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1
Zanoli, Juliana Carla Castanha [UNESP]. "Efeitos da abamectina na bioenergética de mitocôndrias isoladas de fígado de rato: Juliana Carla Castanha Zanoli. -." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/94732.
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zanoli_jcc_me_araca.pdf: 862916 bytes, checksum: 14a8c6ca70d93c05133bf28113b4bac8 (MD5)Abamectina é uma lactona macrocíclica pertencente à família das avermectinas, utilizada mundialmente como agente antiparasitário em animais de criação e estimação, além do emprego agrícola como princípio ativo dos inseticidas e nematicidas. Mitocôndrias são responsáveis pela conversão da energia liberada pelo transporte de elétrons e armazenamento como energia de ligação na molécula de ATP, um componente metabólico essencial. Interferências em sua síntese ou utilização caracterizam mecanismos pelos quais os xenobióticos podem expressar toxicidade aguda ou crônica. Neste trabalho, os efeitos da abamectina na bioenergética de mitocôndrias isoladas de fígado de rato foram avaliados. Nas concentrações utilizadas (5 a 25 µM), abamectina causou inibição da cadeia respiratória, sem afetar a atividade das enzimas NADH desidrogenase, succinato desidrogenase e o potencial de membrana, comportando-se de maneira semelhante à oligomicina e ao atractilosídeo. A principal atuação da abamectina foi reduzir o potencial mitocondrial de fosforilação oxidativa, diminuindo os níveis de ATP provavelmente como resultado de sua ação direta sobre a FoF1-ATPase, uma vez que inibiu a atividade desta enzima, e/ou sobre o translocador de ADP/ATP. A inibição mais acentuada da atividade fosfohidrolase em mitocôndrias intactas desacopladas do que em mitocôndrias rompidas juntamente com a inibição da despolarização do potencial de membrana induzida pelo ADP sugerem que a abamectina atuou inibindo mais especificamente o translocador de ADP/ATP do que a FoF1-ATPase
Abamectin is a macrocyclic lactone belonging to the avermectin family, used worldwide as antiparasitic agent in farm animals and pets, and agricultural employment as the active ingredient of insecticides and nematicides. Mitochondria are responsible for converting the energy released by electron transport and storage as the binding energy molecule ATP, an essential metabolic component. Interference in its synthesis or utilization characterize mechanisms by which xenobiotics can express acute or chronic toxicity. In this study, the effects of abamectin in the bioenergetics of mitochondria isolated from rat liver were evaluated. At the concentrations used (5-25 mM), abamectin caused inhibition of the respiratory chain without affecting the activity of enzymes NADH dehydrogenase, succinate dehydrogenase and the membrane potential, behaving similarly to oligomycin and Atractyloside. The main activity of abamectin was to reduce the potential of mitochondrial oxidative phosphorylation, decreasing ATP levels probably as a result of its direct action on the Fo-F1 ATPase, since it inhibited the activity of this enzyme, and/or the ADP/ATP translocator. The more pronounced inhibition of the fosfohydrolase activity in intact uncoupled mitochondria than in disrupted mitochondria, in addition to the inhibition of the ADP-stimulated depolarization of mitochondrial membrane potential suggest that abamectin acted more specifically by inhibiting the ADP/ATP translocator than the FoF1-ATPase
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Dulla, Chris. "Adenosine and adenosine triphosphate link Pco2 to cortical excitability via pH /." Connect to full text via ProQuest. IP filtered, 2005.
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Soledade, Cinira Santana. "O efeito do DMA (composto quinazolinico) sobre o processo inflamatorio." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310436.
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Orientadores: Lilian Tereza Lavras Costallat, Kleber Gomes FranchiniTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A inflamação é apontada como o principal processo mediador das diversas doenças do tecido conjuntivo e um componente importante da fisiopatologia das doenças infecciosas. Mais recentemente também tem lhe sido atribuído papel de destaque na obesidade, diabetes e doenças cardiovasculares, em especial a aterosclerose. Dentre os vários mediadores envolvidos no processo inflamatório, a adenosina tem sido apontada como um potente mediador endógeno. A adenosina é um autacóide, cuja ação se dá pela interação com quatro receptores de superfície celular (A1, A2A, A2B e A3), sendo a sua concentração modulada pelo equilíbrio entre os processos de síntese (5- nucleotidases), fosforilação (adenosina quinase), e deaminação (adenosina deaminase). A adenosina sabidamente age em múltiplos aspectos do processo inflamatório, como: