time points

  9. Adenosine A2A receptor signaling attenuates LPS-induced pro-inflammatory cytokine formation of mouse macrophages by inducing the expression of DUSP1.

    Köröskényi, Krisztina; Kiss, Beáta; Szondy, Zsuzsa

    2016-07-01

    Adenosine is known to reduce inflammation by suppressing the activity of most immune cells. Previous studies have shown that lipopolysaccharide (LPS) stimulated mouse macrophages produce adenosine, and the adenosine A2A receptor (A2AR) signaling activated in an autocrine manner attenuates LPS-induced pro-inflammatory cytokine formation. It has been suggested that A2AR signaling inhibits LPS-induced pro-inflammatory cytokine production through a unique cAMP-dependent, but PKA- and Epac-independent signaling pathway. However, the mechanism of inhibition was not identified so far. Here we report that LPS stimulation enhances A2AR expression in mouse bone marrow derived macrophages, and loss of A2ARs results in enhanced LPS-induced pro-inflammatory response. Loss of A2ARs in A2AR null macrophages did not alter the LPS-induced NF-κB activation, but an enhanced basal and LPS-induced phosphorylation of MAP kinases (especially that of JNKs) was detected in A2AR null cells. A2AR signaling did not alter the LPS-induced phosphorylation of their upstream kinases, but by regulating adenylate cyclase activity it enhanced the expression of dual specific phosphatase (DUSP)1, a negative regulator of MAP kinases. As a result, lower basal and LPS-induced DUSP1 mRNA and protein levels can be detected in A2AR null macrophages. Silencing of DUSP1 mRNA expression resulted in higher basal and LPS-induced JNK phosphorylation and LPS-induced pro-inflammatory cytokine formation in wild type macrophages, but had no effect on that in A2AR null cells. Our data indicate that A2AR signaling regulates both basal and LPS-induced DUSP1 levels in macrophages via activating the adenylate cyclase pathway. PMID:27066978

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

    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

  11. Neuroprotective effects of adenosine isolated from Cordyceps cicadae against oxidative and ER stress damages induced by glutamate in PC12 cells.

    Olatunji, Opeyemi J; Feng, Yan; Olatunji, Oyenike O; Tang, Jian; Ouyang, Zhen; Su, Zhaoliang; Wang, Dujun; Yu, Xiaofeng

    2016-06-01

    Glutamate has been proven to induce oxidative stress through the formation of reactive oxygen species (ROS) and increased calcium overload which results in neuronal injury, development of neurodegenerative diseases and death. Adenosine is one of the bioactive nucleosides found in Cordyceps cicadae and it has displayed several pharmacological activities including neuroprotection. In this study, the protective effects of adenosine from C. cicadae against glutamate-induce oxidative stress in PC12 cells were evaluated. The exposure of PC12 cells to glutamate (5mM) induced the formation of ROS, increased Ca(2+) influx, endoplasmic reticulum (ER) stress and up regulated the expression of pro-apoptotic factor Bax. However, pretreatment with adenosine markedly increased cell viability, decreased the elevated levels of ROS and Ca(2+) induced by glutamate. Furthermore adenosine increased the activities of GSH-Px and SOD, as well as retained mitochondria membrane potential (MMP), increased Bcl-2/Bax ratio, and reduced the expression of ERK, p38, and JNK. Overall, our results suggest that adenosine may be a promising potential therapeutic agent for the prevention and treatment of neurodegenerative disorders. PMID:27114365

  12. A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival.

    Vyas, Falguni S; Hargreaves, Alan J; Bonner, Philip L R; Boocock, David J; Coveney, Clare; Dickenson, John M

    2016-05-01

    The regulation of tissue transglutaminase (TG2) activity by the GPCR family is poorly understood. In this study, we investigated the modulation of TG2 activity by the A1 adenosine receptor in cardiomyocyte-like H9c2 cells. H9c2 cells were lysed following stimulation with the A1 adenosine receptor agonist N(6)-cyclopentyladenosine (CPA). Transglutaminase activity was determined using an amine incorporating and a protein cross linking assay. TG2 phosphorylation was assessed via immunoprecipitation and Western blotting. The role of TG2 in A1 adenosine receptor-induced cytoprotection was investigated by monitoring hypoxia-induced cell death. CPA induced time and concentration-dependent increases in amine incorporating and protein crosslinking activity of TG2. CPA-induced increases in TG2 activity were attenuated by the TG2 inhibitors Z-DON and R283. Responses to CPA were blocked by PKC (Ro 31-8220), MEK1/2 (PD 98059), p38 MAPK (SB 203580) and JNK1/2 (SP 600125) inhibitors and by removal of extracellular Ca(2+). CPA triggered robust increases in the levels of TG2-associated phosphoserine and phosphothreonine, which were attenuated by PKC, MEK1/2 and JNK1/2 inhibitors. Fluorescence microscopy revealed TG2-mediated biotin-X-cadaverine incorporation into proteins and proteomic analysis identified known (Histone H4) and novel (Hexokinase 1) protein substrates for TG2. CPA pre-treatment reversed hypoxia-induced LDH release and decreases in MTT reduction. TG2 inhibitors R283 and Z-DON attenuated A1 adenosine receptor-induced cytoprotection. TG2 activity was stimulated by the A1 adenosine receptor in H9c2 cells via a multi protein kinase dependent pathway. These results suggest a role for TG2 in A1 adenosine receptor-induced cytoprotection. PMID:27005940

  13. Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism.

    Ledent, C; Dumont, J E; Vassart, G.; Parmentier, M

    1992-01-01

    Cyclic AMP (cAMP) is the major intracellular second messenger of thyrotropin (TSH) action on thyroid cells. It stimulates growth as well as the function and differentiation of cultured thyrocytes. The adenosine A2 receptor, which activates adenylyl cyclase via coupling to the stimulating G protein (Gs), has been shown to promote constitutive activation of the cAMP cascade when transfected into various cell types. In order to test whether the A2 receptor was able to function similarly in vivo ...

  14. Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism.

    Ledent, C; Dumont, J E; Vassart, G; Parmentier, M

    1992-02-01

    Cyclic AMP (cAMP) is the major intracellular second messenger of thyrotropin (TSH) action on thyroid cells. It stimulates growth as well as the function and differentiation of cultured thyrocytes. The adenosine A2 receptor, which activates adenylyl cyclase via coupling to the stimulating G protein (Gs), has been shown to promote constitutive activation of the cAMP cascade when transfected into various cell types. In order to test whether the A2 receptor was able to function similarly in vivo and to investigate the possible consequences of permanent adenylyl cyclase activation in thyroid cells, lines of transgenic mice were generated expressing the canine A2 adenosine receptor under control of the bovine thyroglobulin gene promoter. Thyroid-specific expression of the A2 adenosine receptor transgene promoted gland hyperplasia and severe hyperthyroidism causing premature death of the animals. The resulting goitre represents a model of hyperfunctioning adenomas: it demonstrates that constitutive activation of the cAMP cascade in such differentiated epithelial cells is sufficient to stimulate autonomous and uncontrolled function and growth. PMID:1371462

  15. Interaction-Induced Enhancement and Oscillations of the Persistent Current

    Stafford, C. A.; Wang, D. F.

    1997-01-01

    The persistent current $I$ in integrable models of multichannel rings with both short- and long-ranged interactions is investigated. $I$ is found to oscillate in sign and increase in magnitude with increasing interaction strength due to interaction-induced correlations in the currents contributed by different channels. For sufficiently strong interactions, the contributions of all channels are found to add constructively, leading to a giant enhancement of $I$. Numerical results confirm that t...

  16. Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury

    Yang ZHOU; Schneider, Daniel J.; Morschl, Eva; Song, Ling; Pedroza, Mesias; Karmouty-Quintana, Harry; Le, Thuy.; Sun, Chun-Xiao; Blackburn, Michael R.

    2010-01-01

    Adenosine is an extracellular signaling molecule that is generated in response to cell injury where it orchestrates tissue protection and repair. Whereas adenosine is best known for promoting anti-inflammatory activities during acute injury responses, prolonged elevations can enhance destructive tissue remodeling processes associated with chronic disease states. The generation of adenosine and the subsequent activation of the adenosine 2B receptor (A2BR) is an important processes in the regul...

  17. Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy.

    Min, Hye Sook; Cha, Jin Joo; Kim, Kitae; Kim, Jung Eun; Ghee, Jung Yeon; Kim, Hyunwook; Lee, Ji Eun; Han, Jee Young; Jeong, Lak Shin; Cha, Dae Ryong; Kang, Young Sun

    2016-09-01

    The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria. PMID:27510383

  18. Adenosine A{sub 1} receptors in contrast media-induced renal dysfunction in the normal rat

    Liss, Per; Palm, Fredrik [Department of Diagnostic Radiology, University Hospital, 75185, Uppsala (Sweden); Department of Medical Cell Biology, University Hospital, 75185, Uppsala (Sweden); Carlsson, Per-Ola [Department of Medical Cell Biology, University Hospital, 75185, Uppsala (Sweden); Department of Medical Sciences, University Hospital, 75185, Uppsala (Sweden); Hansell, Peter [Department of Medical Cell Biology, University Hospital, 75185, Uppsala (Sweden)

    2004-07-01

    Renal vasoconstriction with resultant tissue hypoxia, especially in the renal medulla, has been suggested to play a role in contrast media (CM)-induced nephropathy. In this study we investigated the effects of injection of the non-ionic low-osmolar CM iopromide with and without pretreatment with the selective adenosine A{sub 1}-receptor antagonist DPCPX. The effects were evaluated on regional renal blood flow, outer medullary oxygen tension (PO{sub 2}) and urine output in normal anaesthetised rats. A laser-Doppler technique was used for recording haemodynamic changes while oxygen microelectrodes were used for oxygen measurements. The A{sub 1}-receptor antagonist per se elevated glomerular filtration rate (+44%), cortical blood flow (+15%) and urine output (threefold) while reducing outer medullary PO{sub 2} (-24%). Administration of CM reduced outer medullary blood flow (OMBF; -26%) and PO{sub 2} (-80%) but did not affect cortical blood flow. Urine output increased 28-fold by CM while arterial blood pressure was reduced. The CM-mediated effect on haemodynamics, PO{sub 2}, urine output and blood pressure was unaffected by the A{sub 1}-receptor antagonist. Adenosine A{sub 1}-receptors are not important mediators of the depression of outer medullary blood flow and PO{sub 2} caused by the CM iopromide in the normal rat; however, A{sub 1}-receptors are tonically active to regulate renal haemodynamics, PO{sub 2} and urine production during normal physiological conditions. (orig.)

  19. Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

    Lauro, Clotilde; Cipriani, Raffela; Catalano, Myriam; Trettel, Flavia; Chece, Giuseppina; Brusadin, Valentina; Antonilli, Letizia; Van Roijen, Nico; Euebi, Fabrizio; Fredholm, Bertil B.; Limatola, Cristina

    2010-01-01

    Abstract Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-? (TNF-?), interleukin-1? (IL1-?) and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A1 receptors (A1R) with...

  20. Single photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia: Correlation with coronary arteriography, exercise thallium imaging and two-dimensional echocardiography

    The feasibility, safety and diagnostic accuracy of single photon emission computed tomography (SPECT) with thallium-201 imaging during adenosine-induced coronary hyperemia were evaluated in 53 patients with and 7 without coronary artery disease proved by coronary angiography. Adenosine was infused intravenously at a dose of 0.14 mg/kg body weight per min for 6 min and thallium was injected at 3 min. Adenosine caused an increase in heart rate (68 +/- 12 at baseline versus 87 +/- 18 beats/min at peak effect, p less than 0.0001) but no change in blood pressure. The sensitivity and specificity were 92% (95% confidence intervals 81% to 98%) and 100% (95% confidence intervals 59% to 100%), respectively; 20 (61%) of 33 patients with multivessel coronary artery disease were also correctly identified. In 30 patients, the predictive accuracy of adenosine thallium imaging was slightly higher than that of exercise SPECT thallium imaging (90% versus 80%, p = NS) (95% confidence intervals 72% to 97% and 61% to 92%, respectively). In 25 patients, two-dimensional echocardiography during adenosine infusion disclosed a new wall motion abnormality in 2 (10%) of 20 patients with coronary artery disease; 80% of these patients had reversible thallium defects (p less than 0.001). Side effects were mild and transient; aminophylline was used in only three patients. Thus, adenosine SPECT thallium imaging provides a high degree of accuracy in the diagnosis of coronary artery disease. The results are comparable with those of exercise SPECT thallium imaging. Most reversible defects in the adenosine study are not associated with any transient wall motion abnormality

  1. Early adenosine release contributes to hypoxia-induced disruption of stimulus-induced sharp wave-ripple complexes in rat hippocampal area CA3.

    Jarosch, Marlene S; Gebhardt, Christine; Fano, Silvia; Huchzermeyer, Christine; Ul Haq, Rizwan; Behrens, Christoph J; Heinemann, Uwe

    2015-07-01

    We investigated the effects of hypoxia on sharp wave-ripple complex (SPW-R) activity and recurrent epileptiform discharges in rat hippocampal slices, and the mechanisms underlying block of this activity. Oxygen levels were measured using Clark-style oxygen sensor microelectrodes. In contrast to recurrent epileptiform discharges, oxygen consumption was negligible during SPW-R activity. These network activities were reversibly blocked when oxygen levels were reduced to 20% or less for 3 min. The prolongation of hypoxic periods to 6 min caused reversible block of SPW-Rs during 20% oxygen and irreversible block when 0% oxygen (anoxia) was applied. In contrast, recurrent epileptiform discharges were more resistant to prolonged anoxia and almost fully recovered after 6 min of anoxia. SPW-Rs were unaffected by the application of 1-butyl-3-(4-methylphenylsulfonyl) urea, a blocker of KATP channels, but they were blocked by activation of adenosine A1 receptors. In support of a modulatory function of adenosine, the amplitude and incidence of SPW-Rs were increased during application of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Interestingly, hypoxia decreased the frequency of miniature excitatory post-synaptic currents in CA3 pyramidal cells, an effect that was converted into increased frequency by the adenosine A1 agonist DPCPX. In addition, DPCPX also delayed the onset of hypoxia-mediated block of SPW-Rs. Our data suggest that early adenosine release during hypoxia induces a decrease in pre-synaptic glutamate release and that both might contribute to transient block of SPW-Rs during hypoxia/anoxia in area CA3. PMID:25959377

  2. Inhibition of adenosine diphosphate-induced platelet aggregation by alpha-lipoic acid and dihydroquercetin in vitro

    Ivan S Ivanov

    2014-01-01

    Full Text Available Objectives: To investigate the antiplatelet activity of alpha-lipoic acid (α-LA and dihydroquercetin (DHQ. Materials and Methods: Antiplatelet activity of the α-LA and DHQ was evaluated in rich platelet plasma of rat. The platelet aggregation was induced by adenosine diphosphate (ADP in concentration of 4 Χ 10 -5 Μ. Results: α-LA and DHQ inhibited platelet aggregation in concentration-dependent manner. The antiplatelet activity of α-LA was more pronounced than DHQ. DHQ also increased the antiplatelet activity of α-LA by 1.4 times. Conclusion: Combined simultaneous use of α-LA and DHQ possessed the high antiplatelet activity, and DHQ potentiated the activity of α-LA.

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

    Mortensen, Stefan P; Gonzalez-Alonso, Jose; Bune, Laurids; Saltin, Bengt; Pilegaard, Henriette; Hellsten, Ylva

    2009-01-01

    -arterial infusion of ATP (0.45-2.45 micromol/min; mean+/-SEM) in 19 healthy, male subjects with and without co-infusion of NG-mono-methyl-L-arginine (L-NMMA; NO formation inhibitor; 12.3+/-0.3 mg/min), indomethacin (INDO; prostaglandin formation blocker; 613+/-12 microg/min) and/or theophylline (adenosine receptor...... 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...

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

    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.

  5. Possible involvement of A1 receptors in the inhibition of gonadotropin secretion induced by adenosine in rat hemipituitaries in vitro

    D.L.W. Picanço-Diniz

    1999-09-01

    Full Text Available We investigated the participation of A1 or A2 receptors in the gonadotrope and their role in the regulation of LH and FSH secretion in adult rat hemipituitary preparations, using adenosine analogues. A dose-dependent inhibition of LH and FSH secretion was observed after the administration of graded doses of the R-isomer of phenylisopropyladenosine (R-PIA; 1 nM, 10 nM, 100 nM, 1 µM and 10 µM. The effect of R-PIA (10 nM was blocked by the addition of 8-cyclopentyltheophylline (CPT, a selective A1 adenosine receptor antagonist, at the dose of 1 µM. The addition of an A2 receptor-specific agonist, 5-N-methylcarboxamidoadenosine (MECA, at the doses of 1 nM to 1 µM had no significant effect on LH or FSH secretion, suggesting the absence of this receptor subtype in the gonadotrope. However, a sharp inhibition of the basal secretion of these gonadotropins was observed after the administration of 10 µM MECA. This effect mimicked the inhibition induced by R-PIA, supporting the hypothesis of the presence of A1 receptors in the gonadotrope. R-PIA (1 nM to 1 µM also inhibited the secretion of LH and FSH induced by phospholipase C (0.5 IU/ml in a dose-dependent manner. These results suggest the presence of A1 receptors and the absence of A2 receptors in the gonadotrope. It is possible that the inhibition of LH and FSH secretion resulting from the activation of A1 receptors may have occurred independently of the increase in membrane phosphoinositide synthesis.

  6. Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2A adenosine receptor in rats

    Masaru Odashima; Reina Ohba; Sumio Watanabe; Joel Linden; Michiro Otaka; Mario Jin; Koga Komatsu; Isao Wada; Youhei Horikawa; Tamotsu Matsuhashi; Natsumi Hatakeyama; Jinko Oyake

    2006-01-01

    AIM: To determine whether a specific adenosine A2A receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines.METHODS: Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L,8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e,2.5-5 μg/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion.RESULTS: Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8±7.75 mm and was reduced to 3.8±1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P< 0.01).The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e.Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e.CONCLUSION: The specific adenosine A2A receptor agohist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

  7. Specificity of synergistic coronary flow enhancement by adenosine and pulsatile perfusion in the dog.

    Pagliaro, P; Senzaki, H; Paolocci, N; Isoda, T; Sunagawa, G; Recchia, F A; Kass, D A

    1999-10-01

    1. Coronary flow elevation from enhanced perfusion pulsatility is synergistically amplified by adenosine. This study determined the specificity of this interaction and its potential mechanisms. 2. Mean and phasic coronary flow responses to increasing pulsatile perfusion were assessed in anaesthetized dogs, with the anterior descending coronary artery servoperfused to regulate real-time physiological flow pulsatility at constant mean pressure. Pulsatility was varied between 40 and 100 mmHg. Hearts ejected into the native aorta whilst maintaining stable loading. 3. Increasing pulsatility elevated mean coronary flow +11.5 +/- 1.7 % under basal conditions. Co-infusion of adenosine sufficient to raise baseline flow 66 % markedly amplified this pulsatile perfusion response (+82. 6 +/- 14.3 % increase in mean flow above adenosine baseline), due to a leftward shift of the adenosine-coronary flow response curve at higher pulsatility. Flow augmentation with pulsatility was not linked to higher regional oxygen consumption, supporting direct rather than metabolically driven mechanisms. 4. Neither bradykinin, acetylcholine nor verapamil reproduced the synergistic amplification of mean flow by adenosine and higher pulsatility, despite being administered at doses matching basal flow change with adenosine. 5. ATP-sensitive potassium (KATP) activation (pinacidil) amplified the pulse-flow response 3-fold, although this remained significantly less than with adenosine. Co-administration of the phospholipase A2 inhibitor quinacrine virtually eliminated adenosine-induced vasodilatation, yet synergistic interaction between adenosine and pulse perfusion persisted, albeit at a reduced level. 6. Thus, adenosine and perfusion pulsatility specifically interact to enhance coronary flow. This synergy is partially explained by KATP agonist action and additional non-flow-dependent mechanisms, and may be important for modulating flow reserve during exercise or other high output states where

  8. Persistence of the immune response induced by BCG vaccination

    Blitz Rose

    2008-01-01

    Full Text Available Abstract Background Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. Methods A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-γ response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD in a whole blood assay before, 3 months, 12 months (n = 148 and 3 years (n = 19 after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16. Results A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13% failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13% or 3 (3/19; 16% years. IFN-γ response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81% made a detectable IFN-γ response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38% matched unvaccinated controls (p = 0.012; teenagers vaccinated in infancy were 19 times more likely to make an IFN-γ response of > 500 pg/ml than unvaccinated teenagers. Conclusion BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the

  9. Relationship Between Adenosine - Induced ST Segment Depression During 99mTc-MIBI Scintigraphy and The Severity of Coronary Artery Disease

    Pharmacologic coronary vasodilation in conjunction with myocardial perfusion scintigraphy has become an alternative to dynamic exercise test for the diagnosis and risk stratification of coronary artery disease, especially in patients who are unable to perform adequate exercise. Dipyridamole and adenosine have been used for pharmacologic stress testing with myocardial perfusion imaging. Adenosine is a potent, coronary vasodilator with rapid onset of action, short half life, near maximal coronary vasodilation and less serious side effects. ST segment depression has been reported in about 7-15% of patients with coronary artery disease receiving dipyridamole in conjunction with myocardial perfusion imaging. The exact cause and clinical significance are not known. In order to evaluate the relationship between adenosine-induced ST segment depression during 99mTc-MIBI myocardial perfusion scintigraphy and the severity of coronary artery disease, we performed 99m-MIBI imaging after intravenous infusion of adenosine in 120 patients with suspected coronary artery disease. Of the 120 patients, 28 also performed coronary angiography. There were 24 patients with ST segment depression during 99mTc-MIIBI scintigraphy and 96 patients without ST segment depression. Adenosine was infused intravenously at a dose of 0.14 mg/kg per minute for 6 minutes and 99MmTc-MIB1 was injected at 3 minute. We then compared the hemodynamic changes, side effects, scintigraphic and angiographic findings. Heart rate increased 90 ± 19 beats/minute in the group with ST depression compared with 80 ±16 beats/minute in the group without ST depression(p9mTc-MIBI images were abnormal in 23(96%) patients with ST segment depression and 66(69%) patients without ST segment depression(p99mTc-MIBI myocardial perfusion scintigraphy with intravenous adenosine is related to the severity of coronary artery disease.