apoptose, migração de leucócitos, liberação de mediadores (citocinas, quimiocinas) e mecanismos vasoregulatórios. No nível celular os efeitos da adenosina incluem várias vias de sinalização, modulando a ativação de importantes fatores de transcrição como o NF-?B. Neste contexto, a imunomodulação exercida pela adenosina tem seu potencial terapêutico reconhecido e avaliado na literatura, através do estudo de compostos que agem sobre seus receptores específicos ou através do aumento de sua concentração. O objetivo geral deste trabalho foi avaliar as propriedades antiinflamatórias e mecanismos de ação de um novo composto, inibidor de adenosina quinase (6,7-dimetóxi-4-N-(3'-N,N-dimetilfenil)aminoquinazolina, DMA), cuja ação resulta no aumento da concentração tecidual de adenosina. Para isso, foram utilizados modelos de inflamação aguda em animais de experimentação e ensaios in vitro em cultura de células. No modelo de peritonite aguda induzida por thioglicolato em camundongos, o tratamento com DMA reduziu o acúmulo de neutrófilos, (?55%, p < 0,05) e esse efeito foi bloqueado por um antagonista de receptor de adenosina, a 8-sulpho-phenil- theophilina. Ainda neste modelo, houve diminuição de Interleucina-6 no exudato dos animais tratados com DMA (?35%; p < 0,005). O DMA também foi efetivo na redução da inflamação nos modelos de artrite aguda em ratos, reduzindo o volume articular (?30% na segunda hora e ?35% na quarta hora; p < 0,05), número de leucócitos no líquido sinovial (?50% ; 28,6 x 106 ± 5,2 células/ml vs. 13,8 x 106 ± 1,7 células/ml; p < 0,05) e escala de dor (2,62 ± 0,18 vs. 1,53 ± 0,136; p < 0,05). No modelo de edema de pata induzidos por carragenina demonstrou-se uma redução do edema
Abstract: : Inflammation has a main role in several connective tissue diseases and is an important element of infectious disease physiopathology. Recently it has been linked to obesity, diabetes and cardiovascular diseases. Adenosine, among the various inflammatory process mediators, is a potent autocoid and its bioavailability is limited by catabolism to inosine by adenosine deaminase or by salvage following cellular uptake via adenosine kinase (ADK). Once in extracellular space adenosine interacts with specific cell-surface receptors (A1, A2, A2B, A3) and acts on multiples aspects of the inflammatory process: apoptosis, leukocyte migration, release of proinflammatory cytokines and vascular regulation. At cellular level adenosine acts in a wide-range of pathways, modulating important transcription factors like NF-?B. Based on these premises, adenosine immune regulatory properties and potential in therapeutics have been acknowledged and investigated through the study of specific receptors agonists and compounds able to increase its concentration. The main objective of this study was to evaluate the antiinflammatory properties and mechanisms of DMA, a novel adenosine kinase inhibitor, which increases adenosine tissue concentration. In order to accomplished that, animal models of acute inflammation and cell culture assay were used. DMA was orally effective to reduce neutrophils migration (~55%; p < 0,05) and IL-6 concentration (~35%; p < 0,005) in the aseptic thioglycollate peritonitis model. DMA significantly inhibited arthritis in an acute arthritis carrageenan model, decreasing articular volume (~30% second hour and ~35% fourth hour, p < 0,05), leukocytes on synovial liquid (~50% ; 28,6 x 106 ± 5,2 cells/ml vs. 13,8 x 106 ± 1,7 cells/ml; p < 0,05) and pain score (2,62 ± 0,18 vs. 1,53 ± 0,136; p <0 ,05). DMA was also effective in reducing edema in the carrageenan-induced paw edema model (~30% second hour and 36% fourth hour; p < 0,05) and pain in the second phase of the "Liking test" induced by formalin (~40% in liking time; p < 0,01). In vitro, macrophage expression of TLR4, an important cell receptor in recognizing and processing antigens, was decreased after DMA treatment. The results suggest that DMA also impacts the inflammatory cascade by modulating inflammatory related nuclear transcription. It was demonstrated that DMA was also able to inhibit macrophages and neutrophils, LPS induced NF-?B activation and promote PPAR activation in THP-1 cells. Antiinflammatories are drugs in high demand, but their use is still limited by side-effects. The DMA is a novel, potent non-nucleoside ADK inhibitor, orally effective to improve inflammation in some well characterized animal models and in vitro assays. New studies, based on this data, will be design to further explore the therapeutic use of DMA in inflammatory diseases
Doutorado
Ciencias Basicas
Doutor em Clínica Médica
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Zanoli, Juliana Carla Castanha. "Efeitos da abamectina na bioenergética de mitocôndrias isoladas de fígado de rato / Juliana Carla Castanha Zanoli. -." Araçatuba : [s.n.], 2011. http://hdl.handle.net/11449/94732.
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Orientador: Fabio Erminio MingattoBanca: Flavia Thomaz Verechia Pereira
Banca: Tiago Rodrigues
Resumo: Abamectina é uma lactona macrocíclica pertencente à família das avermectinas, utilizada mundialmente como agente antiparasitário em animais de criação e estimação, além do emprego agrícola como princípio ativo dos inseticidas e nematicidas. Mitocôndrias são responsáveis pela conversão da energia liberada pelo transporte de elétrons e armazenamento como energia de ligação na molécula de ATP, um componente metabólico essencial. Interferências em sua síntese ou utilização caracterizam mecanismos pelos quais os xenobióticos podem expressar toxicidade aguda ou crônica. Neste trabalho, os efeitos da abamectina na bioenergética de mitocôndrias isoladas de fígado de rato foram avaliados. Nas concentrações utilizadas (5 a 25 µM), abamectina causou inibição da cadeia respiratória, sem afetar a atividade das enzimas NADH desidrogenase, succinato desidrogenase e o potencial de membrana, comportando-se de maneira semelhante à oligomicina e ao atractilosídeo. A principal atuação da abamectina foi reduzir o potencial mitocondrial de fosforilação oxidativa, diminuindo os níveis de ATP provavelmente como resultado de sua ação direta sobre a FoF1-ATPase, uma vez que inibiu a atividade desta enzima, e/ou sobre o translocador de ADP/ATP. A inibição mais acentuada da atividade fosfohidrolase em mitocôndrias intactas desacopladas do que em mitocôndrias rompidas juntamente com a inibição da despolarização do potencial de membrana induzida pelo ADP sugerem que a abamectina atuou inibindo mais especificamente o translocador de ADP/ATP do que a FoF1-ATPase
Abstract: Abamectin is a macrocyclic lactone belonging to the avermectin family, used worldwide as antiparasitic agent in farm animals and pets, and agricultural employment as the active ingredient of insecticides and nematicides. Mitochondria are responsible for converting the energy released by electron transport and storage as the binding energy molecule ATP, an essential metabolic component. Interference in its synthesis or utilization characterize mechanisms by which xenobiotics can express acute or chronic toxicity. In this study, the effects of abamectin in the bioenergetics of mitochondria isolated from rat liver were evaluated. At the concentrations used (5-25 mM), abamectin caused inhibition of the respiratory chain without affecting the activity of enzymes NADH dehydrogenase, succinate dehydrogenase and the membrane potential, behaving similarly to oligomycin and Atractyloside. The main activity of abamectin was to reduce the potential of mitochondrial oxidative phosphorylation, decreasing ATP levels probably as a result of its direct action on the Fo-F1 ATPase, since it inhibited the activity of this enzyme, and/or the ADP/ATP translocator. The more pronounced inhibition of the fosfohydrolase activity in intact uncoupled mitochondria than in disrupted mitochondria, in addition to the inhibition of the ADP-stimulated depolarization of mitochondrial membrane potential suggest that abamectin acted more specifically by inhibiting the ADP/ATP translocator than the FoF1-ATPase
Mestre
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Silva, Aleksandro Schafer da. "Atividade da adenosina desaminase, concentração de nucleotideos e nucleosideo de adenina em ratos Infectados com Trypanosoma evansi." Universidade Federal de Santa Maria, 2011. http://repositorio.ufsm.br/handle/1/4058.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorThe purinergic system is known to be an important signaling pathway in different tissues. Among the components of this system have adenosine, a modulator of central nervous, circulatory and immune systems. The concentration of adenosine in the host is controlled by the enzyme adenosine deaminase (ADA), present in tissues, cells and fluids. As a result, the objectives of this study were (1) to determine the ADA activity in Trypanosoma evansi, (2) evaluate the activity of ADA in serum, erythrocytes, lymphocytes and brain of infected rats, and (3) determine the concentration of nucleotides and nucleosides in serum and cerebral cortex of rats infected with T. evansi. In the first study two mice were infected with T. evansi. When these animals showed high parasitemia (±108 parasites/uL) was performed with blood collection and separation of trypomastigotes by DEAE-cellulose column for performing the assays. Spectrometry was performed by the biochemical detection of ADA in the form trypomastigotes of T. evansi. In a second study, we used 39 rats divided into three groups: group A and B (infected) and group C (C1 and C2 control group) Samples of blood and brain samples were collected on day 4 PI (A and C1) and 20 PI (B and C2). From the blood (with anticoagulant) were separated lymphocytes and erythrocytes for measurement of ADA activity, since the serum was obtained from blood samples stored in tubes without anticoagulant. The brain was separated into cerebellum, cerebral cortex, hippocampus and striatum to evaluate the ADA activity in each structure. Decrease of ADA activity in serum and erythrocytes in rats infected with T. evansi when compared not-infected (P<0.05). ADA activity in lymphocytes was decreased at day 4 PI and increased in day 20 PI. There was no difference in ADA activity in the cerebellum. In the cerebral cortex caused a reduction of ADA activity on days 4 and 20 PI. Decrease of ADA activity in hippocampus and striatum in the day 4 and day 20 PI, respectively. In a third study, 24 rats were used, 12 used as a negative control and 12 infected with T. evansi. On day 4 (n = 6 per group) and 20 PI (n = 6 per group) were performed to obtain blood samples of serum and cerebral cortex for analysis. The samples were prepared for quantification of ATP, ADP, AMP and adenosine. This study found increased concentrations of ATP, AMP and adenosine in the brain and serum of rats infected with T. evansi in both periods, except that the levels of adenosine decreased on day 4 PI. The ADP concentration did not change in this study. Therefore, the infection by T. evansi purinergic system components can be changed, may be involved in immune response, in anemia and neurological signs.