  10. Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2.

    Peng, Shuang; Gerasimenko, Julia V; Tsugorka, Tatiana; Gryshchenko, Oleksiy; Samarasinghe, Sujith; Petersen, Ole H; Gerasimenko, Oleg V

    2016-08-01

    Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca(2+) signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca(2+) elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca(2+) signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5-10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca(2+) release followed by Ca(2+) entry and also substantially reduced Ca(2+) extrusion because of decreased intracellular ATP levels. The toxic Ca(2+) signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca(2+) signals and necrosis. We tested the effects of inhibiting the Ca(2+) release-activated Ca(2+) entry by the Ca(2+) channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca(2+) entry and also protected effectively against the development of necrosis.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. PMID:27377732

  11. Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2

    Peng, Shuang; Gerasimenko, Julia V.; Tsugorka, Tatiana; Gryshchenko, Oleksiy; Samarasinghe, Sujith; Gerasimenko, Oleg V.

    2016-01-01

    Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca2+ signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5–10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca2+ release followed by Ca2+ entry and also substantially reduced Ca2+ extrusion because of decreased intracellular ATP levels. The toxic Ca2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca2+ signals and necrosis. We tested the effects of inhibiting the Ca2+ release-activated Ca2+ entry by the Ca2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’. PMID:27377732

  12. Bond cleavages of adenosine 5'-triphosphate induced by monochromatic soft X-rays

    To investigate which type of bond is likely to be cleaved by soft X-ray exposure to an adenosine 5'-triphosphate (ATP), we observed spectral changes in X-ray absorption near edge structure (XANES) around nitrogen and oxygen K-edge of an ATP film by soft X-ray irradiation. Experiments were performed at a synchrotron soft X-ray beamline at SPring-8, Japan. The XANES spectra around the nitrogen and oxygen .K-edge slightly varied by exposure to 560 eV soft X-rays. These changes are originated from the cleavage of C-N bonds between a sugar and a nucleobase site and of C-O, P-O or O-H bond of sugar and phosphate site. From the comparison between the change in XANES intensity of σ* peak at nitrogen and that at oxygen K-edges, it is inferred that the C-O, P-O or O-H bond of sugar and phosphate is much efficiently cleaved than the C-N of N-glycoside bond by the exposure of 560 eV soft X-ray to ATP film.

  13. Adenosine and Sleep

    Bjorness, Theresa E.; Greene, Robert W.

    2009-01-01

    Over the last several decades the idea that adenosine (Ado) plays a role in sleep control was postulated due in large part to pharmacological studies that showed the ability of Ado agonists to induce sleep and Ado antagonists to decrease sleep. A second wave of research involving in vitro cellular analytic approaches and subsequently, the use of neurochemical tools such as microdialysis, identified a population of cells within the brainstem and basal forebrain arousal centers, with activity t...

  14. Autophagy occurs within an hour of adenosine triphosphate treatment after nerve cell damage:the neuroprotective effects of adenosine triphosphate against apoptosis

    Na Lu; Baoying Wang; Xiaohui Deng; Honggang Zhao; Yong Wang; Dongliang Li

    2014-01-01

    After hypoxia, ischemia, or inlfammatory injuries to the central nervous system, the damaged cells release a large amount of adenosine triphosphate, which may cause secondary neuronal death. Autophagy is a form of cell death that also has neuroprotective effects. Cell Counting Kit assay, monodansylcadaverine staining, lfow cytometry, western blotting, and real-time PCR were used to determine the effects of exogenous adenosine triphosphate treatment at different concentrations (2, 4, 6, 8, 10 mmol/L) over time (1, 2, 3, and 6 hours) on the apoptosis and autophagy of SH-SY5Y cells. High concentrations of extracellular adenosine triphosphate induced autophagy and apoptosis of SH-SY5Y cells. The enhanced autophagy ifrst appeared, and peaked at 1 hour after treatment with adenosine triphosphate. Cell apoptosis peaked at 3 hours, and persisted through 6 hours. With prolonged exposure to the adenosine triphosphate treatment, the fraction of apoptotic cells increased. These data suggest that the SH-SY5Y neural cells initiated autophagy against apoptosis within an hour of adenosine triphosphate treatment to protect themselves against injury.

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

    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.

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

    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.

  17. Hepatitis C virus core protein induces energy metabolism disorders of hepatocytes by down-regulation of silent mating type information regulation 2 homolog-1 and adenosine monophosphate-acti vated protein kinase signaling pathway

    于建武

    2013-01-01

    Objective To study the role of silent mating type information regulation2homotog-1(SIRT1)-adenosine monophosphate(AMP)-activated protein kinase(AMPK) signaling pathway in hepatitis C virus core protein(HCV-core)induced energy metabolism disorders

  18. Ultracytochemical localization of H+—adenosine triphosphatase activity in autophagic vacuoles induced by vinblastine in rat liver

    LUOSHENQIU; MASAHIROSAKAI; 等

    1990-01-01

    H-adenosine triphosphatase (H+-ATPase) activity was demonstrated cytochemically in autophagic vacuoles(AVs) of rat hepatocytes using a modification of the method for the demonstration of neutral p-nitrophenyl phosphatase(p-NPPase) activity[1].When an inhibitor of H+-ATPase,N-ethylmaleimide (NEM) or 4,4'-diisothiocyanostilbene-2,2'disulfonic acid,disodium salt (DIDS) was included in the incubation medium the enyzme activity was abolished indicating that p-NPPase demonstrated in this study represents H+-ATPase.Autophagy was induced by a single intraperitoneal injection of vinblastine sulfate(VBL).The number of AVs increased remarkably in hepatocytes from 40 min after VBL treatment.H+-ATPase activity was observed mainly on the membranes of lysosomes and AVs.However,early forms of AVs containing only incompletely digested material showed no H+-ATPase activity.Most AVs revealing a positive reaction seemed to be in advanced stages of development.Acid phosphatase acticity was demonstrable in mature but not in early forms of AVs.The present investigation showed that membranes of advanced stage AVs possess an H+-ATPase which may be derived from lysosomal membranes.

  19. [Thallium-201 myocardial perfusion imaging during adenosine-induced coronary vasodilation in patients with ischemic heart disease].

    Takeishi, Y; Chiba, J; Abe, S; Ikeda, K; Tonooka, I; Komatani, A; Takahashi, K; Nakagawa, Y; Shiraishi, T; Tomoike, H

    1992-09-01

    201Tl myocardial perfusion imaging during adenosine infusion was performed in consecutive 55 patients with suspected coronary artery disease. Adenosine was infused intravenously at a rate of 0.14 mg/kg/min for 6 minutes and a dose of 111 MBq of 201Tl was administered in a separate vein at the end of third minute of infusion. Myocardial SPECT imaging was begun 5 minutes and 3 hours after the end of adenosine infusion. For evaluating the presence of perfusion defects, 2 short axis images at the basal and apical levels and a vertical long axis image at the mid left ventricle were used. The regions with decreased 201Tl uptake were assessed semi-quantitatively. Adenosine infusion caused a slight reduction in systolic blood pressure and an increase in heart rate. The rate pressure products increased slightly (9314 +/- 2377 vs. 10360 +/- 2148, p < 0.001). Chest pain (24%) and headache (13%) were the frequent side effects. The second-degree atrioventricular block was developed in 11 of 55 (20%) patients. All symptoms and hemodynamic changes were well tolerated and disappeared within 1 or 2 minutes after discontinuing adenosine infusion. The sensitivity and specificity for the detection of patients with coronary artery disease were 100% (31/31) and 88% (7/8), respectively. 201Tl myocardial imaging during adenosine infusion was considered to be safe and useful for evaluating the patients with ischemic heart disease. PMID:1453559

  20. The Role of Adenosine A1 and A2A Receptors in the Caffeine Effect on MDMA-Induced DA and 5-HT Release in the Mouse Striatum

    Górska, A. M.; Gołembiowska, K.

    2014-01-01

    3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) popular as a designer drug is often used with caffeine to gain a stronger stimulant effect. MDMA induces 5-HT and DA release by interaction with monoamine transporters. Co-administration of caffeine and MDMA may aggravate MDMA-induced toxic effects on DA and 5-HT terminals. In the present study, we determined whether caffeine influences DA and 5-HT release induced by MDMA. We also tried to find out if adenosine A1 and A2A receptors play a ro...

  1. Enhanced Antitumor Effects of Adenoviral-Mediated siRNA against GRP78 Gene on Adenosine-Induced Apoptosis in Human Hepatoma HepG2 Cells

    Ling-Fei Wu

    2014-01-01

    Full Text Available Our previous studies show that adenosine-induced apoptosis is involved in endoplasmic reticulum stress in HepG2 cells. In this study, we have investigated whether knockdown of GRP78 by short hairpin RNA (shRNA increases the cytotoxic effects of adenosine in HepG2 cells. The adenovirus vector-delivered shRNA targeting GRP78 (Ad-shGRP78 was constructed and transfected into HepG2 cells. RT-PCR assay was used to determine RNA interference efficiency. Effects of knockdown of GRP78 on adenosine-induced cell viabilities, cell-cycle distribution and apoptosis, as well as relative protein expressions were determined by flow cytometry and/or Western blot analysis. The intracellular Ca2+ concentration was detected by laser scanning confocal microscope. Mitochondrial membrane potential (ΔΨm was measured by a fluorospectrophotometer. The results revealed that GRP78 mRNA was significantly downregulated by Ad-shGRP78 transfection. Knockdown of GRP78 enhanced HepG2 cell sensitivity to adenosine by modulating G0/G1 arrest and stimulating Bax, Bak, m-calpain, caspase-4 and CHOP protein levels. Knockdown of GRP78 worsened cytosolic Ca2+ overload and ΔΨm loss. Knockdown of caspase-4 by shRNA decreased caspase-3 mRNA expression and cell apoptosis. These findings indicate that GRP 78 plays a protective role in ER stress-induced apoptosis and show that the combination of chemotherapy drug and RNA interference adenoviruses provides a new treatment strategy against malignant tumors.

  2. High-dose adenosine overcomes the attenuation of myocardial perfusion reserve caused by caffeine.

    Reyes, E.; Loong, C Y; Harbinson, Mark; Donovan, J; Anagnostopoulos, C.; Underwood, S. R.

    2008-01-01

    Objectives:We studied whether an increase in adenosine dose overcomes caffeine antagonism on adenosine-mediated coronary vasodilation.Background:Caffeine is a competitive antagonist at the adenosine receptors, but it is unclear whether caffeine in coffee alters the actions of exogenous adenosine, and whether the antagonism can be surmounted by increasing the adenosine dose.Methods:Myocardial perfusion scintigraphy (MPS) was used to assess adenosine-induced hyperemia in 30 patients before (bas...

  3. Effect of adenosine and adenosine analogs on [14C]aminopyrine accumulation by rabbit parietal cells

    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

  4. Temperature induced decay of persistent currents in superfluid ultracold gas

    Kumar, Avinash; Jendrzejewski, Fred; Campbell, Gretchen K

    2016-01-01

    We study how temperature affects the lifetime of a quantized, persistent current state in a toroidal Bose-Einstein condensate (BEC). When the temperature is increased, we find a decrease in the persistent current lifetime. Comparing our measured decay rates to simple models of thermal activation and quantum tunneling, we do not find agreement. The measured critical velocity is also found to depend strongly on temperature, approaching the zero temperature mean-field solution as the temperature is decreased. This indicates that an appropriate definition of critical velocity must incorporate the role of thermal fluctuations, something not explicitly contained in traditional theories.

  5. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats.

    Zheng, Xinyan; Hasegawa, Hiroshi

    2016-01-01

    We examined the effects of an adenosine receptor agonist on caffeine-induced changes in thermoregulation, neurotransmitter release in the preoptic area and anterior hypothalamus, and endurance exercise performance in rats. One hour before the start of exercise, rats were intraperitoneally injected with either saline alone (SAL), 10 mg kg(-1) caffeine and saline (CAF), a non-selective adenosine receptor agonist (5'-N-ethylcarboxamidoadenosine [NECA]: 0.5 mg kg(-1)) and saline (NECA), or the combination of caffeine and NECA (CAF+NECA). Rats ran until fatigue on the treadmill with a 5% grade at a speed of 18 m min(-1) at 23 °C. Compared to the SAL group, the run time to fatigue (RTTF) was significantly increased by 52% following caffeine administration and significantly decreased by 65% following NECA injection (SAL: 91 ± 14.1 min; CAF: 137 ± 25.8 min; NECA: 31 ± 13.7 min; CAF+NECA: 85 ± 11.8 min; p<0.05). NECA decreased the core body temperature (Tcore), oxygen consumption, which is an index of heat production, tail skin temperature, which is an index of heat loss, and extracellular dopamine (DA) release at rest and during exercise. Furthermore, caffeine injection inhibited the NECA-induced decreases in the RTTF, Tcore, heat production, heat loss, and extracellular DA release. Neither caffeine nor NECA affected extracellular noradrenaline or serotonin release. These results support the findings of previous studies showing improved endurance performance and overrides in body limitations after caffeine administration, and imply that the ergogenic effects of caffeine may be associated with the adenosine receptor blockade-induced increases in brain DA release. PMID:26604076

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

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

    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...

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

    Ya-kun DONG; Li, Ai-zhen; Li-heng ZHENG; Yue-peng CHI; Wang, Yu-Hong; Qiu-mei WANG; Zhu, Gui-Yun; Lan-pin XIE

    2015-01-01

    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 highe...

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

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

    2014-01-01

    altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FI O2 . The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses...... protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. RESULTS: At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at...... blood pressure and reduces the vasodilatory responses to adenosine and ATP....

  9. Drugs elevating extracellular adenosine administered in vivo induce serum colony-stimulating activity and interleukin-6 in mice

    Weiterová, Lenka; Hofer, Michal; Pospíšil, Milan; Znojil, V.; Štreitová, Denisa

    2007-01-01

    Roč. 56, č. 4 (2007), s. 463-473. ISSN 0862-8408 R&D Projects: GA ČR(CZ) GP305/03/D050 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : extracellular adenosine * serum colony-stimulating activity * interleukin -6 Subject RIV: BO - Biophysics Impact factor: 1.505, year: 2007

  10. Effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on ocular blood flow in rabbits.

    Konno, Takashi; Uchibori, Takehiro; Nagai, Akihiko; Kogi, Kentaro; Nakahata, Norimichi

    2007-02-27

    Previously, we reported that a relatively selective adenosine A(2A) receptor agonist 2-(6-cyano-1-hexyn-1-yl)adenosine (2-CN-Ado) elicited ocular hypotension in rabbits (Journal of Pharmacological Sciences 2005;97:501-509). In the present study, we investigated the effect of 2-CN-Ado on ocular blood flow in rabbit eyes. An intravitreal injection of 2-CN-Ado increased ocular blood flow, measured by a non-contact laser flowmeter. 2-CN-Ado-induced increase in ocular blood flow was accompanied with the retinal vasodilation. The increase in ocular blood flow was inhibited by an adenosine A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, but not by an adenosine A(2B) receptor antagonist alloxazine or an adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. The repetitive applications of topical 2-CN-Ado twice a day for 7 days produced a persistent increase in ocular blood flow with ocular hypotension. These results suggest that 2-CN-Ado increases the ocular blood flow mainly via adenosine A(2A) receptor, and that the topical application of 2-CN-Ado for several days not only increases the ocular blood flow but also prolong ocular hypotension, indicating that 2-CN-Ado may be a useful lead compound for the treatment of ischemic retinal diseases such as glaucoma. PMID:17239401

  11. Systemic administration of the adenosine A2A agonist CGS 21680 induces sedation at doses that suppress lever pressing and food intake

    Mingote, Susana; Pereira, Mariana; Farrar, Andrew M.; McLaughlin, Peter J.; Salamone, John D.

    2008-01-01

    Adenosine A2A receptors are involved in the regulation of several behavioral functions. Adenosine A2A antagonists exert antiparkinsonian effects in animal models, and adenosine A2A agonists suppress locomotion and impair various aspects of motor control. The present experiments were conducted to study the effects of low doses of the adenosine A2A agonist CGS 21680 on lever pressing, specific parameters of food intake, and sedation. In the first experiment, the effects of CGS 21680 on fixed ra...

  12. Turbulence-induced persistence in laser beam wandering.

    Zunino, Luciano; Gulich, Damián; Funes, Gustavo; Pérez, Darío G

    2015-07-01

    We have experimentally confirmed the presence of long-memory correlations in the wandering of a thin Gaussian laser beam over a screen after propagating through a turbulent medium. A laboratory-controlled experiment was conducted in which coordinate fluctuations of the laser beam were recorded at a sufficiently high sampling rate for a wide range of turbulent conditions. Horizontal and vertical displacements of the laser beam centroid were subsequently analyzed by implementing detrended fluctuation analysis. This is a very well-known and widely used methodology to unveil memory effects from time series. Results obtained from this experimental analysis allow us to confirm that both coordinates behave as highly persistent signals for strong turbulent intensities. This finding is relevant for a better comprehension and modeling of the turbulence effects in free-space optical communication systems and other applications related to propagation of optical signals in the atmosphere. PMID:26125388

  13. Turbulence-induced persistence in laser beam wandering

    Zunino, Luciano; Funes, Gustavo; Pérez, Darío G

    2015-01-01

    We have experimentally confirmed the presence of long-memory correlations in the wandering of a thin Gaussian laser beam over a screen after propagating through a turbulent medium. A laboratory-controlled experiment was conducted in which coordinate fluctuations of the laser beam were recorded at a sufficiently high sampling rate for a wide range of turbulent conditions. Horizontal and vertical displacements of the laser beam centroid were subsequently analyzed by implementing detrended fluctuation analysis. This is a very well-known and widely used methodology to unveil memory effects from time series. Results obtained from this experimental analysis allow us to confirm that both coordinates behave as highly persistent signals for strong turbulent intensities. This finding is relevant for a better comprehension and modeling of the turbulence effects in free-space optical communication systems and other applications related to propagation of optical signals in the atmosphere.