O sistema purinérgico é conhecido por ser uma via de sinalização importante em diversos tecidos. Entre os componentes desse sistema destacamos a adenosina, um modulador do sistema nervoso central, circulatório e imunológico. A concentração de adenosina no hospedeiro é controlada pela enzima adenosina deaminase (ADA), presentes em tecidos, células e fluidos. Em virtude disso, os objetivos deste estudo foram (1) determinar a atividade da ADA no Trypanosoma evansi; (2) avaliar a atividade da ADA no soro, eritrócitos, linfócitos e encéfalo e (3) determinar a concentração de nucleotídeos e nucleosideos no soro e córtex cerebral de ratos infectados com T. evansi. Para um primeiro estudo foram infectados dois camundongos com T. evansi. Quando estes animais apresentavam elevada parasitemia (±108 parasito/μL) foi realizada a coleta de sangue e separação dos flagelados por coluna de DEAE-celulose, a fim realização dos ensaios enzimáticos no parasito. Atividade da ADA nas formas trypomastigotas de T. evansi foi determinada por espectofotometria. Em um segundo estudo foi utilizado 39 ratos, divididos em três grupos: grupo A e B (infectado) e grupo C (C1 e C2/controle). Amostras de sangue e encéfalo foram colhidas nos dias 4 pós-infecção (PI) (grupos A e C1) e 20 PI (grupos B e C2). A partir do sangue total colhido com anticoagulante foram separados os linfócitos e eritrócitos para mensuração da atividade da ADA, já o soro foi obtido de amostras de sangue armazenadas em tubos sem anticoagulante. O encéfalo foi separado em cerebelo, córtex cerebral, hipocampo e estriado para avaliar a atividade da ADA em cada estrutura. Então, observou-se redução da atividade de ADA no soro e eritrócitos em ratos infectados com T. evansi em comparação com não-infectados (P <0,05). A atividade de ADA em linfócitos estava diminuída no dia 4 PI e aumentou no dia 20 PI. Não houve diferença da ADA no cerebelo. No córtex cerebral, no hipocampo e estriado ocorreu redução da atividade da ADA nos dia 4 e 20 PI, respectivamente. Em todas as estruturas do encéfalo foi detectada a presença do parasito por PCR. Em um terceiro estudo foram utilizados 24 ratos, sendo 12 controles negativos e outros 12 infectados com T. evansi. Nos dias 4 (n=6 por grupo) e 20 (n=6 por grupo) foram realizadas as coletas de sangue para obtenção do soro e amostras do córtex cerebral para mensuração dos níveis de ATP, ADP, AMP e adenosina. Neste estudo, foi constatado aumento das concentrações de ATP, AMP e adenosina no encéfalo e soro de ratos infectados com T. evansi nos dois períodos avaliados, com exceção dos níveis de adenosina que reduziram no dia 4 PI. Não houve alteração na concentração de ADP. Portanto, na infecção por T. evansi os componentes do sistema purinérgico pode ser alterados, podendo estar envolvido na resposta imunológica, na anemia e nos sinais neurológicos.
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Chevallier, Olivier Paul. "Adenosine diphosphoribose synthetic analogues." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501244.
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Wang, Jianjie. "Modulation of coronary and skeletal muscle exchange by adenosine : role of adenosine receptors /." Free to MU Campus, others may purchase, 2005. http://wwwlib.umi.com/cr/mo/fullcit?p3204635.
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Carlos, Carolina Dias. "Polimorfismos nos Receptores de Adenosina, suas Associações com Características Fisiopatológicas e Avaliação de Componentes na Biossíntese da Adenosina em Pacientes com Doença Falciforme." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-12062013-074600/.
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Na Anemia Falciforme em situações de baixa tensão de oxigênio, a hemoglobina mutante S (HbS) sofre polimerização promovendo a falcização das hemácias, que podem aderir ao endotélio vascular, causando a oclusão de vasos (VO) e isquemia tecidual (crises dolorosas) que caracterizam o quadro clínico da doença. Além disso, os pacientes falciformes apresentam outras manifestações clínicas como o priapismo, alterações ósseas, certas complicações pulmonares entre outros. Além das células eritróides, células endoteliais, leucócitos e plaquetas também desempenham um papel fundamental na fisiopatologia da anemia falciforme. A hidroxiuréia (HU), na anemia falciforme, aumenta a produção de hemoglobina fetal (HbF) em células eritróides, reduzindo a polimerização da HbS, diminuindo os sintomas clínicos dos pacientes. O aumento da HbF, no entanto, não implica necessariamente na melhora clínica, indicando desta forma a potencial ação da HU sobre outros processos. Estudos recentes vêm relacionando priapismo e asma com elevados níveis de adenosina. Devido a esta importância da adenosina relacionada a patologias comuns a AF, tivemos como objetivo identificar polimorfismos em genes de receptores de adenosina e na adenosina deaminase e verificar a possível associação entre as manifestações clínicas, além de investigar o papel da HU na modulação de marcadores envolvido na síntese e degradação da adenosina. Foram analisados diversos sítios polimórficos nos genes que codificam ADORA1, ADORA 2b, ADORA 3 e ADA, seguindo com a genotipagem em pacientes com AF, comparando afetados e não afetados. Em adição foi avaliada a expressão diferencial de mRNA de ADA pela HU em monócitos destes pacientes, comparando tratados e não tratados e também avaliamos por citometria de fluxo a modulação de marcadores de superfície CD39, CD73 e CD26, pela HU. As análises estatísticas foram realizadas utilizando os softwares GenePop 3.4 para análises de associação, cálculo do HWE, GraphPad Prism 5, Arlequin para identificação de desequilíbrio de ligação, haplótipos, heterozigozidade e SAS 9.13 para associação dos haplótipos as características. Os resultados mostraram que os pacientes sob tratamento com HU apresentaram um aumento da expressão de mRNA de ADA, aumento