  14. Non-selective and selective adenosine receptor agonists in the treatment of radiation- and chemotherapy-induced myelosuppression

    Hofer, Michal; Pospíšil, Milan

    Nurnberg, 2008. A-127. [EHRLICH II - 2nd World Conference on Magic Bullets, Celebrating the 100th Anniversary of the Nobel Prize Award to Paul Ehrlich. 03.10.2008-05.10.2008, Nurnberg] R&D Projects: GA ČR(CZ) GA305/06/0015; GA ČR(CZ) GA305/08/0158 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : adenosine receptor agonists * hematopoiesis * treatment of myelosuppression Subject RIV: BO - Biophysics

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

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

    2002-01-01

    been established. Microdialysis (molecular mass cut-off 5 kDa) was performed simultaneously in calf muscle and peritendinous Achilles tissue at rest and during 10 min periods of incremental (0.75 W, 2 W, 3.5 W and 4.75 W) dynamic plantar flexion exercise in 10 healthy individuals (mean age 27 years......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...... 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 <0.05) and in the peritendinous tissue (from 27.7 +/- 7.8 nmol l(-1) to 105.0 +/- 37.9 nmol l(-1); P <0.05). In parallel, the adenosine concentration...

  16. Recent results and persisting problems in modeling flow induced coalescence

    Fortelný, Ivan; Jůza, Josef

    Melville: American Institute of Physics, 2014, Roč. 1593, s. 646-649. ISSN 0094-243X. [International Conference of the Polymer Processing Society /29./ - PPS-29. Nuremberg (DE), 15.07.2013-19.07.2013] R&D Projects: GA ČR GAP106/11/1069 Institutional support: RVO:61389013 Keywords : flow induced coalescence * polymer blends * viscoelasticity Subject RIV: BK - Fluid Dynamics

  17. The A3 Adenosine Receptor Agonist CF502 Inhibits the PI3K, PKB/Akt and NF-κB Signaling Pathway in Synoviocytes from Rheumatoid Arthritis Patients and in Adjuvant Induced Arthritis Rats

    Ochaion, A.; BAR-YEHUDA, S.; Cohen, S.; Amital, H; Jacobson, K. A.; Joshi, B.V.; Gao, Z. G.; Barer, F.; PATOKA, R.; Del Valle, L; Perez-Liz, G.; Fishman, P

    2008-01-01

    The A3 adenosine receptor (A3AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant and collagen induced arthritis.

  18. Adenosine in exercise adaptation.

    Simpson, R E; Phillis, J. W.

    1992-01-01

    By influencing the regulation of the mechanisms of angiogenesis, erythropoietin production, blood flow, myocardial glucose uptake, glycogenolysis, systolic blood pressure, respiration, plasma norepinephrine and epinephrine levels, adenosine may exert a significant effect on the body's adaptation response to exercise. However, adenosine's possible influence over the vasodilatory response to exercise in skeletal muscle is controversial and more research is required to resolve this issue. Variou...

  19. Cordycepin induces apoptosis of C6 glioma cells through the adenosine 2A receptor-p53-caspase-7-PARP pathway.

    Chen, Ying; Yang, Shih-Hung; Hueng, Dueng-Yuan; Syu, Jhih-Pu; Liao, Chih-Chen; Wu, Ya-Chieh

    2014-06-01

    Cordycepin, 3'-deoxyadenosine from Cordyceps sinensis, has been shown to exert anti-tumor effects in several cancer cell lines. This study investigated the effect of cordycepin on a rat glioma cell line. Cordycepin caused apoptosis in C6 glioma cells in a time- and concentration-dependent manner, but did not affect the survival of primary cultured rat astrocytes. Cordycepin increased the total protein levels of p53 and phosphorylated p53 in the C6 cells. Levels of cleaved caspase-7 and poly (ADP-ribose) polymerase (PARP), but not cleaved caspase-3, were also increased after cordycepin treatment. Specific inhibitors for p53 and caspases abrogated cordycepin-induced caspase-7 and PARP cleavage, and prevented cordycepin-induced apoptosis. Moreover, siRNA knockdown of p53 blocked cordycepin-induced cleavage of caspase-7 and PARP. Both adenosine 2A receptor (A2AR) antagonist and small interference RNA (siRNA) knockdown of A2AR blocked cordycepin-induced apoptosis, p53 activation, and caspase-7 and PARP cleavage. These may provide a new strategy of cordycepin for glioma therapy in the future. PMID:24704558

  20. Role of adenosine receptors in caffeine tolerance

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity

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

    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...

  2. Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model.

    Bleickardt, Carina J; Kazdoba, Tatiana M; Jones, Nicholas T; Hunter, John C; Hodgson, Robert A

    2014-03-01

    Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisia-like behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A2A receptor antagonists for the treatment of antipsychotic-induced movement disorders. PMID:24211858

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

    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.

  4. Adenosine Triphosphate (ATP) Inhibits Voltage-Sensitive Potassium Currents in Isolated Hensen's Cells and Nifedipine Protects Against Noise-Induced Hearing Loss in Guinea Pigs.

    Ye, Rui; Liu, Jun; Jia, Zhiying; Wang, Hongyang; Wang, YongAn; Sun, Wei; Wu, Xuan; Zhao, Zhifei; Niu, Baolong; Li, Xingqi; Dai, Guanghai; Li, Jianxiong

    2016-01-01

    BACKGROUND There is increasing evidence that adenosine triphosphate (ATP), a well-known neurotransmitter and neuromodulator in the central nervous system, plays an important role as an extracellular chemical messenger in the cochlea. MATERIAL AND METHODS Using a whole-cell recording technique, we studied the effects of ATP on isolated Hensen's cells, which are supporting cells in the cochlea, to determine if they are involved in the transduction of ions with hair cells. RESULTS ATP (0.1-10 µM) reduced the potassium current (IK+) in the majority of the recorded Hensen's cells (21 out of 25 cells). An inward current was also induced by high concentrations of ATP (100 µM to 10 mM), which was reversibly blocked by 100 µM suramin (a purinergic antagonist) and blocked by nifedipine (an L-type calcium channel blocker). After the cochleas were perfused with artificial perilymph solutions containing nifedipine and exposed to noise, the amplitude increase in the compound action potential (CAP) threshold and the reduction in cochlear microphonics was lower than when they were exposed to noise alone. CONCLUSIONS Our results suggest that ATP can block IK+ channels at a low concentration and induce an inward Ca2+ current at high concentrations, which is reversed by purinergic receptors. Nifedipine may have a partially protective effect on noise-induced hearing loss (NIHL). PMID:27292522

  5. Adenosine Triphosphate (ATP) Inhibits Voltage-Sensitive Potassium Currents in Isolated Hensen’s Cells and Nifedipine Protects Against Noise-Induced Hearing Loss in Guinea Pigs

    Ye, Rui; Liu, Jun; Jia, Zhiying; Wang, Hongyang; Wang, YongAn; Sun, Wei; Wu, Xuan; Zhao, Zhifei; Niu, Baolong; Li, Xingqi; Dai, Guanghai; Li, Jianxiong

    2016-01-01

    Background There is increasing evidence that adenosine triphosphate (ATP), a well-known neurotransmitter and neuromodulator in the central nervous system, plays an important role as an extracellular chemical messenger in the cochlea. Material/Methods Using a whole-cell recording technique, we studied the effects of ATP on isolated Hensen’s cells, which are supporting cells in the cochlea, to determine if they are involved in the transduction of ions with hair cells. Results ATP (0.1–10 μM) reduced the potassium current (IK+) in the majority of the recorded Hensen’s cells (21 out of 25 cells). An inward current was also induced by high concentrations of ATP (100 μM to 10 mM), which was reversibly blocked by 100 μM suramin (a purinergic antagonist) and blocked by nifedipine (an L-type calcium channel blocker). After the cochleas were perfused with artificial perilymph solutions containing nifedipine and exposed to noise, the amplitude increase in the compound action potential (CAP) threshold and the reduction in cochlear microphonics was lower than when they were exposed to noise alone. Conclusions Our results suggest that ATP can block IK+ channels at a low concentration and induce an inward Ca2+ current at high concentrations, which is reversed by purinergic receptors. Nifedipine may have a partially protective effect on noise-induced hearing loss (NIHL). PMID:27292522

  6. Evaluation of coronary artery disease using myocardial thallium-201 imaging with single photon emission computed tomography during adenosine induced coronary vasodilation

    Adenosine-loaded Tl-201 myocardial SPECT was performed in consecutive 55 patients with suspected ischemic heart disease. Among these patients, 22 had cuncurrently exercise Tl-201 myocardial SPECT imaging for comparison. Adenosine was intravenously injected at a dose of 0.14 mg/kg/min continuously for 6 min, and 3 min after the stard of injection Tl-201 was injected via the different vein. Myocardial SPECT images were acquired at 5 min and 3 hr after the completion of intravenous injection of adenosine. Perfusion defect and the presence or absence of redistribution (RD) were visually interpreted from the short- and long-axial tomograms. Relative Tl-201 regional uptake ratios were quantitatively determined. Decreased systolic arterial pressure, increased heart rate, and slightly increased rate-pressure product were observed with adenosine injection. Chest pain (13 patients), head-ache (7), ST depression (17), and A-V block II were also seen; however, these symptoms rapidly disappeared with the withdrawal of adenosine. The findings by adenosine loading were concordent with those by exercise loading (91% for perfusion defect and 86% for presence or absence of RD). According to segments, both loading tests were concordent in 90% for persusion and 89% for RD. Both adenosine- and exercise-loaded imagings correlated well with regional Tl uptake by segements, the lowest value of Tl-201 defect, and extent score of Tl-201 defect. Adenosine-loaded imaging had a sensitivity of 100%, a specificity of 88%, and an accuracy of 97% for detecting parenchymal coronary lesions in evaluable 39 patients. In evaluable 22 patients, the sensitivity, specificity, and accuracy were 100%, 83%, and 95% for adenosine-loaded imaging and 88%, 83%, and 86% for exercise-loaded imaging. Thus, adenosine-loaded Tl-201 myocardial SPECT may be a safety and useful method for diagnosing ischemic heart disease. (N.K.)

  7. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment

    Ohta, Akio

    2016-01-01

    Within tumors, some areas are less oxygenated than others. Since their home ground is under chronic hypoxia, tumor cells adapt to this condition by activating aerobic glycolysis; however, this hypoxic environment is very harsh for incoming immune cells. Deprivation of oxygen limits availability of energy sources and induces accumulation of extracellular adenosine in tumors. Extracellular adenosine, upon binding with adenosine receptors on the surface of various immune cells, suppresses pro-inflammatory activities. In addition, signaling through adenosine receptors upregulates a number of anti-inflammatory molecules and immunoregulatory cells, leading to the establishment of a long-lasting immunosuppressive environment. Thus, due to hypoxia and adenosine, tumors can discourage antitumor immune responses no matter how the response was induced, whether it was spontaneous or artificially introduced with a therapeutic intention. Preclinical studies have shown the significance of adenosine in tumor survival strategy by demonstrating tumor regression after inactivation of adenosine receptors, inhibition of adenosine-producing enzymes, or reversal of tissue hypoxia. These promising results indicate a potential use of the inhibitors of the hypoxia–adenosine pathway for cancer immunotherapy. PMID:27066002

  8. Adenosine A2A Receptor Blockade Prevents Rotenone-Induced Motor Impairment in a Rat Model of Parkinsonism.

    Fathalla, Ahmed M; Soliman, Amira M; Ali, Mohamed H; Moustafa, Ahmed A

    2016-01-01

    Pharmacological studies implicate the blockade of adenosine receptorsas an effective strategy for reducing Parkinson's disease (PD) symptoms. The objective of this study is to elucidate the possible protective effects of ZM241385 and 8-cyclopentyl-1, 3-dipropylxanthine, two selective A2A and A1 receptor antagonists, on a rotenone rat model of PD. Rats were split into four groups: vehicle control (1 ml/kg/48 h), rotenone (1.5 mg/kg/48 h, s.c.), ZM241385 (3.3 mg/kg/day, i.p) and 8-cyclopentyl-1, 3-dipropylxanthine (5 mg/kg/day, i.p). After that, animals were subjected to behavioral (stride length and grid walking) and biochemical (measuring concentration of dopamine levels using high performance liquid chromatography, HPLC). In the rotenone group, rats displayed a reduced motor activity and disturbed movement coordination in the behavioral tests and a decreased dopamine concentration as foundby HPLC. The effect of rotenone was partially prevented in the ZM241385 group, but not with 8-cyclopentyl-1,3-dipropylxanthine administration. The administration of ZM241385 improved motor function and movement coordination (partial increase of stride length and partial decrease in the number of foot slips) and an increase in dopamine concentration in the rotenone-injected rats. However, the 8-cyclopentyl-1,3-dipropylxanthine and rotenone groups were not significantly different. These results indicate that selective A2A receptor blockade by ZM241385, but not A1 receptor blockadeby 8-cyclopentyl-1,3-dipropylxanthine, may treat PD motor symptoms. This reinforces the potential use of A2A receptor antagonists as a treatment strategy for PD patients. PMID:26973484

  9. 31P MR spectroscopy of the liver showing dose dependent adenosine triphosphate decreases after radiation induced hepatic injury

    Objective: To study the relationship between ATP level changes detected by hepatic 31P MRS with the pathologic changes of liver in rabbits and to investigate the diagnostic value of ATP level changes in acute hepatic radiation injury. Methods: A total of 30 rabbits received different radiation doses (ranging from 5,10,20 Gy) to establish acute hepatic injury models. Blood hepatic function tests, 31P MRS and pathological examinations were carded out 24 h after irradiation. The degree of injury was evaluated according to hepatocyte pathology. Ten healthy rabbits served as controls. The MR examination was performed on a 1.5 T imager using a 1H-31P surface coil with 2D chemical shift imaging technique. The relative quantities of phosphomonoesters (PME), phosphodiesters (PDE), inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured. Analysis of variance was used to compare the results of 31P MRS and histopathology under various acute hepatic radiation injuries, and SNK was used further to conduct comparison between each other if there was significant difference. Results: The ATP relative quantification in control (n=10), mild (n=12), moderate (n=11), and severe (n=7) injury groups according to pathological grading were 1.83±0.33, 1.58±0.25, 1.32±0.07 and 1.02±0.18, with significant differences among them (F=22.878, P<0.01), and it decreased progressively with the increased degree of injury. The PDE index showed no significant trend for the evaluation of hepatic radiation injury. The area under the peak of β-ATP decreased with the increased severity of radiation injury. Conclusions: The relative quantification of hepatic ATP levels can reflect the pathological severity of acute hepatic radiation injury. The decreasing hepatic ATP levels may be used as biomarker of acute liver injury following radiation. (authors)

  10. Comparison of myocardial blood flow induced by adenosine triphosphate and dipyridamole in patients with coronary artery disease

    Myocardial perfusion imaging with adenosine triphosphate (ATP) has been used increasingly to diagnose coronary artery disease (CAD) and assess risk for this disease. This study compared absolute myocardial blood flow (MBF) and myocardial flow reserve index (MFR) with ATP and dipyridamole (DIP) in patients with CAD. MBF was quantified by 15O-H2O PET in 21 patients with CAD (17 male, 4 female), aged 55 to 81 years. MBF was measured at rest, during intravenous injection of ATP (0.16 mg/kg/min), and again after DIP infusion (0.56 mg/kg). Regions of interest were drawn in nonischemic and ischemic segments based on findings from thallium-201 (201Tl) scintigraphy and coronary angiography (CAG). Absolute MBF values and indexes of MFR were calculated in nonischemic and ischemic segments. Intravenous injection of ATP and DIP significantly increased MBF in nonischemic (2.4±0.9 and 2.1±0.8 ml/g/min, respectively; p<0.01, for both) and in ischemic segments (1.3±0.4 and 1.5±0.4 ml/g/min, respectively; p<0.01, for both). There was a significant difference in MBF values between ATP and DIP in nonischemic segments (p<0.05), which was not observed in ischemic segments. In nonischemic segments, ATP produced higher MFR than DIP (2.1±0.8 and 1.8±0.7, respectively; p<0.05), while no significant difference was observed in ischemic segments (1.5±0.6 and 1.7±0.3, respectively). ATP produced a greater hyperemia than DIP between the ischemic and nonischemic myocardium in patients with CAD. ATP is as effective as DIP for the diagnosis of CAD. (author)

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

    V Haktan Ozacmak; Hale Sayan

    2007-01-01

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

  12. Adenosine Receptors and Asthma

    Wilson, Constance N; Nadeem, Ahmed; Spina, Domenico; Brown, Rachel; Page, Clive P.; Jamal Mustafa, S.

    2009-01-01

    The pathophysiological processes underlying respiratory diseases like asthma are complex, resulting in an overwhelming choice of potential targets for the novel treatment of this disease. Despite this complexity, asthmatic subjects are uniquely sensitive to a range of substances like adenosine, thought to act indirectly to evoke changes in respiratory mechanics and in the underlying pathology, and thereby to offer novel insights into the pathophysiology of this disease. Adenosine is of partic...

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

    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. PMID:24485458

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

    Ma, Ying Jie; Kim, Chan-Hee; Ryu, Kyoung-Hwa; Kim, Min-Su; So, Young-In; Lee, Kong-Joo; Garred, Peter; Lee, Bok-Luel

    2011-01-01

    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...

  15. Transient and persistent pain induced connectivity alterations in pediatric complex regional pain syndrome.

    Clas Linnman

    Full Text Available 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.

  16. Transient and persistent pain induced connectivity alterations in pediatric complex regional pain syndrome.

    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

  17. Familial factors responsible for persistent crying-induced asthma: a case report.

    Weinstein, A G

    1987-10-01

    Crying behavior of the asthmatic child may induce wheezing symptoms. This may be a clinical problem for families with asthmatic children who exhibit frequent and persistent crying behavior. This case report identifies behaviors by the child and parents that may be responsible for continual crying. Child factors include (1) "spoiled" personality, (2) poor self-image, (3) biologic sensitivity to foods, medication, and environmental allergens producing irritability. Parental factors include poor disciplinary practices secondary to (1) disrupted home life, (2) guilt, and (3) overprotective behavior. Identification of these factors may be helpful in establishing clinical management strategies to reduce crying-induced asthma. PMID:3116889

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

    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...

  19. Role of endoplasmic reticular stress in aortic endothelial apoptosis induced by intermittent/persistent hypoxia

    YANG Yuan-yuan; SHANG Jin; LIU Hui-guo

    2013-01-01

    Background Accumulated evidence shows that hypoxia can induce endothelial apoptosis,however the mechanism is still unknown.We hypothesized whether intermittent or persistent hypoxia could induce endoplasmic reticular stress,leading to endothelial apoptosis.Methods Twenty-four 8-week male Sprague Dawley (SD) rats were divided into three groups:normoxia (NC) group,intermittent hypoxia (IH) group and persistent hypoxia (PH) group.TUNEL staining was performed to detect aortic arch endotheliar apoptosis,and immunohistochemistry for BIP,CHOP and caspase12 to test protein expression;human umbilical vein endothelial cells (HUVECs) of the line ECV304 were cultured (with or without taurodeoxycholic acid (TUDCA) 10 mmol/L,100 mmol/L) and divided into four groups:NC group (20.8% O2 for 4 hours),PH1 group (5% O2 for 4 hours),PH2 group (5% O2 for 12 hours) and IH group (20.8% O2 and 5% O2 alternatively for 8 hours).Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in each group.The expressions of GRP78,CHOP and caspase12 were detected by real-time quantitative reverse-transcription PCR.Result Intermittent and persistent hypoxia could increase the rate of endothelium apoptosis and the expressions of GRP78,CHOP and caspase12 compared with the control,induction by intermittent hypoxia was slightly higher than persistent hypoxia.In the HUVEC experiment,TUDCA significantly reduced apoptosis and the expressions of GRP78,CHOP and caspase12.Conclusion Hypoxia,especially intermittent,can induce endothelial cell apoptosis possibly through endoplasmic reticulum stress pathway,which can be attenuated by taurodeoxycholic acid.

  20. E2F1 enhances 8-chloro-adenosine-induced G2/M arrest and apoptosis in A549 and H1299 lung cancer cells.

    Duan, Hong-Ying; Cao, Ji-Xiang; Qi, Jun-Juan; Wu, Guo-Sheng; Li, Shu-Yan; An, Guo-Shun; Jia, Hong-Ti; Cai, Wang-Wei; Ni, Ju-Hua

    2012-03-01

    The E2F1 transcription factor is a well known regulator of cell proliferation and apoptosis, but its role in response to DNA damage is less clear. 8-Chloro-adenosine (8-Cl-Ado), a nucleoside analog, can inhibit proliferation in a variety of human tumor cells. However, it is still elusive how the agent acts on tumors. Here we show that A549 and H1299 cells formed DNA double-strand breaks after 8-Cl-Ado exposure, accompanied by E2F1 upregulation at protein level. Overexpressed wild-type (E2F1-wt) colocalized with double-strand break marker γ-H2AX and promoted G2/M arrest in 8-Cl-Ado-exposed A549 and H1299, while expressed S31A mutant of E2F1 (E2F1-mu) significantly reduced ability to accumulate at sites of DNA damage and G2/M arrest, suggesting that E2F1 is required for activating G2/M checkpoint pathway upon DNA damage. Transfection of either E2F1-wt or E2F1-mu plasmid promoted apoptosis in 8-Cl-Ado-exposed cells, indicating that 8-Cl-Ado may induce apoptosis in E2F1-dependent and E2F1-independent ways. These findings demonstrate that E2F1 plays a crucial role in 8-Cl-Ado-induced G2/M arrest but is dispensable for 8-Cl-Ado-induced apoptosis. These data also suggest that the mechanism of 8-Cl-Ado action is complicated. PMID:22803943

  1. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.

    Batalha, Vânia L; Ferreira, Diana G; Coelho, Joana E; Valadas, Jorge S; Gomes, Rui; Temido-Ferreira, Mariana; Shmidt, Tatiana; Baqi, Younis; Buée, Luc; Müller, Christa E; Hamdane, Malika; Outeiro, Tiago F; Bader, Michael; Meijsing, Sebastiaan H; Sadri-Vakili, Ghazaleh; Blum, David; Lopes, Luísa V

    2016-01-01

    Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions. PMID:27510168

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

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

    2016-03-01

    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 vasoconstriction that continues beyond the active cooling period despite skin temperatures returning toward baseline values. The significant and persistent reduction in skin perfusion may contribute to nonfreezing cold injury (NFCI) associated with cryotherapy. PMID:26632263

  3. Oxidative stress parameters and erythrocyte membrane adenosine triphosphatase activities in streptozotocin-induced diabetic rats administered aqueous preparation of Kalanchoe Pinnata leaves

    Nikhil Menon

    2016-01-01

    Full Text Available Background: Diabetes mellitus is a chronic metabolic disease that according to the World Health Organization affects more than 382 million people. The rise in diabetes mellitus coupled with the lack of an effective treatment has led many to investigate medicinal plants to identify a viable alternative. Objective: To evaluate red blood cell (RBC membrane adenosine triphosphatase (ATPase activities and antioxidant levels in streptozotocin-induced diabetic rats administered aqueous preparation of Kalanchoe pinnata leaves. Materials and Methods: Diabetes mellitus was induced in rats by a single administration of streptozotocin (60 mg/kg. Diabetic rats were then treated with aqueous K. pinnata preparation (three mature leaves ~ 9.96 g/70 kg body weight or about 0.14 g/kg body weight/day for 30 days. Serum glucose, RBC membrane ATPase activities, and antioxidant levels were determined. Results: We noted weight loss and reduced food consumption in the treated diabetic group. Serum glucose levels were reduced in the treated diabetic group compared to the other groups. Superoxide dismutase activity and glutathione levels were not significantly elevated in the treated group compared to the diabetic group. However, serum catalase activity was significantly (P < 0.05 increased in the treated diabetic group compared to the other groups. Serum thiobarbituric acid reactive substances were not significantly altered among the groups. There was a significant (P < 0.05 increase in Mg2+ ATPase activity and a nonsignificant increase in Na+/K+ ATPase activity in the RBC membrane of the treated diabetic group compared to the diabetic group. Conclusion: The consumption of aqueous preparation of K. pinnata may accrue benefits in the management of diabetes by lowering oxidative stress often associated with the disease and improving the availability of cellular magnesium through an increase in the magnesium ATPase pump in the RBC membrane for increased cellular metabolism

  4. Genetic deletion of the adenosine A(2A) receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain.

    Metaxas, Athanasios; Al-Hasani, Ream; Farshim, Pamela; Tubby, Kristina; Berwick, Amy; Ledent, Catherine; Hourani, Susanna; Kitchen, Ian; Bailey, Alexis

    2013-08-01

    Considerable evidence indicates that adenosine A(2A) receptors (A(2A)Rs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A(2A) and nAChRs, we examined if the complete genetic deletion of adenosine A(2A)Rs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A(2A)R gene. Quantitative autoradiography was used to measure cytisine-sensitive [¹²⁵I]epibatidine and [¹²⁵I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5-7), wild-type and adenosine A(2A)R knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A(2A)R knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A(2A)Rs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10-50 ng ml⁻¹). Our data highlight the involvement of adenosine A(2A)Rs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A(2A)Rs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors. PMID:23583933

  5. Role of hypothalamic adenosine 5'-monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia.

    Alquier, Thierry; Kawashima, Junji; Tsuji, Youki; Kahn, Barbara B

    2007-03-01

    Antecedent hypoglycemia blunts counterregulatory responses that normally restore glycemia, a phenomenon known as hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to impaired counterregulatory responses are largely unknown. Hypothalamic AMP-activated protein kinase (AMPK) acts as a glucose sensor. To determine whether failure to activate AMPK could be involved in the etiology of HAAF, we developed a model of HAAF using repetitive intracerebroventricular (icv) injection of 2-deoxy-D-glucose (2DG) resulting in transient neuroglucopenia in normal rats. Ten minutes after a single icv injection of 2DG, both alpha1- and alpha2-AMPK activities were increased 30-50% in arcuate and ventromedial/dorsomedial hypothalamus but not in other hypothalamic regions, hindbrain, or cortex. Increased AMPK activity persisted in arcuate hypothalamus at 60 min after 2DG injection when serum glucagon and corticosterone levels were increased 2.5- to 3.4-fold. When 2DG was injected icv daily for 4 d, hypothalamic alpha1- and alpha2-AMPK responses were markedly blunted in arcuate hypothalamus, and alpha1-AMPK was also blunted in mediobasal hypothalamus 10 min after 2DG on d 4. Both AMPK isoforms were activated normally in arcuate hypothalamus at 60 min. Counterregulatory hormone responses were impaired by recurrent neuroglucopenia and were partially restored by icv injection of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside, an AMPK activator, before 2DG. Glycogen content increased 2-fold in hypothalamus after recurrent neuroglucopenia, suggesting that glycogen supercompensation could be involved in down-regulating the AMPK glucose-sensing pathway in HAAF. Thus, activation of hypothalamic AMPK may be important for the full counterregulatory hormone response to neuroglucopenia. Furthermore, impaired or delayed AMPK activation in specific hypothalamic regions may play a critical role in the etiology of HAAF. PMID:17185376

  6. A single dose biodegradable vaccine depot that induces persistently high levels of antibody over a year.

    Chua, Brendon Y; Sekiya, Toshiki; Al Kobaisi, Mohammad; Short, Kirsty R; Mainwaring, David E; Jackson, David C

    2015-06-01

    In this study, we describe a biodegradable vaccine depot which persists in vivo for at least 4-months, provides synergistic adjuvant effects and also allows dose sparing of both antigen and adjuvant. A single administration results in immediate release of a priming dose of vaccine, by a process of syneresis, which is then followed by release of remaining vaccine which maintains robust antibody levels that last for more than a year. The platform technology comprises two aqueous components; one contains chitosan and hydroxyapatite, in which the vaccine is incorporated, and the other consists of a crosslinking agent, tripolyphosphate (TPP) and chondroitin sulphate. When co-injected into tissue, they spontaneously crosslink forming a firm yet compliant vaccine-containing depot. Whole body imaging of animals inoculated with the material show that the depot persists in situ for up to 19 weeks. Vaccination of mice with depot formulations containing ovalbumin (OVA) emulsified in Montanide ISA 61 adjuvant results in the induction of robust antibody responses using doses of adjuvant 40-fold less than those recommended by the manufacturer. Dose sparing effects were also apparent with antigen when delivered in the depot. Similar dose sparing effects were observed with Montanide ISA 50, complete and incomplete Freund's adjuvants but not with aluminium hydroxide nor Quil A. Antibody titres, induced by a single dose of antigen/adjuvant formulation incorporated in the depot, persisted at high levels for at least 55 weeks following a single dose of vaccine. PMID:25890706

  7. 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

    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 t...

  8. Adenosine and sleep

    Behavioral and biochemical approaches have been used to determine the relative contribution of endogenous adenosine and adenosine receptors to the sleep-wake cycle in the rat. Adenosine concentrations in specific areas of the rat brain were not affected by 24 hours of total sleep deprivation, or by 24 or 48 hours of REM sleep deprivation. In order to assess the effect of REM sleep deprivation on adenosine A1 receptors, 3H-L-PIA binding was measured. The Bmax values for 3H-L-PIA binding to membrane preparations of the cortices and corpus striata from 48 hour REM sleep-deprived animals were increased 14.8% and 23%, respectively. These increases were not maintained following the cessation of sleep deprivation and recovered within 2 hours. The results of a 96 hour REM deprivation experiment were similar to those of the 48 hour REM sleep deprivation experiment. However, these increases were not evident in similar structures taken from stress control animals, and conclusively demonstrated that the changes in 3H-L-PIA binding resulted from REM sleep deprivation and not from stress

  9. Adenosine and sleep

    Yanik, G.M. Jr.

    1987-01-01

    Behavioral and biochemical approaches have been used to determine the relative contribution of endogenous adenosine and adenosine receptors to the sleep-wake cycle in the rat. Adenosine concentrations in specific areas of the rat brain were not affected by 24 hours of total sleep deprivation, or by 24 or 48 hours of REM sleep deprivation. In order to assess the effect of REM sleep deprivation on adenosine A/sub 1/ receptors, /sup 3/H-L-PIA binding was measured. The Bmax values for /sup 3/H-L-PIA binding to membrane preparations of the cortices and corpus striata from 48 hour REM sleep-deprived animals were increased 14.8% and 23%, respectively. These increases were not maintained following the cessation of sleep deprivation and recovered within 2 hours. The results of a 96 hour REM deprivation experiment were similar to those of the 48 hour REM sleep deprivation experiment. However, these increases were not evident in similar structures taken from stress control animals, and conclusively demonstrated that the changes in /sup 3/H-L-PIA binding resulted from REM sleep deprivation and not from stress.

  10. Effect of theophylline on adenosine production in the canine myocardium

    Adenosine is thought to participate in local regulation of coronary blood flow. However, competitive antagonists of adenosine fail to block myocardial active hyperemia. The authors examined the effect of locally administered theophylline on active hyperemia and myocardial adenosine production during intracoronary isoproterenol infusion in the dog heart. Isoproterenol decreased coronary resistance and increased myocardial adenosine production. Infusion of theophylline at a rate that attenuated the vasodilator response to exogenously administered adenosine failed to attenuate the increase in coronary blood flow produced by isoproterenol. However, theophylline plus isoproterenol production greater increases in myocardial adensine production than isoproterenol alone. The curves relating resistance and adenosine in the presence of theophylline fell to the right of those in the absence of theophylline. These findings suggest that the failure of theophylline to attenuate isoproterenol hyperemia in the dog heart results at least in part from an increase in adenosine concentration at the arteriole to a level beyond that blocked by this competitive antagonist and that adenosine may in fact play a role in isoproterenol-induced active hyperemia

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

    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.

  12. Boosting persistence time of laser-induced plasma by electric arc discharge for optical emission spectroscopy

    Plasma induced by nanosecond laser ablation is re-excited by a pulsed electric discharge and the parameters and optical emission of the plasma are measured. The discharge is a low-voltage and high-current electric arc that is triggered by the laser-induced plasma and slowly decaying with time. The optical emission of such combined plasma lasts up to several milliseconds which is much longer than without re-excitation (μs range). The emission spectra of re-excited plasma measured on different sample materials show higher line intensities than spectra measured by conventional laser-induced breakdown spectroscopy (LIBS). Moreover, emission lines of fluorine (spectral range 683–691 nm) and sulfur (range 520–550 nm) not detected by conventional LIBS become easily detectable with the combined plasma. The concentration of major components in metallurgical slags, as determined by calibration-free LIBS, agrees very well to the reference data evaluating the spectra taken from re-excited plasma. - Highlights: • Persistence time of laser-induced plasma in air is increased from ~ 10 μs to ~ 1 ms. • Laser-induced plasma triggers an electric arc discharge that boosts the plasma. • The combined laser-arc plasma is in LTE state over very long time (ms range). • CF-LIBS method delivers accurate results evaluating spectra of combined plasma. • Emission from S and F, not detected by LIBS, is detected with combined plasma

  13. BDNF-induced presynaptic facilitation of GABAergic transmission in the hippocampus of young adults is dependent of TrkB and adenosine A2A receptors.

    Colino-Oliveira, Mariana; Rombo, Diogo M; Dias, Raquel B; Ribeiro, Joaquim A; Sebastião, Ana M

    2016-06-01

    Brain-derived neurotrophic factor (BDNF) and adenosine are widely recognized as neuromodulators of glutamatergic transmission in the adult brain. Most BDNF actions upon excitatory plasticity phenomena are under control of adenosine A2A receptors (A2ARs). Concerning gamma-aminobutyric acid (GABA)-mediated transmission, the available information refers to the control of GABA transporters. We now focused on the influence of BDNF and the interplay with adenosine on phasic GABAergic transmission. To assess this, we evaluated evoked and spontaneous synaptic currents recorded from CA1 pyramidal cells in acute hippocampal slices from adult rat brains (6 to 10 weeks old). BDNF (10-100 ng/mL) increased miniature inhibitory postsynaptic current (mIPSC) frequency, but not amplitude, as well as increased the amplitude of inhibitory postsynaptic currents (IPSCs) evoked by afferent stimulation. The facilitatory action of BDNF upon GABAergic transmission was lost in the presence of a Trk inhibitor (K252a, 200 nM), but not upon p75(NTR) blockade (anti-p75(NTR) IgG, 50 μg/mL). Moreover, the facilitatory action of BDNF onto GABAergic transmission was also prevented upon A2AR antagonism (SCH 58261, 50 nM). We conclude that BDNF facilitates GABAergic signaling at the adult hippocampus via a presynaptic mechanism that depends on TrkB and adenosine A2AR activation. PMID:26897393

  14. Persistent enhancement of the HF pump-induced plasma line measured with a UHF diagnostic radar at HAARP

    Oyama, S.; B. J. Watkins; Djuth, F.T.; Kosch, Mike J.; Bernhardt, P. A.; Heinselman, C. J.

    2006-01-01

    Plasma lines excited by a powerful, high-frequency (HF) radio wave are studied using data obtained with an ultrahigh frequency (UHF) radar at HAARP (High Frequency Active Auroral Research Program) from 3 to 5 February 2005. Of particular interest is persistent enhancement of the radar backscatter power during HF on at several HF frequencies. The persistent enhancement is induced with the HF frequency slightly lower than foF2 by a few hundred kHz; by contrast the persistent enhancement does no...

  15. Persistent genetic instability induced by synergistic interaction between x-irradiation and 6-thioguanine

    Clonal karyotypic analysis was performed using G-banding on four groups of clones derived from TK6 human lymphoblasts: 25 HPRT- total gene deletion mutants induced by exposure to 2 Gy of x-rays; 8 spontaneous HPRT- total gene deletion mutants; 25 clones irradiated with 2 Gy, not selected with 6-thioguanine. Ten to twenty metaphases were examined for each clone. Extensive karyotypic heterogeneity was observed among x-ray induced HPRT - mutants involving translocations, deletions, duplications and aneuploidy; recovery of chromosomal aberrations and karyotypic heterogeneity was greater than the additive effects of clones treated with x-irradiation or 6-thioguanine alone. This synergistic interaction between x-irradiation and 6-thioguanine was observed despite a 7 day phenotypic expression interval between exposure to the two agents. Thus, x-irradiated TK6 cells appear to be persistently hypersensitive to the induction of genetic instability. Several mutants appeared to exhibit evidence of clonal evolution since aberrant chromosomes observed in one metaphase, were found to be further modified in other metaphases. In order to determine if genetic instability, identified by clonal karyotypic heterogeneity, affected specific locus mutation rates, we utilized the heterozygous thymidine kinase (tk) locus as a genetic marker. Four x-ray induced HPRT- mutants with extensive karyotypic heterogeneity, exhibited mutation rates at tk ranging from 5 to 8 fold higher than the parental TK6 cells. Further analysis, using fractionated low dose radiation exposure, is currently in progress

  16. A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel-Induced Mechanical Hypersensitivity.

    Kozachik, Sharon L; Page, Gayle G

    2016-05-01

    Paclitaxel (PAC) treatment is associated with persistent, debilitating neuropathic pain that affects the hands and feet. Female sex and biological stress responsivity are risk factors for persistent pain, but it is unclear whether these important biologically based factors confer risk for PAC-induced neuropathic pain. To determine the relative contributions of sex and hypothalamic-pituitary-adrenal (HPA)-axis stress responsivity to PAC-induced mechanical hypersensitivity, we employed a PAC protocol consisting of three, 2-week cycles of every-other-day doses of PAC 1 mg/kg versus saline (Week 1) and recovery (Week 2), totaling 42 days, in mature male and female Fischer 344, Lewis, and Sprague Dawley (SD) rats, known to differ in HPA axis stress responsivity. Mechanical sensitivity was operationalized using von Frey filaments, per the up-down method. Among PAC-injected rats, SD rats exhibited significantly greater mechanical hypersensitivity relative to accumulative PAC doses compared to Fischer 344 rats. Lewis rats were not significantly different in mechanical hypersensitivity from SD or Fischer 344 rats. At the end of the protocol, PAC-injected SD rats exhibited profound mechanical hypersensitivity, whereas the PAC-injected Fischer 344 rats appeared relatively resilient to the long-term effects of PAC and exhibited mechanical sensitivity that was not statistically different from their saline-injected counterparts. Sex differences were mixed and noted only early in the PAC protocol. Moderate HPA axis stress responsivity may confer additional risk for the painful effects of PAC. If these findings hold in humans, clinicians may be better able to identify persons who may be at increased risks for developing neuropathic pain during PAC therapy. PMID:26512050

  17. Oxidative stress induces persistent telomeric DNA damage responsible for nuclear morphology change in mammalian cells.

    Elisa Coluzzi

    Full Text Available One main function of telomeres is to maintain chromosome and genome stability. The rate of telomere shortening can be accelerated significantly by chemical and physical environmental agents. Reactive oxygen species are a source of oxidative stress and can produce modified bases (mainly 8-oxoG and single strand breaks anywhere in the genome. The high incidence of guanine residues in telomeric DNA sequences makes the telomere a preferred target for oxidative damage. Our aim in this work is to evaluate whether chromosome instability induced by oxidative stress is related specifically to telomeric damage. We treated human primary fibroblasts (MRC-5 in vitro with hydrogen peroxide (100 and 200 µM for 1 hr and collected data at several time points. To evaluate the persistence of oxidative stress-induced DNA damage up to 24 hrs after treatment, we analysed telomeric and genomic oxidative damage by qPCR and a modified comet assay, respectively. The results demonstrate that the genomic damage is completely repaired, while the telomeric oxidative damage persists. The analysis of telomere length reveals a significant telomere shortening 48 hrs after treatment, leading us to hypothesise that residual telomere damage could be responsible for the telomere shortening observed. Considering the influence of telomere length modulation on genomic stability, we quantified abnormal nuclear morphologies (Nucleoplasmic Bridges, Nuclear Buds and Micronuclei and observed an increase of chromosome instability in the same time frame as telomere shortening. At subsequent times (72 and 96 hrs, we observed a restoration of telomere length and a reduction of chromosome instability, leaving us to conjecture a correlation between telomere shortening/dysfunction and chromosome instability. We can conclude that oxidative base damage leads to abnormal nuclear morphologies and that telomere dysfunction is an important contributor to this effect.