da expressão de CD26 em monócitos e diminuição de CD39 em linfócitos. Sem alterações significativas em relação a CD73. Encontramos também um aumento da freqüência do alelo T do SNP (rs1685103) presente no gene de ADORA 1 associado com pacientes afetados com síndrome torácica aguda. Apesar de não ter sido estatisticamente significante, concorda com dados da literatura. No gene ADORA 2B, verificamos associação do SNP 1007 C>T no desenvolvimento de STA indicando o alelo T como fator de risco e o alelo C para alterações ósseas. Para o SNP 968 G>T houve associação com alterações ósseas. Na análise haplotípica entre os SNPs 968 G>T e 1007 C>T encontramos associação dos haplótipos ht2 e ht3 com STA, como fator de risco, ht2 para hipertensão pulmonar. ht1 para priapismo, alterações ósseas e estenose/AVC. Os haplótipos formados pelos três SNPs 968 G>T, 1007 C>T e rs16851030, encontramos associação entre ht1, ht3 e ht4 entre os afetados com priapismo, caracterizando-o como haplótipo de risco e também ht1 e ht6 associados à estenose/AVC. Concluímos, que a hidroxiuréia participa na modulação da expressão da adenosina deaminase, de CD26 em monócitos e CD39 em linfócitos. Além disso, mostrou-se a importância de sítios polimórfico presente no gene ADORA 2B e ADORA1 envolvido na fisiopatologia das manifestações clínicas da doença falciforme. Associações dos SNPs em ADORA 1 e ADA, devem ser melhor estudados em um número maior de pacientes. A determinação destes polimorfismos associados com diferentes características clínicas pode levar a um melhor entendimento dos processos fisiopatológicos da anemia falciforme, levando à identificação de pacientes de risco, possibilitando um manejamento racional dos mesmos, em termos de cuidados específicos, ou mesmo à determinação de alvos para o desenvolvimento de terapias alternativas.In sickle cell disease in low oxygen tension, mutant hemoglobin S (HbS) undergoes polymerization promoting sickling of red blood cells that can adhere to vascular endothelium, causing vessel occlusion (VO) and tissue ischemia (painful crises) that characterize the clinical disease. In addition, sickle cell patients have other clinical manifestations such as priapism, bone disorders, certain pulmonary complications among others. In addition to the erythroid cells, endothelial cells, white cells and platelets also play a key role in the pathophysiology of sickle cell anemia. Hydroxyurea (HU) in sickle cell anemia, increases the production of fetal hemoglobin (HbF) in erythroid cells, reducing the HbS polymerization, reducing the clinical symptoms of patients. The increase in HbF, however, does not necessarily imply clinical improvement, thus indicating the potential effects of HU on other processes. Recent studies relating asthma and priapism with high levels of adenosine. Due to this importance of adenosine-related pathologies common to AF, we aimed to identify gene polymorphisms in adenosine receptors and adenosine deaminase and verify the possible association between clinical manifestations, and to investigate the role of HU in the modulation of markers involved synthesis and degradation of adenosine. We analyzed several polymorphic sites in genes that encode ADORA1, ADORA 2b, 3 and ADORA ADA, according to the genotype in patients with AF, comparing affected and unaffected. In addition we assessed the differential expression of ADA mRNA by HU in monocytes of these patients, comparing treated and untreated, and also evaluated by flow cytometry modulation of surface markers CD39, CD73 and CD26 by HU. Statistical analysis was performed using the software GenePop 3.4 for association analysis, calculation of HWE, GraphPad Prism 5, Arlequin for identification of linkage disequilibrium, haplotypes, heterozygosity and SAS 9.13 for association of haplotypes features. The results showed that patients treated with HU showed an increase in mRNA expression of ADA, increased expression of CD26 on monocytes and decreased CD39 on lymphocytes. No significant changes in relation to CD73. We also found an increased frequency of allele T (SNP rs1685103) present in a gene associated with ADORA affected patients with acute chest syndrome. Although not statistically significant, agrees with literature data. ADORA 2B gene, we found association of the SNP 1007 C> T in the development of STA indicating the T allele as a risk factor for the C allele and bone changes. For the SNP 968 G> T was associated with bone disorders. In haplotype analysis between SNPs 968 G> T and 1007 C> T found association of haplotypes ht2 and HT3 with STA as a risk factor for pulmonary hypertension ht2. ht1 for priapism, stenosis and bone disorders / stroke. The three haplotypes formed by SNPs 968 G> T, 1007 C> T and rs16851030, we found association between ht1, HT3 and HT4 among those affected with priapism, characterizing it as a risk haplotype and also ht1 ht6 associated with renal and / AVC. We conclude that hydroxyurea participates in modulating the expression of adenosine deaminase of CD26 on monocytes and CD39 on lymphocytes. Moreover, he showed the importance of polymorphic sites in this gene and ADORA 2B ADORA1 involved in the pathophysiology of clinical manifestations of sickle cell disease. Associations of SNPs in ADORA 1 and ADA should be better studied in a larger number of patients. The determination of these polymorphisms associated with different clinical characteristics can lead to a better understanding of the pathophysiological processes of sickle cell anemia, leading to the identification of patients at risk, enabling a rational handling of the same in terms of specific care, or even the determination of targets for the development of alternative therapies.
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STEFANELLI, Angela. "Adenosine receptors in health and disease." Doctoral thesis, Università degli studi di Ferrara, 2014. http://hdl.handle.net/11392/2388942.