  18. Commonly prescribed β-lactam antibiotics induce C. trachomatis persistence/stress in culture at physiologically relevant concentrations.

    Jennifer eKintner

    2014-04-01

    Full Text Available Chlamydia trachomatis, the most common bacterial sexually transmitted disease agent worldwide, enters a viable, non-dividing and non-infectious state (historically termed persistence and more recently referred to as the chlamydial stress response when exposed to penicillin G in culture. Notably, penicillin G-exposed chlamydiae can reenter the normal developmental cycle upon drug removal and are resistant to azithromycin-mediated killing. Because penicillin G is less frequently prescribed than other β-lactams, the clinical relevance of penicillin G-induced chlamydial persistence/stress has been questioned. The goal of this study was to determine whether more commonly used penicillins also induce C. trachomatis serovar E persistence/stress. All penicillins tested, as well as clavulanic acid, induced formation of aberrant, enlarged reticulate bodies (called aberrant bodies or AB characteristic of persistent/stressed chlamydiae. Exposure to the penicillins and clavulanic acid also reduced chlamydial infectivity by >95%. None of the drugs tested significantly reduced chlamydial unprocessed 16S rRNA or genomic DNA accumulation, indicating that the organisms were viable, though non-infectious. Finally, recovery assays demonstrated that chlamydiae rendered essentially non-infectious by exposure to ampicillin, amoxicillin, carbenicillin, piperacillin, penicillin V and clavulanic acid recovered infectivity after antibiotic removal. These data definitively demonstrate that several commonly used penicillins induce C. trachomatis persistence/stress at clinically relevant concentrations.

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

    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.

  20. Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin.

    Hershfield, M S; Kurtzberg, J; Harden, E; Moore, J O; Whang-Peng, J; Haynes, B. F.

    1984-01-01

    Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatm...

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

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

    2006-01-01

    STUDY OBJECTIVE: To compare the acute bronchodilatory effect of the long-acting beta2-agonist formoterol against the short-acting beta2-agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma. DESIGN: A randomized, double-blind, placebo-controlled, cro......STUDY OBJECTIVE: To compare the acute bronchodilatory effect of the long-acting beta2-agonist formoterol against the short-acting beta2-agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma. DESIGN: A randomized, double-blind, placebo......-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...... dose. RESULTS: Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dosecompared with placebo (p < 0.001). There was no difference between formoterol and terbutaline in FEV1 5 min after dose (p = 0.15), with a mean increase from each predrug baseline of 62% of...

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

    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

  3. Effects of adenosine metabolism in astrocytes on central nervous system oxygen toxicity.

    Chen, Yu-liang; Zhang, Ya-nan; Wang, Zhong-zhuang; Xu, Wei-gang; Li, Run-ping; Zhang, Jun-dong

    2016-03-15

    Hyperbaric oxygen (HBO) is widely used in military operations, especially underwater missions. However, prolonged and continuous inhalation of HBO can cause central nervous system oxygen toxicity (CNS-OT), which greatly limits HBO's application. The regulation of astrocytes to the metabolism of adenosine is involved in epilepsy. In our study, we aimed to observe the effects of HBO exposure on the metabolism of adenosine in the brain. Furthermore, we aimed to confirm the possible mechanism underlying adenosine's mediation of the CNS-OT. Firstly, anesthetized rats exposed to 5 atm absolute HBO for 80 min. The concentrations of extracellular adenosine, ATP, ADP, and AMP were detected. Secondly, free-moving rats were exposed to HBO at the same pressure for 20 min, and the activities of 5'-nucleotidase and ADK in brain tissues were measured. For the mechanism studies, we observed the effects of a series of different doses of drugs related to adenosine metabolism on the latency of CNS-OT. Results showed HBO exposure could increase adenosine content by inhibiting ADK activity and improving 5'-nucleotidase activity. And adenosine metabolism during HBO exposure may be a protective response against HBO-induced CNS-OT. Moreover, the improvement of adenosine concentration, activation of adenosine A1R, or suppression of ADK and adenosine A2AR, which are involved in the prevention of HBO-induced CNS-OT. This is the first study to demonstrate HBO exposure regulated adenosine metabolism in the brain. Adenosine metabolism and adenosine receptors are related to HBO-induced CNS-OT development. These results will provide new potential targets for the termination or the attenuation of CNS-OT. PMID:26806404

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

    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

  5. Persistence of asthmatic response after ammonium persulfate-induced occupational asthma in mice.

    Marta Ollé-Monge

    Full Text Available INTRODUCTION: Since persulfate salts are an important cause of occupational asthma (OA, we aimed to study the persistence of respiratory symptoms after a single exposure to ammonium persulfate (AP in AP-sensitized mice. MATERIAL AND METHODS: BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO on days 1 and 8. On day 15, they received a single nasal instillation of AP or saline. Airway hyperresponsiveness (AHR was assessed using methacholine provocation, while pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL, and total serum immunoglobulin E (IgE, IgG1 and IgG2a were measured in blood at 1, 4, 8, 24 hours and 4, 8, 15 days after the single exposure to the causal agent. Histological studies of lungs were assessed. RESULTS: AP-treated mice showed a sustained increase in AHR, lasting up to 4 days after the challenge. There was a significant increase in the percentage of neutrophils 8 hours after the challenge, which persisted for 24 hours in AP-treated mice. The extent of airway inflammation was also seen in the histological analysis of the lungs from challenged mice. Slight increases in total serum IgE 4 days after the challenge were found, while IgG gradually increased further 4 to 15 days after the AP challenge in AP-sensitized mice. CONCLUSIONS: In AP-sensitized mice, an Ig-independent response is induced after AP challenge. AHR appears immediately, but airway neutrophil inflammation appears later. This response decreases in time; at early stages only respiratory and inflammatory responses decrease, but later on immunological response decreases as well.

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

    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 hum...

  7. Interaction of light with the ZnO surface: Photon induced oxygen "breathing," oxygen vacancies, persistent photoconductivity, and persistent photovoltage

    Gurwitz, Ron; Cohen, Rotem; Shalish, Ilan

    2014-01-01

    ZnO surfaces adsorb oxygen in the dark and emit CO2 when exposed to white light, reminiscent of the lungs of living creatures. We find that this exchange of oxygen with the ambient affects the integrity of the ZnO surface. Thus, it forms a basis for several interesting surface phenomena in ZnO, such as photoconductivity, photovoltage, and gas sensing, and has a role in ZnO electrical conduction. Using x-ray photoelectron spectroscopy on ZnO nanowires, we observed a decomposition of ZnO under white light and formation of oxygen-depleted surface, which explains photoconductivity by the electron donation of oxygen vacancies. Our findings suggest that the observed decomposition of the ZnO lattice may only take place due to photon-induced reduction of ZnO by carbon containing molecules (or carbo-photonic reduction), possibly from the ambient gas, accounting in a consistent way for both the reduced demands on the energy required for decomposition and for the observed emission of lattice oxygen in the form of CO2. The formation of oxygen-vacancy rich surface is suggested to induce surface delta doping, causing accumulation of electrons at the surface, which accounts for both the increase in conductivity and the flattening of the energy bands. Using surface photovoltage spectroscopy in ultra high vacuum, we monitored changes in the deep level spectrum. We observe a wide optical transition from a deep acceptor to the conduction band, which energy position coincides with the position of the so called "green luminescence" in ZnO. This green transition disappears with the formation of surface oxygen vacancies. Since the oxygen vacancies are donors, while the green transition involves surface acceptors, the results suggest that the initial emission of oxygen originates at the defect sites of the latter, thereby eliminating each other. This suggests that the green transition originates at surface Zn vacancy acceptors. Removing an oxygen atom from a Zn vacancy completes the

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

    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 the expression of BRCA1. Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153 and PCB#180]) was measured by a reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold concentration range was analyzed in MCF-7, and the results were supported by northern blot analysis of BRCA1 mRNA using the highest concentrations of the chemicals. All three polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin reduced 17β-estradiol (E2)-induced expression as well as basal reporter gene expression in both cell lines, whereas northern blot analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in MCF-7 cells. Toxaphene, like E2, induced BRCA1 expression in MCF-7. The present study shows that some POCs have the capability to alter the expression of the tumor suppressor gene BRCA1 without affecting the cell-cycle control protein p21Waf/Cip1. Some POCs therefore have the potential to affect breast cancer risk

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

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

    2007-01-01

    calcium from the sarcoplasmic reticulum (SR), stimulated presumably by IP(3), is involved in the adenosine contraction mechanism of the afferent arteriole. In agreement with this notion is the observation that 2 aminoethoxydiphenyl borate (100 microM) blocked the adenosine-induced constriction whereas 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....... METHODS AND RESULTS: Adenosine (10(-7) M) significantly increased the intracellular calcium concentration in mouse isolated afferent arterioles measured by fura-2 fluorescence. Pre-treatment with thapsigargin (2 microM) blocked the vasoconstrictor action of adenosine (10(-7) M) indicating that release of...

  10. 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

    Gomes Catarina

    2013-01-01

    Full Text Available Abstract 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.

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

    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. PMID:25683553

  12. Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland

    Breast tissue is among the most sensitive tissues to the carcinogenic actions of ionizing radiation and epidemiological studies have linked radiation exposure to breast cancer. Currently, molecular understanding of radiation carcinogenesis in mammary gland is hindered due to the scarcity of in vivo long-term follow up data. We undertook this study to delineate radiation-induced persistent alterations in gene expression in mouse mammary glands 2-month after radiation exposure. Six to eight week old female C57BL/6J mice were exposed to 2 Gy of whole body γ radiation and mammary glands were surgically removed 2-month after radiation. RNA was isolated and microarray hybridization performed for gene expression analysis. Ingenuity Pathway Analysis (IPA) was used for biological interpretation of microarray data. Real time quantitative PCR was performed on selected genes to confirm the microarray data. Compared to untreated controls, the mRNA levels of a total of 737 genes were significantly (p<0.05) perturbed above 2-fold of control. More genes (493 genes; 67%) were upregulated than the number of downregulated genes (244 genes; 33%). Functional analysis of the upregulated genes mapped to cell proliferation and cancer related canonical pathways such as ‘ERK/MAPK signaling’, ‘CDK5 signaling’, and ‘14-3-3-mediated signaling’. We also observed upregulation of breast cancer related canonical pathways such as ‘breast cancer regulation by Stathmin1’, and ‘HER-2 signaling in breast cancer’ in IPA. Interestingly, the downregulated genes mapped to fewer canonical pathways involved in cell proliferation. We also observed that a number of genes with tumor suppressor function (GPRC5A, ELF1, NAB2, Sema4D, ACPP, MAP2, RUNX1) persistently remained downregulated in response to radiation exposure. Results from qRT-PCR on five selected differentially expressed genes confirmed microarray data. The PCR data on PPP4c, ELF1, MAPK12, PLCG1, and E2F6 showed similar trend in

  13. Respiratory stimulant effects of adenosine in man after caffeine and enprofylline.

    Smits, P; Schouten, J; Thien, T.

    1987-01-01

    In a double-blind and randomized study the respiratory stimulant effect of continuous intravenous adenosine infusion was studied after previous administration of caffeine, placebo and enprofylline in 10 healthy young volunteers. After placebo, adenosine induced an increase of minute ventilation (from 6.3 to 12.5 l min-1), tidal volume (from 0.60 to 0.96 l), and breathing rate (from 11.0 to 14.8 min-1). Venous pCO2 fell and pH rose after adenosine. Caffeine significantly reduced the adenosine-...

  14. Persistence of enhanced aerosol deposition in the lung after recovery from carbachol-induced airway obstruction.

    Kim, C S; Garcia, L; Eldridge, M A; Wanner, A

    1990-12-01

    Time course recovery from induced airway obstruction by carbachol infusion (CI; 0.2 microgram.kg-1.min-1 for 40 min), carbachol aerosol (CA; 10 breaths of 2% solution), and histamine aerosol (HA; 25-50 breaths of 5% solution) challenge was investigated in conscious sheep (n = 6 each). Total lung aerosol deposition and airway caliber as assessed by pulmonary airflow resistance (RL) were measured every 20-30 min up to 4 h after the challenges. Aerosol deposition was measured by monitoring aerosol concentration continuously with a laser aerosol photometer while the sheep rebreathed 1.0-micron-diam inert oil droplets delivered by a 0.25-liter bag-in-box system driven by a respiratory pump at a breathing frequency of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as percentage of the initial aerosol concentration was determined and used as an aerosol deposition index. Percent changes in AD5 from baseline were compared with corresponding changes in RL. Both RL and AD5 increased after Cl, CA, and HA: 192-477% for RL and 23-44% for AD5 (P less than 0.05). Mean RL return to baseline values 1 h after CI and HA and 2 h after CA. Mean AD5 returned to baseline at 1 h post-HA. In contrast, mean AD5 remained elevated for 2-4 h after CI and CA (P less than 0.05), and the increased AD5 could not be reversed by a bronchodilator aerosol. The persistence of enhanced aerosol deposition long after the return of RL to baseline suggests that complete recovery of airway conditions after CI and CA takes much longer than predicted by RL.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2077007

  15. Adenosine-Associated Delivery Systems

    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

  16. Adenosine stimulates DNA fragmentation in human thymocytes by Ca(2+)-mediated mechanisms.

    Szondy, Z

    1994-12-15

    Incubation of human thymocytes with an optimum concentration of adenosine and its receptor site agonist, 2-chloroadenosine, induced increases in intracellular cyclic AMP (cAMP) (from a resting 0.6 +/- 0.1 to 4.1 +/- 0.2 pmol/10(7) cells within 5 min) and Ca2+ (from the resting 85 +/- 7 nM to a peak of 210 +/- 25 nM) levels and resulted in internucleosomal DNA fragmentation and cell death (apoptosis). Other adenosine analogues were also effective at inducing DNA fragmentation, the order of potency being 2-p-(carboxyethylphenylethylamino)-5'-carboxyamidoadenosine 13399-13402], at 60 ng/ml concentration also prevented adenosine-induced DNA fragmentation when added prior to adenosine. This suggested a complex cross-talk between the adenosine-triggered signal transduction cascade and the activation state of protein kinase C in regulating apoptosis of human thymocytes. PMID:7818494

  17. Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice

    Sela, Uri; Olds, Peter; Park, Andrew; Schlesinger, Sarah J.; Steinman, Ralph M.

    2011-01-01

    Foxp3+ regulatory T cells (T reg cells) effectively suppress immunity, but it is not determined if antigen-induced T reg cells (iT reg cells) are able to persist under conditions of inflammation and to stably express the transcription factor Foxp3. We used spleen cells to stimulate the mixed leukocyte reaction (MLR) in the presence of transforming growth factor β (TGF-β) and retinoic acid. We found that the CD11chigh dendritic cell fraction was the most potent at inducing high numbers of allo...

  18. Persistence of Yellow Fever vaccine-induced antibodies after cord blood stem cell transplant.

    Avelino-Silva, Vivian Iida; Freire, Marcos da Silva; Rocha, Vanderson; Rodrigues, Celso Arrais; Novis, Yana Sarkis; Sabino, Ester C; Kallas, Esper Georges

    2016-04-01

    We report the case of a cord blood haematopoietic stem cell transplant recipient who was vaccinated for Yellow Fever (YF) 7 days before initiating chemotherapy and had persistent YF antibodies more than 3 years after vaccination. Since the stem cell donor was never exposed to wild YF or to the YF vaccine, and our patient was not exposed to YF or revaccinated, this finding strongly suggests the persistence of recipient immunity. We briefly discuss potential consequences of incomplete elimination of recipient's leukocytes following existing haematopoietic cancer treatments. PMID:26618995

  19. Severe anaphylactoid reactions and renal damage induced by adenosine cyclophosphate%环磷腺苷致严重过敏样反应及肾损害

    李静; 赵敏

    2011-01-01

    A 71-year-old woman received an IV infusion of adenosine cyclophosphate 40 mg in 0.9% sodium chloride 250 ml for her hyperthyroid heart disease.About five minutes after the infusion started, she experienced severe lumhago and palpilation, followed by bilateral palpehral oedema, chest distress and vomiting 30 minutes later.Her blood pressure was 180-190/100-105 mm Hg, and moist rales were heard in the lower lungs.Renal function tests showed the following values : occult blood ( + + + ) , protein ( + + + ) ,and 1-2 RBC/high power field.Adenosine cyclophosphate was discontinued immediately and she received oxygen inhalation,dexamethasone, furosemide, omeprazole, and nifedipine.About two hours later, the patient urinated > 1000 ml.She had a blood pressure of 159/65 mm Hg, an oxygen saturation 0.97, and a heart rate of 85 beats/min.Moist rales in both lungs reduced significantly.Three days later.the patient basically retumed to normal.%1例71岁女性患者因甲状腺功能亢进性心脏病,给予环磷腺苷40 mg加入0.9%氯化钠注射液250 ml静脉滴注.用药5 min后.患者出现剧烈腰痛、心悸,30 min后出现双侧眼睑水肿、胸闷、呕吐.血压180~190/100~105 mm Hg(1 mm Hg=0.133 kPa),两下肺闻及湿哆音.肾功能检查:潜血(+++),蛋白质(+++),红细胞1~2个/高倍视野.立即停用环磷腺苷,给予吸氧、地塞米松、呋塞米、奥美拉唑和硝苯地平治疗.约2 h后,患者排出尿量>1000 ml,血压159/65 mm Hg,心率85次/min,血氧饱和度0.97,双肺湿哆音明显减少.3 d后患者基本恢复正常.

  20. Dose-dependence, sex- and tissue-specificity, and persistence of radiation-induced genomic DNA methylation changes

    Radiation is a well-known genotoxic agent and human carcinogen that gives rise to a variety of long-term effects. Its detrimental influence on cellular function is actively studied nowadays. One of the most analyzed, yet least understood long-term effects of ionizing radiation is transgenerational genomic instability. The inheritance of genomic instability suggests the possible involvement of epigenetic mechanisms, such as changes of the methylation of cytosine residues located within CpG dinucleotides. In the current study we evaluated the dose-dependence of the radiation-induced global genome DNA methylation changes. We also analyzed the effects of acute and chronic high dose (5 Gy) exposure on DNA methylation in liver, spleen, and lung tissues of male and female mice and evaluated the possible persistence of the radiation-induced DNA methylation changes. Here we report that radiation-induced DNA methylation changes were sex- and tissue-specific, dose-dependent, and persistent. In parallel we have studied the levels of DNA damage in the exposed tissues. Based on the correlation between the levels of DNA methylation and DNA damage we propose that radiation-induced global genome DNA hypomethylation is DNA repair-related

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

    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.

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

    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.

  3. Persistence of radiation-induced translocations in rat peripheral blood determined by chromosome painting

    In this article, we address the issue of persistence of chromosome exchanges following acute in vitro exposure of rat peripheral blood to 137Cs. Irradiation occurred 24 hr after culture initiation, and metaphase chromosomes were prepared 2, 3, 4, and 5 days later. Chromosomes 1, 2, and 4 were painted in unique colors and scored for structural aberrations. Dicentric chromosomes an acentric fragments diminished rapidly with time, as expected. Translocations exhibited greater persistence, but still showed a reduction in frequency, reaching a plateau of approximately 65 and 55% of their initial values, 4 days after exposure to 1 and 2 Gy, respectively. An exponentially declining model was fit to the combined dicentric, acentric fragment, and translocation frequencies, which showed that all three aberration types declined at equivalent rates. The frequencies of dicentrics and fragments declined to a plateau of zero, while translocations reached a plateau at frequencies significantly greater than zero. The decline in translocations with time is inconsistent with prevailing theoretical expectations, but is consistent with a model where some translocations are fully stable (persistent) and some are unstable (not persistent) through cell division. These results may have implications for radiation biodosimetry in humans. have implications for radiation biodosimetry in humans

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

    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.