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Adenosine (Ado) is an endogenous nucleoside released from almost all cell types. It exerts neuroprotective and anti-inflammatory functions by acting through four receptor subtypes A1, A2A, A2B and A3 (ARs). These receptors differ in their affinity for Ado, in the type of G protein that they recruit and finally in the downstream signalling that are activated in target cells. The levels of Ado in the interstitial fluid are in the range of 20-200 nM, but many pathophysiological conditions such as asthma, neurodegenerative disorders, chronic inflammatory diseases and cancer are associated with changes in Ado levels. The primary aim of Ado is to reduce tissue injury and promote repair by different receptor-mediated mechanisms, including the increase of oxygen supply/demand ratio, anti-inflammatory effects and stimulation of angiogenesis. The investigation of ARs and their ligands is a rapidly growing field; there is extensive evidence for the involvement of ARs in the physiological regulation of several homeostatic processes and their implication in the ethiology of many diseases. The aim of this work was to analyse the expression of ARs and the signalling pathway, transcription factors and cytochines activated by them in different pathophysiological conditions linked to hypoxic and inflammatory conditions.
At first, the role of ARs was studied in healthy and aneuploid pregnancies to understand reasons of spontaneous abortion (SA). It has been suggested that the causes of SA in aneuploidy are no different to those in euploidy, with the increased frequency in the former perhaps being ascribable to a genetically-determined imbalance in the mediators of placental perfusion and uterine contraction. So aneuploidy can be used as a model of this event. The ado transduction cascade appears to be disturbed in Trisomy 21 (TR21) through reduced expression of A2BAR and A1AR. These anomalies may be implicated in complications such as fetal growth restriction, malformation and/or SA, well known features of aneuploid pregnancies. Therefore A1AR and A2BAR could be potential biomarkers able to provide an early indication of SA risk and their stimulation may turn out to improve fetoplacental perfusion by increasing nitric oxide (NO) and vascular endothelial growth factor (VEGF). Next, the effects of ARs in glial cells under inflammatory conditions have been investigated. Glial cells, astrocytes and microglia, are important contributors to inflammatory immune responses and hypoxia-inducible factor 1 (HIF-1α) is the key transcription factor that is upregulated in response to hypoxia and inflammatory stimuli. Ado, through A1AR and A3AR activation, reduces lipopolysaccharide (LPS)-stimulated HIF-1α mRNA expression and protein accumulation by inhibiting LPS-triggered p42/p44 mitogen-activated protein kinase (p44/42 MAPK) and
serine/threonine protein kinase (Akt) phosphorylation in normoxic and hypoxic conditions. This leads to an inhibition of genes involved in inflammation like Inducible Nitric Oxide Synthase (iNOS) and A2BARs, that are stimulated by LPS and further increased by LPS in concert with hypoxia, whilst does not affect angiogenesis and metabolic related genes, with the exception of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) that are stimulated by LPS in normoxia and reduced by A1AR and A3AR activation. These findings add a new molecular pathway activated by Ado in astrocytes to give a reduction of genes involved in inflammation and hypoxic injury that may cohexist in stroke, ischemia and other central nervous system (CNS) disorders.
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Molaudzi, Mulalo. "The usefulness of the adenosine deaminase assay for diagnosing tuberculosis pleuritis in immunocompromised patients at Dr George Mukhari tertiary laboratory, Pretoria." Thesis, University of Limpopo (Medunsa Campus), 2012. http://hdl.handle.net/10386/671.
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Thesis (MSc (Med)(Microbiology)) -- University of Limpopo, 2012.Mycobacterium tuberculosis is the most common cause of death world-wide and its incidence has been steadily increasing, which is more evident when comparing the global tuberculosis (T8) incidence of 9.24 million in 2006 to 9.27 million cases in 2007. African countries are the second most affected by the epidemic and South Africa is among the 22 highest burden countries most affected by T8 with a very high number of cases relative to the total population. The early diagnosis of tuberculosis and screening of contacts is the cornerstone for controlling spread of active T8 infection. T8 diagnosis becomes even more challenging in patients with immunosuppression (for example in human immunodeficiency virus (HIV) infected), in the case of latent infection and extra pulmonary T8 such as pleural T8. The definitive diagnosis of pleural T8 depends on the demonstration of M. tuberculosis in sputum, pleural fluid and pleural biopsy. Although acid fast bacilli (AF8) microscopy is a rapid, inexpensive and relatively simple method, it has low sensitivity. The culture method is more sensitive than AF8 microscopy, detecting 25-37% of all pleural tuberculosis cases however it takes 4 to 8 weeks for a visible growth on a solid medium. Therefore it is important to find a rapid and reliable test for the diagnosis of pleural T8 particularly in developing countries such as South Africa where there is a high T8 incidence and HIV infection rate.
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Crummy, F. "Adenosine, mast cells and asthma." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403238.
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Svenningsson, Per. "Striatal adenosine A₂A receptors /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19981015sven.
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Conn, Michael Morgan. "Molecular recognition of adenosine derivatives." Thesis, Massachusetts Institute of Technology, 1994. http://hdl.handle.net/1721.1/17346.
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Niebauer, Ronald Thomas. "Engineering yeast cells for optimal expression of the human adenosine (A2a) receptor." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file 4.52 Mb., 175 p, 2005. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3181857.
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Newton, Adam J. H. "Modelling adenosine dynamics in neural tissues." Thesis, University of Warwick, 2015. http://wrap.warwick.ac.uk/81484/.