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

    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.

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

    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

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

    Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

    2015-01-01

    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. PMID:25860995

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

    Johansen, Torben

    1980-01-01

    1 The relation between A23187-induced histamine release and the energy metabolism of the rat mast cells has been studied. 2 Ethacrynic acid was used as an inhibitor of calcium-induced histamine release from mast cells primed with the ionophore A23187, and to study calcium-induced changes in the a......1 The relation between A23187-induced histamine release and the energy metabolism of the rat mast cells has been studied. 2 Ethacrynic acid was used as an inhibitor of calcium-induced histamine release from mast cells primed with the ionophore A23187, and to study calcium-induced changes...

  9. Persistent colonization of Helicobacter pylori in human gut induces gastroduodenal diseases

    Animesh Sarker

    2014-12-01

    Full Text Available Helicobacter pylori are gut bacteria colonize in the epithelial cell lining of the stomach and persist there for long du­ration. Around two-thirds of the world’s populations are infected with H. pylori and cause more than 90 percent of ulcers. The development of persistent inflammation is the main cause of chronic gastritis that finally results in a severe consequence known as stomach cancer. Two major virulence factors cytotoxin-associated gene product (cagA and the vacuolating toxin (vacA are mostly investigated as their close association with gastric carcinoma. In this review, host im­munity against H. pylori infection and their evasion mechanism are intensely explored. It is the fact, that understanding pin point molecular mechanisms of any infection is critical to develop novel strategies to prevent pertinent diseases. .J Microbiol Infect Dis 2014; 4(4: 170-176

  10. Persistent Oxytetracycline Exposure Induces an Inflammatory Process That Improves Regenerative Capacity in Zebrafish Larvae

    Francisco Barros-Becker; Jaime Romero; Alvaro Pulgar; Feijóo, Carmen G.

    2012-01-01

    BACKGROUND: The excessive use of antibiotics in aquaculture can adversely affect not only the environment, but also fish themselves. In this regard, there is evidence that some antibiotics can activate the immune system and reduce their effectiveness. None of those studies consider in detail the adverse inflammatory effect that the antibiotic remaining in the water may cause to the fish. In this work, we use the zebrafish to analyze quantitatively the effects of persistent exposure to oxytetr...

  11. Pregnancy-induced changes in ultradian rhythms persist in circadian arrhythmic Siberian hamsters

    Wang, Z. Yan; Cable, Erin J.; Zucker, Irving; Prendergast, Brian J.

    2014-01-01

    The impact of pregnancy and lactation on ultradian rhythms (URs) and circadian rhythms (CRs) of locomotor activity was assessed in circadian rhythmic and arrhythmic Siberian hamsters maintained in a long-day photoperiod (16 h light/day). Progressive decrements in CR robustness and amplitude over the course of gestation were accompanied by enhanced URs. Dark-phase UR period and amplitude increased during early gestation and complexity and robustness increased during late gestation. The persist...

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

    Christoffersen Mette; Woodward Elizabeth; Bojesen Anders M; Jacobsen Stine; Petersen Morten R; Troedsson Mats HT; Lehn-Jensen Henrik

    2012-01-01

    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 ute...

  13. Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart

    Yong-Cheol Lee

    2016-01-01

    Full Text Available The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs and adenosine receptors (ADRs in remifentanil preconditioning (R-Pre and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP,velocity of contraction (+dP/dtmax, and coronary flow (CF were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax,and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia. These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross-talk.

  14. A2A adenosine receptor-mediated increase in coronary flow in hyperlipidemic APOE–knockout mice

    Teng, Bunyen

    2011-01-01

    Bunyen Teng, S Jamal MustafaDepartment of Physiology and Pharmacology and Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USAAbstract: Adenosine-induced coronary vasodilation is predominantly A2A adenosine receptor (AR)-mediated, whereas A1 AR is known to negatively modulate the coronary flow (CF). However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not well understood. Using hyperlipidemic/atherosclerotic apolip...

  15. Alpha-Crystalline Protein Expression & Inducing of the Nonreplicating Persistence States of Mycobacterium Tuberculosis

    M NajafiMosleh

    2007-06-01

    Full Text Available Background: Latent tuberculosis infection (LTBI is caused by mycobacterium tuberculosis in a state of non-replicating persistence (NRP. Recent evidence suggests that some very specific adaptations to oxygen depletion occur that MTB undergoes to hypoxic RNP state. In this study the modified slowly stirred, limited Head Space Ratio (0.5HSR method was used to investigate the physiological response of MTB to different oxygen tension levels. Methods: For setting up the various NRP stages 100 susceptible & drugs resistant clinically isolated strains of MTB were cultivated in Dubos Albomin Tween medium via hypoxically, slow stirring 0.5 HSR method and the effects of isoniazid ,rifampin, pyrazinamide .ciprofloxacin & metronidazole against MTB were examined during NRP-1 and NRP-2 stages . The α-crystalline protein was detected during NRP-1 stage of the MTB cultures via performance of the suitable procedures for pellet preparation, washing and cell disruption and SDS-PAGE technique. Results: NRP-1, NRP-2 stages of MTB subjected to be test documentary were seen. The first three of the four drugs mentioned above affected the MTB at actively replicating period and the rifampin effect was continued slightly during NRP-1 stage. Meteronidazole was affected the MTB at anaerobic NRP-2 stage. α- crystalline protein was detected at NRP -1 stage but do not detect at aerated cultures. Conclusion: Induction of the α-crystalline protein during hypoxic shift-down of MTB metabolism, its function as a chaperone, suggests a critical role for this protein in the ability of MTB to persist without replicating in the hostile regions of the host's tissues. Therefore, understanding of the mechanisms of induction of factors associated with the hypoxic condition of tubercle bacilli that should be contribute to the development of strategies for identification of the new drugs targets and preventing the persistence states in human lesions must be critical for affective TB

  16. Oxygen vacancies induced DX center and persistent photoconductivity properties of high quality ZnO nanorods

    Xie, Yong; Madel, Manfred; Feneberg, Martin; Neuschl, Benjamin; Jie, Wanqi; Hao, Yue; Ma, Xiaohua; Thonke, Klaus

    2016-04-01

    Ultraviolet sensors based on homoepitaxially grown ZnO nanorods were fabricated using clean room technology. We study the spectral dependence and frequency dependence of the photoresponse of these rods at different temperatures and ambient conditions. Whereas the response for above-bandgap light is fast, we find a slow response to light below band gap and clear signatures of persistent photoconductivity. These findings are explained by switching oxygen vacancies by light from nonconductive to conductive state, whereas the oxygen vacancies undergo a large lattice relaxation. The threshold photon energy for this process is found to be 2.6 eV at room temperature.

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

    Christoffersen, Mette; Woodward, Elizabeth; Bojesen, Anders Miki;

    2012-01-01

    The objective of the study was to evaluate the gene expression of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-a, 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...

  18. Effects of adenosine and adenosine A2A receptor agonist on motor nerve conduction velocity and nerve blood flow in experimental diabetic neuropathy.

    Kumar, Sokindra; Arun, K H S; Kaul, Chaman L; Sharma, Shyam S

    2005-01-01

    This study examined the effects of chronic administration of adenosine and CGS 21680 hydrochloride (adenosine A(2A) receptor agonist) on motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and histology of sciatic nerve in animal model of diabetic neuropathy. Adenosinergic agents were administered for 2 weeks after 6 weeks of streptozotocin-induced (50 mg/kg i.p.) diabetes in male Sprague-Dawley rats. Significant reduction in sciatic MNCV and NBF were observed after 8 weeks in diabetic animals in comparison with control (non diabetic) rats. Adenosine (10 mg/kg, i.p.) significantly improved sciatic MNCV and NBF in diabetic rats. The protective effect of adenosine on MNCV and NBF was completely reversed by theophylline (50 mg/kg, i.p.), a non-selective adenosine receptor antagonist, suggesting that the adenosine effect was mediated via adenosinergic receptors. CGS 21680 (0.1 mg/kg, i.p.) significantly improved NBF; however, MNCV was not significantly improved in diabetic rats. At a dose of 1 mg/kg, neither MNCV nor NBF was improved by CGS 21680 in diabetic rats. ZM 241385 (adenosine A(2A) receptor antagonist) prevented the effect of CGS 21680 (0.1 mg/kg, i.p.). Histological changes observed in sciatic nerve were partially improved by the adenosinergic agents in diabetic rats. Results of the present study, suggest the potential of adenosinergic agents in the therapy of diabetic neuropathy. PMID:15829161

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

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

    2002-01-01

    polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin reduced 17beta-estradiol (E2)-induced expression as well as basal reporter gene expression in both cell lines, whereas northern blot analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in MCF-7 cells. Toxaphene, like E2...

  20. The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kappaB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats.

    Ochaion, A; Bar-Yehuda, S; Cohen, S; Amital, H; Jacobson, K A; Joshi, B V; Gao, Z G; Barer, F; Patoka, R; Del Valle, L; Perez-Liz, G; Fishman, P

    2008-08-15

    The A(3) adenosine receptor (A(3)AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant- and collagen-induced arthritis. In this study we present a novel A(3)AR agonist, CF502, with high affinity and selectivity at the human A(3)AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-kappaB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of adjuvant-induced arthritis (AIA) in a rat experimental model when given orally at a low dose (100 microg/kg). As is typical of other G-protein coupled receptors, the A(3)AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of protein kinase B/Akt (PKB/Akt), IkappaB kinase (IKK), I kappa B (IkappaB), NF-kappaB and tumor necrosis factor-alpha (TNF-alpha) took place. In addition, the expression levels of glycogen synthase kinase-3 beta (GSK-3beta), beta-catenin, and poly(ADP-ribose)polymerase (PARP), known to control the level and activity of NF-kappaB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A(3)AR agonists for the treatment of rheumatoid arthritis. PMID:18602896

  1. The A3 Adenosine Receptor Agonist CF502 Inhibits the PI3K, PKB/Akt and NF-κB Signaling Pathway in Synoviocytes from Rheumatoid Arthritis Patients and in Adjuvant Induced Arthritis Rats

    Ochaion, A.; Bar-Yehuda, S.; Cohen, S.; Amital, H.; Jacobson, K.A.; Joshi, B.V.; Gao, Z.G.; Barer, F.; Patoka, R.; Del Valle, L.; Perez-Liz, G.; Fishman, P.

    2009-01-01

    The A3 adenosine receptor (A3AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant and collagen induced arthritis. In this study we present a novel A3AR agonist, CF502, with high affinity and selectivity at the human A3AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of Adjuvant Induced Arthritis (AIA) in a rat experimental model when given orally at a low dose (100 μg/kg). As is typical of other G-protein coupled receptors, the A3AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of Protein Kinase B/Akt (PKB/Akt), IκB kinase (IKK), (I kappa B) IκB, NF-κB and tumor necrosis factor-alpha (TNF-α) took place. In addition, the expression levels of Glycogen synthase kinase-3 beta (GSK-3β), β-catenin, and Poly (ADP-ribose) polymerase (PARP), known to control the level and activity of NF-κB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A3AR agonists for the treatment of rheumatoid arthritis. PMID:18602896

  2. Genistein suppresses tumor necrosis factor α-induced inflammation via modulating reactive oxygen species/Akt/nuclear factor ΚB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells

    Li J

    2014-03-01

    inhibit IL-1β, IL-6, and IL-8 production induced by TNF-α. In addition, we also found that pretreatment with the adenosine monophosphate-activated protein kinase (AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside obviously inhibited TNF-α-induced proinflammatory cytokine production. These observations suggest that the inhibitory effect of genistein on TNF-α-induced proinflammatory cytokine production is dependent on AMPK activation. Conclusion: These findings indicate that genistein suppressed TNF-α-induced inflammation by inhibiting the ROS/Akt/NF-ΚB pathway and promoting AMPK activation in MH7A cells. Keywords: genistein, rheumatoid arthritis, cytokine, signal transduction, inflammation

  3. Persistent impairment of mitochondrial and tissue redox status during lithium-pilocarpine-induced epileptogenesis

    Waldbaum, Simon; Liang, Li-Ping; Patel, Manisha

    2016-01-01

    Mitochondrial dysfunction and oxidative stress are known to occur following acute seizure activity but their contribution during epileptogenesis is largely unknown. The goal of this study was to determine the extent of mitochondrial oxidative stress, changes to redox status, and mitochondrial DNA (mtDNA) damage during epileptogenesis in the lithium-pilocarpine model of temporal lobe epilepsy. Mitochondrial oxidative stress, changes in tissue and mitochondrial redox status, and mtDNA damage were assessed in the hippocampus and neocortex of Sprague–Dawley rats at time points (24 h to 3 months) following lithium-pilocarpine administration. A time-dependent increase in mitochondrial hydrogen peroxide (H2O2) production coincident with increased mtDNA lesion frequency in the hippocampus was observed during epileptogenesis. Acute increases (24–48 h) in H2O2 production and mtDNA lesion frequency were dependent on the severity of convulsive seizure activity during initial status epilepticus. Tissue levels of GSH, GSH/GSSG, coenzyme A (CoASH), and CoASH/CoASSG were persistently impaired at all measured time points throughout epileptogenesis, that is, acutely (24–48 h), during the ‘latent period’ (48 h to 7 days), and chronic epilepsy (21 days to 3 months). Together with our previous work, these results demonstrate the model independence of mitochondrial oxidative stress, genomic instability, and persistent impairment of mitochondrial specific redox status during epileptogenesis. Lasting impairment of mitochondrial and tissue redox status during the latent period, in addition to the acute and chronic phases of epileptogenesis, suggests that redox-dependent processes may contribute to the progression of epileptogenesis in experimental temporal lobe epilepsy. PMID:21219330

  4. Experimentally induced innovations lead to persistent culture via conformity in wild birds.

    Aplin, Lucy M; Farine, Damien R; Morand-Ferron, Julie; Cockburn, Andrew; Thornton, Alex; Sheldon, Ben C

    2015-02-26

    In human societies, cultural norms arise when behaviours are transmitted through social networks via high-fidelity social learning. However, a paucity of experimental studies has meant that there is no comparable understanding of the process by which socially transmitted behaviours might spread and persist in animal populations. Here we show experimental evidence of the establishment of foraging traditions in a wild bird population. We introduced alternative novel foraging techniques into replicated wild sub-populations of great tits (Parus major) and used automated tracking to map the diffusion, establishment and long-term persistence of the seeded innovations. Furthermore, we used social network analysis to examine the social factors that influenced diffusion dynamics. From only two trained birds in each sub-population, the information spread rapidly through social network ties, to reach an average of 75% of individuals, with a total of 414 knowledgeable individuals performing 57,909 solutions over all replicates. The sub-populations were heavily biased towards using the technique that was originally introduced, resulting in established local traditions that were stable over two generations, despite a high population turnover. Finally, we demonstrate a strong effect of social conformity, with individuals disproportionately adopting the most frequent local variant when first acquiring an innovation, and continuing to favour social information over personal information. Cultural conformity is thought to be a key factor in the evolution of complex culture in humans. In providing the first experimental demonstration of conformity in a wild non-primate, and of cultural norms in foraging techniques in any wild animal, our results suggest a much broader taxonomic occurrence of such an apparently complex cultural behaviour. PMID:25470065

  5. Physical Exercise Counteracts Stress-induced Upregulation of Melanin-concentrating Hormone in the Brain and Stress-induced Persisting Anxiety-like Behaviors.

    Kim, Tae-Kyung; Han, Pyung-Lim

    2016-08-01

    Chronic stress induces anxiety disorders, whereas physical exercise is believed to help people with clinical anxiety. In the present study, we investigated the mechanisms underlying stress-induced anxiety and its counteraction by exercise using an established animal model of anxiety. Mice treated with restraint for 2 h daily for 14 days exhibited anxiety-like behaviors, including social and nonsocial behavioral symptoms, and these behavioral impairments lasted for more than 12 weeks after the stress treatment was removed. Despite these lasting behavioral changes, wheel-running exercise treatment for 1 h daily from post-stress days 1 - 21 counteracted anxiety-like behaviors, and these anxiolytic effects of exercise persisted for more than 2 months, suggesting that anxiolytic effects of exercise stably induced. Repeated restraint treatment up-regulated the expression of the neuropeptide, melanin-concentrating hormone (MCH), in the lateral hypothalamus, hippocampus, and basolateral amygdala, the brain regions important for emotional behaviors. In an in vitro study, treatment of HT22 hippocampal cells with glucocorticoid increased MCH expression, suggesting that MCH upregulation can be initially triggered by the stress hormone, corticosterone. In contrast, post-stress treatment with wheel-running exercise reduced the stress-induced increase in MCH expression to control levels in the lateral hypothalamus, hippocampus and basolateral amygdala. Administration of an MCH receptor antagonist (SNAP94847) to stress-treated mice was therapeutic against stress-induced anxiety-like behaviors. These results suggest that repeated stress produces long-lasting anxiety-like behaviors and upregulates MCH in the brain, while exercise counteracts stress-induced MCH expression and persisting anxiety-like behaviors. PMID:27574483

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

    Linnman, Clas; Becerra, Lino; Lebel, Alyssa; Berde, Charles Benjamin; 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. u...

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

    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.

  8. Adenosine in inflammatory joint diseases

    Chan, E. S. L.; Fernandez, P.; Cronstein, B. N.

    2007-01-01

    Inflammatory joint diseases are a group of heterogeneous disorders with a variety of different etiologies and disease manifestations. However, there are features that are common to all of them: first, the recruitment of various inflammatory cell types that are attracted to involved tissues over the course of the disease process. Second, the treatments used in many of these diseases are commonly medications that suppress or alter immune function. The demonstration that adenosine has endogenous...

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

    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

  10. Persistence and prevention of aluminium- and paraquat-induced adaptive response to methyl mercuric chloride in plant cells in vivo.

    Patra, Jita; Sahoo, Malaya K; Panda, Brahma B

    2003-07-01

    Induction and persistence of adaptive response by aluminium (Al), 1 or 10 microM, and paraquat (PQ), 5 or 10 microM, against genotoxicity of methyl mercuric chloride (MMCl), 1.26 microM, a standard environmental genotoxin, was investigated in root meristem cells of Allium cepa. Subsequently, three metabolic inhibitors, namely, 3-aminobezamide (3-AB, 10 or 100 microM), an inhibitor of poly(ADP-ribose) polymerase (PARP) implicated in DNA repair and/or apoptosis, cycloheximide (CH, 0.1 or 1 microM), an inhibitor of protein synthesis, and buthionine sulfoximine (BSO, 100 microM or 1mM), an inhibitor of glutathione synthesis were tested for their ability to prevent the adaptive response induced by conditioning doses of Al, 10 or 100 microM; and PQ, 5 or 100 microM, against MMCl-challenge, 1.26 or 100 microM, in root meristems of A. cepa or embryonic shoots of Hordeum vulgare, respectively. The findings demonstrated that once triggered, the Al- or PQ-adaptive response to MMCl could persist for at least 48h in root meristems of A. cepa. Furthermore, the adaptive response could effectively be prevented by 3-AB, to a lesser degree by CH, and the least by BSO, suggesting primarily the involvement of PARP and implicating DNA repair in the underlying mechanisms of adaptive response in plant cells in vivo. PMID:12834754

  11. Berberine treatment prevents cardiac dysfunction and remodeling through activation of 5'-adenosine monophosphate-activated protein kinase in type 2 diabetic rats and in palmitate-induced hypertrophic H9c2 cells.

    Chang, Wenguang; Zhang, Ming; Meng, Zhaojie; Yu, Yang; Yao, Fan; Hatch, Grant M; Chen, Li

    2015-12-15

    Diabetic cardiomyopathy is the major cause of death in type 2 diabetic patients. Berberine is an isoquinoline alkaloid extract from traditional chinese herbs and its hypoglycemic and hypolipidemic effects make it a promising drug for treatment of type 2 diabetes. We examined if berberine improved cardiac function and attenuated cardiac hypertrophy and fibrosis in high fat diet and streptozotocin induced-type 2 diabetic rats in vivo and reduced expression of hypertrophy markers in palmitate-induced hypertrophic H9c2 cells in vitro. Treatment of diabetic animals with berberine partially improved cardiac function and restored fasting blood insulin, fasting blood glucose, total cholesterol, and triglyceride levels to that of control. In addition, berberine treatment of diabetic animals increased cardiac 5'-adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) activation and reduced glycogen synthase kinase 3 beta (GSK3β) activation compared to control. Palmitate incubation of H9c2 cells resulted in cellular hypertrophy and decreased expression of alpha-myosin heavy chain (α-MHC) and increased expression of beta-myosin heavy chain (β-MHC) compared to controls. Berberine treatment of palmitate-incubated H9c2 cells reduced hypertrophy, increased α-MHC expression and decreased β-MHC expression. In addition, berberine treatment of palmitate-incubated H9c2 cells increased AMPK and AKT activation and reduced GSK3β activation. The presence of the AMPK inhibitor Compound C attenuated the effects of berberine. The results strongly indicate that berberine treatment may be protective against the development of diabetic cardiomyopathy. PMID:26522928

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

    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.

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

    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.

  14. Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast

    Busti, Stefano; Mapelli, Valeria; Tripodi, Farida;

    2016-01-01

    reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular...

  15. Experimental photoallergic contact dermatitis (photo-ACD) and persistent light reactivity (PLR) induced by bisphenol-A

    Bisphenol-A, a compound widely used in the plastics industry, clinically has been reported to induce photo-ACD and PLR. In mice, the authors find that Bisphenol-A (Bis-A) is a substantial photosensitizer and can serve as a model compound for the study of the cutaneous disorder, PLR. Mice were photosensitized by 2 daily applications of 1% Bis-A followed by irradiation of the skin site with UVB (280-320nm) and UVA (320-400nm). Sometimes, intradermal C.parvum (30 μ g) and/or pretreatment with cyclophosphamide (Cy; 50mg/kg) was used for nonspecific immunopotentiation. Photochallenge of an ear with chemical followed by UVA is usually done on Day 6. The reaction is consistent with that of delayed type hypersensitivity. Positive photochallenge sites react to UVA alone, thereby mimicking the clinical condition of the persistent light reactor

  16. Transient and persistent current induced conductivity changes in GaAs/AlGaAs high-electron-mobility transistors

    We report the observation of a current induced change of the low temperature conductivity of two-dimensional electron gases in GaAs/AlGaAs-high-electron-mobility transistors. By applying voltage pulses on the ohmic contacts of a Hall bar-mesa-structure, both sheet-carrier-density n2D and electron mobility μ are decreased. At temperatures below 50 K, a persistent change combined with a partial transient recovery of n2D has been observed. The transient behaviour and the lateral spreading of the effect are studied. Moreover, a temperature dependent investigation has been done in order to get insight into the addressed defect energy levels. A model based on the phenomenology of the effect is proposed. The observed effect is not a permanent degradation as the original carrier concentration can be restored by warming up the sample to room temperature and recooling it

  17. Persistence of Antibodies Induced by Measles-Mumps-Rubella Vaccine in Children in India

    S. K. Raut; Mr. P.S. Kulkarni; Phadke, M. A.; S. S Jadhav; Kapre, S. V.; Dhere, R. M.; Dhorje, S. P.; Godse, S. R.

    2008-01-01

    Antibody levels in 41 Indian girls were measured 6 years after measles-mumps-rubella (MMR) vaccination. Rates of seropositivity were 88% (measles antibodies), 95% (mumps antibodies), and 100% (rubella antibodies). The MMR vaccine induces long-term immunity in a majority of vaccinees; however, due to the observation of some seronegative vaccinees, the policy of administering a second dose of the MMR vaccine seems appropriate.

  18. Inchoate CD8+ T Cell Responses in Neonatal Mice Permit Influenza Induced Persistent Pulmonary Dysfunction1

    You, Dahui; Ripple, Michael; Balakrishna, Shrilatha; Troxclair, Dana; Sandquist, Dane; Ding, Liren; Ahlert, Terry A; Cormier, Stephania A.

    2008-01-01

    Influenza infection remains a significant cause of pulmonary morbidity and mortality worldwide with the highest hospitalization and mortality rates occurring in infants and elder adults. The mechanisms inducing this considerable morbidity and mortality are largely unknown. To address this question, we established a neonatal mouse model of influenza infection to test the hypothesis that the immaturity of the neonatal immune system is responsible for the severe pulmonary disease observed in inf...

  19. Role of extracellular adenosine in Drosophila

    FENCKOVÁ, Michaela

    2011-01-01

    This thesis describes several aspects of the role for extracellular adenosine in Drosophila. Reverse genetic, molecular and microscopic methods together with the most forefront Drosophila research techniques have been applied to elucidate the role of adenosine signaling in the regulation of development, physiology and metabolism of Drosophila larvae. The thesis helps to establish the model for extracellular adenosine as a stress-signal for the release of energy stores. It also describes the e...

  20. Persistent and heritable structural damage induced in heterochromatic DNA from rat liver by N-nitrosodimethylamine

    Analysis, by benzoylated DEAE-cellulose chromatography, has been made of structural change in eu- and heterochromatic DNA from rat liver following administration of the carcinogen N-nitrosodimethylamine. Either hepatic DNA was prelabeled with [3H]thymidine administered 2-3 weeks before injection of the carcinogen or the labeled precursor was given during regenerative hyperplasia in rats treated earlier with N-nitrosodimethylamine. Following phenol extraction of either whole liver homogenate or nuclease-fractionated eu- and heterochromatin, carcinogen-modified DNA was examined by stepwise or caffeine gradient elution from benzoylated DEAE-cellulose. In whole DNA, nitrosamine-induced single-stranded character was maximal 4-24 h after treatment, declining rapidly thereafter; gradient elution of these DNA preparations also provided short-term evidence of structural change. Caffeine gradient chromatography suggested short-term nitrosamine-induced structural change in euchromatic DNA, while increased binding of heterochromatic DNA was evident for up to 3 months after carcinogen treatment. Preparations of newly synthesized heterochromatic DNA from animals subjected to hepatectomy up to 2 months after carcinogen treatment provided evidence of heritable structural damage. Carcinogen-induced binding of heterochromatic DNA to benzoylated DEAE-cellulose was indicative of specific structural lesions whose affinity equalled that of single-stranded DNA up to 1.0 kilobase in length. The data suggest that structural lesions in heterochromatin, which may be a consequence of incomplete repair, are preferentially degraded by endogenous nuclease(s)

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

    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. Adenosine deaminase regulates Treg expression in autologous T cell-dendritic cell cocultures from patients infected with HIV-1.

    Naval-Macabuhay, Isaac; Casanova, Víctor; Navarro, Gemma; García, Felipe; León, Agathe; Miralles, Laia; Rovira, Cristina; Martinez-Navio, José M; Gallart, Teresa; Mallol, Josefa; Gatell, José M; Lluís, Carme; Franco, Rafael; McCormick, Peter J; Climent, Núria

    2016-02-01

    Regulatory T cells have an important role in immune suppression during HIV-1 infection. As regulatory T cells produce the immunomodulatory molecule adenosine, our aim here was to assess the potential of adenosine removal to revert the suppression of anti-HIV responses exerted by regulatory T cells. The experimental setup consisted of ex vivo cocultures of T and dendritic cells, to which adenosine deaminase, an enzyme that hydrolyzes adenosine, was added. In cells from healthy individuals, adenosine hydrolysis decreased CD4(+)CD25(hi) regulatory T cells. Addition of 5'-N-ethylcarboxamidoadenosine, an adenosine receptor agonist, significantly decreased CD4(+)CD25(lo) cells, confirming a modulatory role of adenosine acting via adenosine receptors. In autologous cocultures of T cells with HIV-1-pulsed dendritic cells, addition of adenosine deaminase led to a significant decrease of HIV-1-induced CD4(+)CD25(hi) forkhead box p3(+) cells and to a significant enhancement of the HIV-1-specific CD4(+) responder T cells. An increase in the effector response was confirmed by the enhanced production of CD4(+) and CD8(+) CD25(-)CD45RO(+) memory cell generation and secretion of Th1 cytokines, including IFN-γ and IL-15 and chemokines MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5. These ex vivo results show, in a physiologically relevant model, that adenosine deaminase is able to enhance HIV-1 effector responses markedly. The possibility to revert regulatory T cell-mediated inhibition of immune responses by use of adenosine deaminase, an enzyme that hydrolyzes adenosine, merits attention for restoring T lymphocyte function in HIV-1 infection. PMID:26310829

  3. Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder.

    Silva-Ramos, M; Silva, I; Faria, M; Magalhães-Cardoso, M T; Correia, J; Ferreirinha, F; Correia-de-Sá, P

    2015-12-01

    This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve-evoked [(3)H]ACh release were evaluated in mucosal-denuded detrusor strips from BPH patients (n = 31) and control organ donors (n = 23). The neurogenic release of ATP and [(3)H]ACh was higher (P bladders. Relaxation of detrusor contractions induced by acetylcholine required 30-fold higher concentrations of adenosine. Despite VAChT-positive cholinergic nerves exhibiting higher A(1) immunoreactivity in BPH bladders, the endogenous adenosine tonus revealed by adenosine deaminase is missing. Restoration of A1 inhibition was achieved by favoring (1) ATP hydrolysis with apyrase (2 U mL(-1)) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A(1) receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A(1) receptor activation might be useful to control bladder overactivity in BPH patients. PMID:26521170

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

    KathleenHansen

    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

  5. Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

    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, ...

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

    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.

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

    Hollegaard, Birgitte; Byars, Sean G; Lykke, Jacob; Boomsma, Jacobus J

    2013-01-01

    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. PMID:23451092

  8. Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast

    Busti, Stefano; Mapelli, Valeria; Tripodi, Farida; Sanvito, Rossella; Magni, Fulvio; Coccetti, Paola; Rocchetti, Marcella; Nielsen, Jens; Alberghina, Lilia; Vanoni, Marco

    2016-01-01

    Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing of secretory proteins. By using the model organism Saccharomyces cerevisiae we show that calcium shortage leads to a slowdown of cell growth and metabolism. Accumulation of unfolded proteins within the calcium-depleted lumen of the endoplasmic reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections linking disturbance of ER calcium equilibrium to ER stress and UPR signaling are evolutionary conserved and highlight the crucial role of metabolism in modulating the effects induced by calcium shortage. PMID:27305947

  9. The role of free radicals and stress signalling in persistent genomic instability induced by long wavelength UV light

    Induction of persistent genomic instability has commonly been investigated with ionising radiation. It has been characterised as a decrease in plating efficiency, and an increase in chromosomal aberrations and mutation frequency in the progeny of cells that survive the initial irradiation. We now present data demonstrating the phenomenon following exposure to long-wavelength solar UV-A (320-400nm) radiation at environmentally relevant doses. Using the spontaneously immortalised human skin keratinocyte line, HaCaT, we observed a significant decrease in plating efficiency (77 +/- 2% of control), and increase in micronuclei (2.5 fold) and mutation frequency (2 fold), 7 days after the initial radiation insult. Modification of UV-A-induced instability by incubation with exogenous catalase implicated reactive oxygen species (ROS), in-particular hydrogen peroxide, in the production and/or maintenance of the phenomenon. Assessment of anti-oxidant enzymes revealed a significant increase in glutathione-s-transferase activity (158 +/- 4% of control) at day 7 in the irradiated cell population, which was inhibited by incubation with exogenous catalase (97 +/- 3%), providing further evidence for an ROS-mediated pathway. Furthermore, inhibition of UV-A-induced micronuclei at day 7 by the flavonoid-containing-protein inhibitor diphenyleneiodonium (DPI) indicates that the NADPH oxidase family of enzymes may be involved in this phenomenon. Measurement of superoxide production by the cytochrome c reduction assay revealed that the irradiated cell population produce 50% more superoxide than the unirradiated controls, and that incubation with DPI led to a preferential reduction in superoxide production in the UV-A treated population at day 7. Finally, NADPH oxidase activity is increased significantly over controls in UV-A-treated cells. These data demonstrate that oxidative stress, analogous to that produced by ionising radiation, induces persistent genomic instability through a

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

    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. PMID:27224055

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

    Hartsteen, Birgitte Hollegaard; Byars, Sean Geoffrey; Lykke, Jacob;

    2013-01-01

    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....

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

    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.

  13. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT.

    Rasche, L; Kapp, M; Einsele, H; Mielke, S

    2014-02-01

    EBV-induced post transplantation lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after allogeneic hematopoietic cell transplantation. Profound T-cell depletion of the allograft represents a major risk factor for EBV-PTLD. With regard to the increasing use of alternative stem cell sources such as cord blood or purified haploidentical stem cell grafts both associated with impaired immune reconstitution, the frequent occurrence of EBV-PTLD demands particular vigilance on laboratory changes and early symptoms. Here we have summarized today's knowledge about EBV-PTLD in a comprehensive review explaining the underlying mechanisms of EBV-based transformation, EBV-PTLD development, clinical presentation, incidence, diagnosis, screening, therapy and prognosis. In this context, we emphasize on the necessity of regularly applied screening tools and pre-emptive treatment strategies including anti-CD20 Abs particularly in high-risk patients to avoid disease progression to malignant lymphoma. Although EBV-PTLD has always been associated with a high mortality rate, novel immunotherapeutic approaches such as the transfer of EBV-specific T cells nowadays offer improved chances of disease control even at late stages. PMID:23832092

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

    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.

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

    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 < 0.05) compared with non-stimulated muscle cells (161 +/- 20 nmol (g protein)-1). The ATP concentration was lower (18%; P < 0.05) in the intensely contracted, but not in the moderately contracted muscle cells....... 3. Addition of microvascular endothelial cells to the cultured skeletal muscle cells enhanced the contraction-induced accumulation of extracellular adenosine (P < 0.05), whereas endothelial cells in culture alone did not cause extracellular accumulation of adenosine. 4. Skeletal muscle cells were...

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

    TANG Yuan-zhang; Moore-Langston Shannon; LAI Guang-hui; LI Xuan-ying; LI Na; NI Jia-xiang

    2013-01-01

    Background 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.Methods 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.Results 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 <0.05).Up to 11/12 patients had satisfactory pain relief at 1 week after discharge,8/12 at 4 weeks,7/12 at 8 weeks,6/12 at 12 weeks,and 5/12 at 24 weeks.Conclusions It is important to consider the possibility of discogenic visceral pain secondary to anterior 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.

  17. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells

    Although commonly used to control a variety of inflammatory diseases, the mechanism of action of a low dose of methotrexate remains a mystery. Methotrexate accumulates intracellularly where it may interfere with purine metabolism. Therefore, the authors determined whether a 48-hr pretreatment with methotrexate affected adenosine release from [14C]adenine-labeled human fibroblasts and umbilical vein endothelial cells. Methotrexate significantly increased adenosine release by fibroblasts. The effect of methotrexate on adenosine release was not due to cytotoxicity since cells treated with maximal concentrations of methotrexate took up [14C]adenine and released 14C-labeled purine (a measure of cell injury) in a manner identical to control cells. Methotrexate treatment of fibroblasts dramatically inhibited adherence to fibroblasts by both unstimulated neutrophils and stimulated neutrophils. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, methotrexate induces the accumulation of AICAR, the nucleoside precursor of which has previously been shown to cause adenosine release from ischemic cardiac tissue. The observation that the antiinflammatory actions of methotrexate are due to the capacity of methotrexate to induce adenosine release may form the basis for the development of an additional class of antiinflammatory drugs

  18. An injectable, low-toxicity phospholipid-based phase separation gel that induces strong and persistent immune responses in mice.

    Han, Lu; Xue, Jiao; Wang, Luyao; Peng, Ke; Zhang, Zhirong; Gong, Tao; Sun, Xun

    2016-10-01

    Sustained antigen delivery using incomplete Freund's adjuvant (IFA) can induce strong, long-term immune response, but it can also cause severe side effects. Here we describe an injectable, phospholipid-based phase separation gel (PPSG) that readily transforms in situ into a drug depot. PPSG loaded with the model antigen ovalbumin (OVA) supported sustained OVA release in mice that lasted nearly one month. Immunizing mice with a single injection of PPSG/OVA elicited a strong and persistent increase in titers of OVA-specific IgG, IgG1 and IgG2a. Co-administering CpG-ODN further increased antibody titers. Such co-administration recruited dendritic cells to injection sites and activated dendritic cells in the draining lymph nodes. Moreover, immunization with PPSG/OVA/CpG resulted in potent memory antibody responses and high frequency of memory T cells. Remarkably, PPSG/OVA/CpG was associated with much lower toxicity at injection sites than IFA/OVA/CpG, and it showed no systemic toxicity such as to lymph nodes or spleen. These findings illustrate the potential of injectable PPSG for sustained, minimally toxic delivery of antigens and adjuvants. PMID:27522253

  19. Optical Aptasensors for Adenosine Triphosphate

    Ng, Stella; Lim, Hui Si; Ma, Qian; Gao, Zhiqiang

    2016-01-01

    Nucleic acids are among the most researched and applied biomolecules. Their diverse two- and three-dimensional structures in conjunction with their robust chemistry and ease of manipulation provide a rare opportunity for sensor applications. Moreover, their high biocompatibility has seen them being used in the construction of in vivo assays. Various nucleic acid-based devices have been extensively studied as either the principal element in discrete molecule-like sensors or as the main component in the fabrication of sensing devices. The use of aptamers in sensors - aptasensors, in particular, has led to improvements in sensitivity, selectivity, and multiplexing capacity for a wide verity of analytes like proteins, nucleic acids, as well as small biomolecules such as glucose and adenosine triphosphate (ATP). This article reviews the progress in the use of aptamers as the principal component in sensors for optical detection of ATP with an emphasis on sensing mechanism, performance, and applications with some discussion on challenges and perspectives. PMID:27446501

  20. Adenosine regulation of alveolar fluid clearance

    Factor, Phillip; Mutlu, Göskhan M.; Chen, Lan; Mohameed, Jameel; Akhmedov, Alexander T.; Meng, Fan Jing; Jilling, Tamas; Lewis, Erin Rachel; Johnson, Meshell D.; Xu, Anna; Kass, Daniel; Martino, Janice M.; Bellmeyer, Amy; Albazi, John S.; Emala, Charles

    2007-01-01

    Adenosine is a purine nucleoside that regulates cell function through G protein-coupled receptors that activate or inhibit adenylyl cyclase. Based on the understanding that cAMP regulates alveolar epithelial active Na+ transport, we hypothesized that adenosine and its receptors have the potential to regulate alveolar ion transport and airspace fluid content. Herein, we report that type 1 (A1R), 2a (A2aR), 2b (A2bR), and 3 (A3R) adenosine receptors are present in rat and mouse lungs and alveol...

  1. Regulation of adenosine triphosphate-sensitive potassium channels suppresses the toxic effects of amyloid-beta peptide (25-35)

    Min Kong; Maowen Ba; Hui Liang; Peng Shao; Tianxia Yu; Ying Wang

    2013-01-01

    In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide (25-35) for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide (25-35) decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nω-nitro-L-arginine, also protected PC12 cells from intracellular reactive oxygen species levels. However, the H2O2-degrading enzyme catalase could that the increases in both mitochondrial membrane potential and reactive oxygen species levels adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β

  2. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library

    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

  3. Employment persistence

    Fleischman, Charles A.; Joshua H. Gallin

    2001-01-01

    The recent U.S. expansion has provided employment experience to individuals at tail of the skill distribution. Will these opportunities bestow persistent benefits in the form of greater future employability? Using synthetic cohorts constructed from the CPS, this paper estimates the degree of persistence in cohort-level employment rates in excess of persistence in aggregate macroeconomic conditions. This approach is in some ways superior to testing for hysteresis in the aggregate unemployment ...