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The neuromodulator adenosine is involved in both physiological and pathological activity, such as sleep, epilepsy and stroke. However, the complex processes underlying the release, transport and clearance of adenosine from the extracellular space and their interactions are still poorly quantified. In this thesis I develop the �rst detailed model of the dynamics of adenosine in neural tissue, including intracellular and extracellular metabolism, using parameters taken from an extensive search of the literature. This approach also identifies physiological and metabolic parameters that have yet to be experimentally measured. The model provides estimates of the range of influence of adenosine, the distance where the extracellular concentration is greater than that required for half of the maximum inhibition by the dominant type of adenosine receptors in the cortex, and suggests that under physiological conditions the adenosine signal will be highly localised. The model predicts that adenosine concentration profiles are primarily determined by diffusion and that neuronal transport and metabolism are the dominant clearance mechanisms. The model can be used with either experimental or endogenous sources of adenosine, and I apply it to the bath application of adenosine to a tissue slice, (a method used extensively to study the e�ect of adenosine on synaptic transmission). The model is used to predict the effective dose response curve of bath applied adenosine and to compare the effects of transporter blockers. I then turn to the modelling of biosensors, which are used extensively to measure the concentration of various analytes in tissue, including adenosine. Biosensors are often calibrated in a flow injection system with a known concentration of the analyte. Mathematical and computational models are used to compare the response characteristics of biosensors in this free environment with the tortuous environment in which they are used. An estimated correction factor is obtained together with the sensitivity of this factor to the characteristics of the biosensor. This work provides a framework to move from qualitative studies of changes of adenosine in the brain to quantitative analysis of the spatio-temporal dynamics of adenosine signalling and its in uence on networks of neurons.
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Jackson, Andrew M. "Aâ†2â†B adenosine receptor signalling." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251985.
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Abbott, C. M. "Adenosine deaminase in the wasted mouse." Thesis, University of Reading, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374695.
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Cohen, Fiona Rachel. "The allosteric regulation of adenosine receptors." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309286.
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James, Stephen. "Adenosine at the striatal chlorinergic synapse." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314824.
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Baines, Abigail. "Adenosine receptor trafficking : implications for epilepsy." Thesis, University of Warwick, 2011. http://wrap.warwick.ac.uk/51350/.
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Adenosine receptors (ARs) modulate many cellular and systems-level processes in the mammalian CNS. However, little is known about the trafficking of ARs in neurons, despite their importance in controlling seizure activity and in neuroprotection in cerebral ischemia. To address this I examined the agonist-dependent internalisation of C-terminal GFP-tagged A1R, A2AR and A3R in primary hippocampal neurons and compared findings to CHO cells. Furthermore, I developed a novel super-ecliptic pHluorin (SEP)-tagged A1R which, via the N-terminal SEP tag, reports the cell-surface expression and trafficking of A1R in real-time. I demonstrate the differential trafficking of ARs in neurons: the A3R internalised rapidly, with the A1R internalising more slowly, and with little evidence of appreciable A2AR trafficking over the time-course of the experiments. These findings were consistent with trafficking data in CHO cells and previous literature. Futhermore, the novel SEP-A1R construct revealed the time-course of internalisation and recovery of cell surface expression to occur within minutes of agonist exposure and removal, respectively. These observations reveal the labile nature of cell surface expression of neuronal adenosine A1R and A3Rs. Given the high levels of adenosine in the brain during seizures, internalisation of the inhibitory A1R may result in hyperexcitability, increased brain damage and the development of chronic epileptic states. To test this I monitored trafficking of A1R in response to two seizure conditions, kainic acid and Mg2+free-/high K+. I observed following acute Mg2+free-/high K+ treatment an increase in dendritic puncta consistent with A1R internalisation. In addition to monitoring changes to GFP-tagged AR constructs I attempted to elucidate the effect of agonist exposure on native A1R. Electrophysical recordings revealed that localisation of ARs may impact on receptor regulation, since no evidence of internalisation was observed. This suggested that post-synaptic A1R may be more resistant to internalisation as previously noted in the literature. This study provides an initial study into the regulation of adenosine receptors in hippocampal neurons and has developed tools that will provide useful in further studies to elucidate the regulation of ARs during pathological conditions.
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Livingston, Mark. "The role of adenosine in asthma." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649365.
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Willems, Laura E., and n/a. "Adenosine and Ischaemia in Young To Aged Hearts." Griffith University. School of Medical Science, 2006. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20061011.163451.