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

    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. PMID:23912595

  5. Anxiolytic activity of adenosine receptor activation in mice.

    Jain, N; Kemp, N; Adeyemo, O; Buchanan, P; Stone, T W

    1995-10-01

    1. Purine analogues have been examined for anxiolytic- and anxiogenic-like activity in mice, by use of the elevated plus-maze. 2. The selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) had marked anxiolytic-like activity at 10 and 50 microg kg(-1), with no effect on locomotor performance at these doses. 3. The A1 selective adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (CPX) had no significant effect on anxiety-related measures or locomotor behaviour, but blocked the anxiolytic-like activity of CPA. The hydrophilic xanthine, 8-(p-sulphophenyl) theophylline did not prevent anxiolysis by CPA. 4. Caffeine had anxiogenic-like activity at 30 mg kg(-1) which was prevented by CPA at 50 micro kg(-1). 5. The A2 receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2(2-methylphenyl)-ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg(-1). The A2 receptor antagonist, 1,3-dimethyl-l-propargylxanthine (DMPX) had no effect on anxiety-related measures or locomotion and did not modify the anxiolytic-like activity of CPA. 6. Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic-like activity of the latter. 7. The results suggest that the selective activation of central A1 adenosine receptors induces anxiolytic-like behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of A1 receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus-maze in mice are not activated tonically by endogenous adenosine. PMID:8640355

  6. Activation of adenosine receptors and inhibition of cyclooxygenases: two recent pharmacological approaches to modulation of radiation suppressed hematopoiesis

    Searching for drugs conforming to requirements for protection and/or treatment of radiation-induced damage belongs to the most important tasks of current radiobiology. In the Laboratory of Experimental Hematology, Institute of Biophysics, v.v.i., Academy of Sciences of the Czech Republic, Brno, Czech Republic, two original approaches for stimulation of radiation-suppressed hematopoiesis have been tested in recent years, namely activation of adenosine receptors and inhibition of cyclooxygenases. Non-selective activation of adenosine receptors, induced by combined administration of dipyridamole, a drug preventing adenosine uptake and supporting thus its extracellular receptor-mediated action, and adenosine monophosphate, an adenosine prodrug, has been found to stimulate hematopoiesis when the drugs were given either pre- or post-irradiation. When synthetic adenosine receptor agonists selective for individual adenosine receptor subtypes were tested, stimulatory effects in myelosuppressed mice have been found after administration of IB-MECA, a selective adenosine A3 receptor agonist. Non-selective cyclooxygenase inhibitors, inhibiting both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), indomethacin, diclofenac, or flurbiprofen, have been observed to act positively on radiation-perturbed hematopoiesis in sublethally irradiated mice. However, their undesirable gastrointestinal side effects have been found to negatively influence survival of lethally irradiated animals. Recently tested selective COX-2 inhibitor meloxicam, preserving protective action of COX-1-synthesized prostaglandins in the gastrointestinal tissues, has been observed to retain the hematopoiesis-stimulating effects of non-selective cyclooxygenase inhibitors and to improve the survival of animals exposed to lethal radiation doses. These findings bear evidence for the possibility to use selective adenosine A3 receptor agonists and selective COX-2 inhibitors in human practice for treatment of

  7. Adenosine triphosphate inhibition of yeast trehalase.

    Panek, A D

    1969-09-01

    Yeast trehalase has been found to be inhibited non-competitively by adenosine triphosphate. Such a biological control could explain the accumulation of trehalose during the stationary phase of the growth curve. PMID:5370287

  8. Subsidence Induced Faulting Hazard Zonation Using Persistent Scatterer Interferometry and Horizontal Gradient Mapping in Mexican Urban Areas

    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

  9. Adenosine A1 Receptor Mediates Delayed Cardioprotective Effect of Sildenafil in Mouse

    Salloum, Fadi N.; Das, Anindita; Thomas, Christopher S; Yin, Chang; Kukreja, Rakesh C.

    2007-01-01

    Sildenafil induces powerful cardioprotection against ischemia/reperfusion (I/R) injury. Since adenosine is known to be major trigger of ischemic preconditioning, we hypothesized that A1 adenosine receptor (A1AR) activation plays a role in sildenafil-induced cardioprotective signaling. Adult male C57BL-wild type (WT) mice or their corresponding A1AR knockout (A1AR-KO) mice were treated intraperitoneally (i.p.) with either sildenafil (0.71 mg/kg, equivalent to 50 mg dose for a 70 kg patient) or...

  10. Electrocardiographic profile of adenosine pharmacological stress testing

    Sun, Hao; TIAN, YUEQIN; ZHENG, LIHUI; Pan, Qingrong; XIE, BOQIA

    2015-01-01

    Adenosine stress testing in conjunction with radionuclide myocardial perfusion imaging has become a common approach for the detection of coronary artery diseases in patients who are unable to perform adequate levels of exercise. However, specific electrocardiographic alterations during the test have been rarely described. Using a Chinese population, the aim of the present study was to provide a detailed electrocardiographic profile of adenosine stress testing. The study population included 1,...

  11. Effects of Persistent Atrial Fibrillation-Induced Electrical Remodeling on Atrial Electro-Mechanics – Insights from a 3D Model of the Human Atria

    Adeniran, Ismail; Maclver, David H.; Garratt, Clifford J.; Ye, Jianqiao; Hancox, Jules C.; Zhang, Henggui

    2015-01-01

    Aims Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. Methods and Results A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on...

  12. Angina pectoris-like pain provoked by intravenous adenosine in healthy volunteers.

    Sylvén, C; Beermann, B; Jonzon, B; Brandt, R

    1986-07-26

    In a study to characterise the chest pain induced by adenosine this agent was given as a bolus into a peripheral vein to six healthy volunteers (five men) aged 30-44. On the first day the maximum tolerable dose was determined in each case. On the second day three doses of adenosine (one third, two thirds, and the full maximum tolerable dose) and three doses of saline were given single blind in randomised order. Thereafter aminophylline 5 mg/kg was given and the procedure repeated in a different randomised order. On the third day between two thirds and the full maximum tolerable dose was given followed by 10 mg dipyridamole intravenously and a second injection of the same dose of adenosine. Heart rate and atrioventricular blocks were recorded by electrocardiography. One minute after each dose of adenosine the chest pain was scored. The maximum tolerable dose of adenosine ranged from 10.6 to 37.1 mg. All subjects experienced uneasy central chest pain provoking anxiety. The pain radiated to the shoulders, ulnar aspect of the arms, epigastric area, back, and into the throat. The pain began about 20 seconds after the injection and lasted 10-15 seconds. Increasing the dose of adenosine increased the intensity of the pain. Administration of aminophylline reduced the pain significantly. Second degree heart block was recorded in five of the six subjects during the time that the pain was experienced. After aminophylline no block was observed. Dipyridamole increased the intensity of pain. The duration of second degree heart block increased in four of the subjects, and in two of these third degree heart block occurred. These findings suggest that adenosine released from the myocardium during ischaemia induces angina pectoris by stimulating theophylline sensitive receptors. PMID:3089465

  13. Adenosine stress protocols for myocardial perfusion imaging

    Baškot Branislav

    2008-01-01

    Full Text Available Background/Aim. Treadmill test combined with myocardial perfusion scintigraphy (MPS is a commonly used technique in the assessment of coronary artery disease. There are many patients, however, who may not be able to undergo treadmill test. Such patients would benefit from pharmacological stress procedures combined with MPS. The most commonly used pharmacological agents for cardiac stress are coronary vasodilatators (adenosine, dipyridamol and catecholamines. Concomitant low-level treadmill exercise with adenosine pharmacologic stress (AdenoEX during MPS has become commonly used in recent years. A number of studies have demonstrated a beneficial impact of AdenoEX protocol. The aim of the study was, besides introducing into practice the two types of protocols of pharmatological stress test with adenosine, as a preparation for MPS, to compare and monitor the frequency of their side effects to quality, acquisition, as well as to standardize the onset time of acquisition (diagnostic imaging for both protocols. Methods. A total of 130 patients underwent pharmacological stress test with adenosine (vasodilatator. In 108 of the patients we performed concomitant exercise (AdenoEX of low level (50W by a bicycle ergometar. In 28 of the patients we performed Adenosine abbreviated protocol (AdenoSCAN. Side effects of adenosine were followed and compared between the two kinds of protocols AdenoEX and AdenoSCAN. Also compared were image quality and suggested time of acquisition after the stress test. Results. Numerous side effects were found, but being short-lived they did not require any active interventions. The benefit of AdenoEX versus AdenoSCAN included decreased side effects (62% vs 87%, improved safety and patients tolerance, improved target-to-background ratios because of less subdiaphragmatic activity, earlier acquisition, and improved sensitivity. Conclusion. The safety and efficacy of adenosine pharmacological stress is even better with concomitant

  14. Adenosine Amine Congener as a Cochlear Rescue Agent

    Srdjan M. Vlajkovic

    2014-01-01

    Full Text Available We have previously shown that adenosine amine congener (ADAC, a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment. Methods. ADAC (25–300 μg/kg was administered intraperitoneally to Wistar rats (8–10 weeks old at intervals (6–72 hours after exposure to traumatic noise (8–16 kHz, 110 dB sound pressure level, 2 hours. Hearing sensitivity was assessed using auditory brainstem responses (ABR before and 12 days after noise exposure. Pharmacokinetic studies investigated ADAC concentrations in plasma after systemic (intravenous administration. Results. ADAC was most effective in the first 24 hours after noise exposure at doses >50 μg/kg, providing up to 21 dB protection (averaged across 8–28 kHz. Pharmacokinetic studies demonstrated a short (5 min half-life of ADAC in plasma after intravenous administration without detection of degradation products. Conclusion. Our data show that ADAC mitigates noise-induced hearing loss in a dose- and time-dependent manner, but further studies are required to establish its translation as a clinical otological treatment.

  15. [Persistent diarrhea

    Andrade, J A; Moreira, C; Fagundes Neto, U

    2000-07-01

    INTRODUCTION: Persistent diarrhea has high impact on infantile morbidity and mortality rates in developing countries. Several studies have shown that 3 to 20% of acute diarrheal episodes in children under 5 years of age become persistent. DEFINITION: Persistent diarrhea is defined as an episode that lasts more than 14 days. ETIOLOGY: The most important agents isolated in persistent diarrhea are: Enteropathogenic E. coli (EPEC), Salmonella, Enteroaggregative E. coli (EAEC), Klebisiella and Cryptosporidium. CLINICAL ASPECTS: In general, the clinical characteristics of patients with persistent diarrhea do not change with the pathogenic agent. Persistent diarrhea seems to represent the final result of a several insults a infant suffers that predisposes to a more severe episode of diarrhea due to a combination of host factors and high rates of enviromental contamination. Therefore, efforts should be made to promptly treat all episodes of diarrhea with apropriate follow-up. THERAPY: The aim of the treatment is to restore hydroelectrolytic deficits and to replace losses until the diarrheal ceases. It is possible in the majority of the cases, using oral rehydration therapy and erly an appropriate type of diet. PREVENTION: It is imperative that management strategies also focus on preventive aspects. The most effective diarrheal prevention strategy in young infants worldwide is promotion of exclusive breast feeding. PMID:14676915

  16. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

    Jie eFeng

    2016-05-01

    Full Text Available 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 effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. While some drug candidates such as daptomycin and clofazimine overlapped with a previous screen against stationary phase B. burgdorferi persisters, additional drug candidates active against round bodies we identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against 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 persisters in vitro, even if pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

  17. Variations of lipid profile in animals caused by adenosine analogs: N6 (amido-3-propyl) adenosine hydrochloride and (carboxamido-3-propylamino)-6-(triproprionyl) 2',3',5'beta (D-ribosyl)-9-purine.

    Laborit, G; Hasni, H; Baron, C; Pierrefiche, G; Laborit, H

    1992-03-01

    N6-substituted adenosine analogues are powerful inhibitors of lipolysis in the adipose tissues of animals and humans, because of their agonist effect on A1 purine receptors. Using a model of hypertriglyceridemia provoked by intravenous injection of Triton WR 1339, we observed that Agr 529 [N6(amido-3-propyl)adenosine hydrochloride] at 2 mg.kg-1 intravenous in rabbits, and intraperitoneally and orally in rats led to a return of the levels of circulating triglycerides to normal values. In addition, Agr 529 and its prodrug, Agr 540 [(carboxamido-3-propylamino)-6-(triproprionyl)2', 3',5'beta(D-ribosyl)-9-purine] administered to rats at 3 and 30 mg.kg-1, respectively, returned plasma triglyceride concentrations to normal levels. Intravenous administration of Agr 529 to normal rats led to decreased concentrations of plasma fatty acids, phospholipids, triglycerides and total cholesterol as a function of dose. The decrease began at 0.1 mg.kg-1 and was highly significant at 3 mg.kg-1. In the same conditions, the intraperitoneal administration of Agr 529 caused a dose-dependent hypolipemia. There was no apparent effect on cholesterol and on the triglycerides of high density lipoproteins. A kinetic study showed that the antilipemic effect of Agr 529 intravenously injected at 3 mg.kg-1 began 30 minutes after the injection with a maximum effect at 2 hours. The effect persisted up to 8 hours after injection. The present results show that the administration of Agr 529 and Agr 540 to normal animals causes hypolipemia (decrease in fatty acids, phospholipids, triglycerides and cholesterol) and restores induced hypertriglyceridemia. These effects may be attributed to an interaction of the molecules with A1 purinergic receptors of adipose tissue. PMID:1509199

  18. Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability.

    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.

  19. Hematopoiesis in 5-Fluorouracil-Treated Adenosine A(3) Receptor Knock-Out Mice

    Hofer, Michal; Pospíšil, Milan; Dušek, L.; Hoferová, Zuzana; Komůrková, Denisa

    2015-01-01

    Roč. 64, č. 2 (2015), s. 255-262. ISSN 0862-8408 Institutional support: RVO:68081707 Keywords : Adenosine A(3) receptor knock-out mice * Hematopoiesis * 5-fluorouracil-induced hematotoxicity Subject RIV: BO - Biophysics Impact factor: 1.293, year: 2014

  20. Downregulation of adenosine and P2X receptor-mediated cardiovascular responses in heart failure rats

    Zhao, Xin; Sun, X Y; Erlinge, D;

    2000-01-01

    degradation product adenosine, experiments were performed in a rat model of ischaemic CHF. In this model, ischaemia was induced in rats by ligation of the left coronary artery. Our results demonstrate that there is a selective downregulation of P2X receptor-mediated pressor effects, while the hypotensive...

  1. The Quintiles Prize Lecture 2004: The identification of the adenosine A2B receptor as a novel therapeutic target in asthma

    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

  2. The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma.

    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. PMID:15980878

  3. Internalization and desensitization of adenosine receptors

    Klaasse, Elisabeth C.; IJzerman, Adriaan P.; de Grip, Willem J.; Beukers, Margot W.

    2007-01-01

    Until now, more than 800 distinct G protein-coupled receptors (GPCRs) have been identified in the human genome. The four subtypes of the adenosine receptor (A1, A2A, A2B and A3 receptor) belong to this large family of GPCRs that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body and involved in a variety of physiological processes and diseases, there is great interest in understanding how the different subtypes are re...

  4. Delayed noradrenergic activation in the dorsal hippocampus promotes the long-term persistence of extinguished fear.

    Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin

    2014-07-01

    Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM. PMID:24553734

  5. Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

    Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin

    2014-01-01

    Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM. PMID:24553734

  6. Persistent Modelling

    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....

  7. Increase of adenosine plasma levels after oral trimetazidine: a pharmacological preconditioning?

    Blardi, Patrizia; de Lalla, Arianna; Volpi, Luciana; Auteri, Alberto; Di Perri, Tullio

    2002-01-01

    Trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine) (TMZ) is a cellular anti-ischemic agent able to prevent intracellular ATP decrease, limit intracellular acidosis, protect against oxygen-free radical-induced toxicity and inhibit neutrophil infiltration. However, its definitive mechanism of action had not been identified. Recent studies showed the existence of an endogenous mechanism of cellular protection against ischemia, defined as 'ischemic preconditioning'. This mechanism was related mainly to cellular liberation of adenosine, a nucleoside with protective effects in myocardial ischemia. Since TMZ acts by increasing cell tolerance to ischemia and adenosine is the mediator of ischemic preconditioning, in this study we investigated a possible interaction between TMZ and adenosine. Two groups of patients affected by angina pectoris, were admitted to the study. They received a single oral dose of TMZ. One group was treated, during different sessions, with TMZ 10 and 20 mg, the other group with TMZ 40 and 80 mg. After a 3 day wash-out from drug administration, each group received a placebo. Blood samples were collected at baseline (time 0) and 1, 2, 3, 4, 6, 8 h after drug administration, in order to detect plasma levels of adenosine by a high-performance liquid chromatography method. We observed that the administration of TMZ at doses of 10, 20, 40 and 80 mg induced an increase of adenosine plasma levels of 19, 50, 62 and 62%, respectively. We hypothesized that the activity of TMZ could depend, at least in part, on adenosine mediation and this interaction opens a new interpretation of the drug antischemic effect. PMID:11820865

  8. Effects of AMP579 and adenosine on L-type Ca2+ current in isolated rat ventricular myocytes

    Xiong WANG; Bo-wei WU; Dong-mei WU

    2005-01-01

    Aim: To compare the effects of AMP579 and adenosine on L-type Ca2+ current (ICa- L) in rat ventricular myocytes and explore the mechanism by which AMP579 acts on ICa-L. Methods: ICa-L was recorded by patch-clamp technique in whole-cell configuration. Results: Adenosine (10 nmol/L to 50 μmol/L) showed no effect on basal ICa- L, but it inhibited the ICa-L induced by isoproterenol 10 nmol/L in a concen tration-dependent manner with the IC50 of 13.06 μmol/L. Similar to adenosine,AMP579 also showed an inhibitory effect on the ICa-L induced by isoproterenol.AMP579 and adenosine (both in 10 μmol/L) suppressed isoproterenol-induced ICa-L by 11.1% and 5.2%, respectively. In addition, AMP579 had a direct inhibitory effect on basal ICa-L in a concentration-dependent manner with IC50 (1.17 μmol/L).PD116948 (30 μmol/L), an adenosine A1 receptor blocker, showed no action on the inhibitory effect of AMP579 on basal ICa-L. However, GF109203X (0.4 μmol/L), a special protein kinase C (PKC) blocker, could abolish the inhibitory effect of AMP579 on basal ICa-L. So the inhibitory effect of AMP579 on basal ICa-L was induced through activating PKC, but not linked to adenosine A1 receptor. Conclusion:AMP579 shows a stronger inhibitory effect than adenosine on the ICa-L induced by isoproterenol. AMP579 also has a strong inhibitory effect on basal ICa-L in rat ventricular myocytes. Activation of PKC is involved in the inhibitory effect of AMP579 on basal ICa-L at downstream-mechanism.

  9. AAVrh.10-Mediated Expression of an Anti-Cocaine Antibody Mediates Persistent Passive Immunization That Suppresses Cocaine-Induced Behavior

    Rosenberg, Jonathan B; Hicks, Martin J.; De, Bishnu P.; Pagovich, Odelya; Frenk, Esther; Kim D. Janda; Wee, Sunmee; Koob, George F.; Hackett, Neil R.; KaMinSky, Stephen M.; Worgall, Stefan; Tignor, Nicole; Mezey, Jason G; Crystal, Ronald G.

    2012-01-01

    Cocaine addiction is a major problem affecting all societal and economic classes for which there is no effective therapy. We hypothesized an effective anti-cocaine vaccine could be developed by using an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain. To accomplish this, we constructed AAVrh.10antiCoc.Mab...

  10. The role of high LET radiation induced persistent oxidative stress and nucleotide excision repair on genomic instability in mammalian cells

    N-Acetyl Cysteine (NAC) is a nontoxic radical scavenger and capable radioprotector against low-linear energy transfer (LET) radiation. Last year we measured the NAC protective effect against accelerated neon ion induced ROS and Hprt mutations. Here we report the ability of NAC to protect against neon ion induced clonogenic cell-killing. We observed that NAC protects against x-ray induced cell-killing, we did not observe NAC protection against neon ion induced cell killing. (author)