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Ischaemic heart disease is a major contributor to premature death and heart failure in the Westernised world. Ischaemic injury within the heart may be beneficially modulated by the nucleoside adenosine. Derived from catabolism of ATP, adenosine was initially known as a potent bradycardic and hypotensive agent. However, more recently the protective function of adenosine has been investigated. The protective effects of adenosine are mediated via activation of adenosine receptors: A1, A2A, A2B, and A3 receptors. Activation of these potentially protective (or retaliatory) adenosine receptors hinges upon accumulation of adenosine during ischaemia-reperfusion. This Thesis examines the role and mechanisms of adenosine mediated cardioprotection in young and aged hearts, exploring endogenous and exogenous adenosine receptor activation, genetic manipulation of A1 receptors and adenosine deaminase and pharmacological manipulation of adenosine metabolism. The effects of age on ischaemic responses and adenosine handling and protection are also assessed. The core approach to assess each of the above issues involved the Langendorff isolated mouse heart preparation. Experiments within Chapter 3 focuses on the contractile effects of adenosine receptors in normoxic hearts. This study indicates A2A receptors have no direct effect on contractility, while adenosine exerts positive inotropy independently of coronary flow and perfusion pressure (i.e. Independent of the Gregg phenomenon). In addition, investigations in genetically modified hearts hint at positive inotropy in response to A1 receptors. Since the latter is only evidenced in modified lines, it is possible A1-mediated inotropy may be abnormal or supraphysiological. In Chapter 4 the impact of genetic 'deletion' of A1ARs and/or adenosine deaminase (ADA) on intrinsic tolerance to ischaemia were studied. Data demonstrate that genetic deletion of A1 receptors significantly limits the ability of the mouse myocardium to withstand injury during ischaemic insult. Thus, providing strong support for a role of A1ARs in determining intrinsic tolerance to ischaemia-reperfusion. ADA KO mice confirm protection afforded by endogenous adenosine and the notion of adenosine metabolism modification as a protective strategy. Interestingly, effects of A1AR KO differ from A1AR overexpression or A1AR agonism in that the latter decrease contractile diastolic dysfunction while A1AR KO selectively increase systolic dysfunction and increase oncosis without altering diastolic injury. This challenges current dogma regarding the action of A1 adenosine receptors on ischaemic injury. In Chapter 5 the effects of adenosine metabolism inhibition (via adenosine deaminase (ADA) and adenosine kinase (AK) inhibitors) were studied. Inhibition of adenosine deaminase with the drug EHNA, and adenosine phosphorylation with iodotubercidin significantly protected mouse hearts from ischaemia-reperfusion, reducing contractile dysfunction and cardiac enzyme efflux. However, inhibitors failed to improve the outcome of the aged myocardium. 8-SPT and 5-HD reduced the protective effects of EHNA and iodotubercidin demonstrating thus; cardioprotection via ADA and AK appears to rely on adenosine receptor activation and involves a mitoK ATP dependent mechanism. Since aging is of considerable importance with regard to outcomes of ischaemic heart disease, experiments in Chapter 6 focused on effects of aging (and gender) on cardiovascular function and injury during ischaemia-reperfusion. In assessing post ischaemic outcomes in hearts from young adult (2-4 months), mature adult (8 months), middle aged (12 months), aged (18 months) and senescent (24-28 months) C57/BL/6J mice, data reveal a substantial age-related decline in ischaemic tolerance (which appears selective for myocardial vs. vascular injury). The decline in ischaemic tolerance is expressed primarily within the initial 12 months in both males and females with relatively little further decline with continued aging. There is evidence of a modest improvement in tolerance in senescence vs. aged hearts possibly reflecting selection of a protected phenotype in senescent populations. In addition, mature and middle-aged female hearts showed improved tolerance to ischaemia-reperfusion compared to males, supporting a role for hormonal changes. Effects of aging and purine metabolism were studied in Chapter 7. Data suggest impaired tolerance to ischaemia-reperfusion in older hearts may stem in part from shifts in myocardial purine catabolism. Data reveal reduced accumulation of salvageable and cardioprotective adenosine and enhanced accumulation of poorly salvaged (and potentially injurious) hypoxanthine and xanthine. These changes may potentially predispose the aged myocardium to ischaemic injury and radical generation via the xanthine oxidase reaction. The final data Chapter of this Thesis describes preliminary data regarding aging, signalling and adenosine mediated protection. It was found that protein kinase C (PKC) and A1 receptors mediate protection in young hearts and also that A1 receptors appear to mediate protection via a PKC LindependentLi signalling cascade. In addition, experiments in aged hearts (attempting to elucidate mechanisms behind impaired adenosinergic protection with age) suggest a PKC-independent A1-mediated protection path may be preserved with aging, since A1 receptors continue to offer some protection while PKC activation does not. It is possible the failure of exogenous adenosine to offer protection in aged hearts may result from a lesion at or downstream of PKC.
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Willems, Laura E. "Adenosine and Ischaemia in Young To Aged Hearts." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/365196.
Full textAbstract:
Ischaemic heart disease is a major contributor to premature death and heart failure in the Westernised world. Ischaemic injury within the heart may be beneficially modulated by the nucleoside adenosine. Derived from catabolism of ATP, adenosine was initially known as a potent bradycardic and hypotensive agent. However, more recently the protective function of adenosine has been investigated. The protective effects of adenosine are mediated via activation of adenosine receptors: A1, A2A, A2B, and A3 receptors. Activation of these potentially protective (or retaliatory) adenosine receptors hinges upon accumulation of adenosine during ischaemia-reperfusion. This Thesis examines the role and mechanisms of adenosine mediated cardioprotection in young and aged hearts, exploring endogenous and exogenous adenosine receptor activation, genetic manipulation of A1 receptors and adenosine deaminase and pharmacological manipulation of adenosine metabolism. The effects of age on ischaemic responses and adenosine handling and protection are also assessed. The core approach to assess each of the above issues involved the Langendorff isolated mouse heart preparation. Experiments within Chapter 3 focuses on the contractile effects of adenosine receptors in normoxic hearts. This study indicates A2A receptors have no direct effect on contractility, while adenosine exerts positive inotropy independently of coronary flow and perfusion pressure (i.e. Independent of the Gregg phenomenon). In addition, investigations in genetically modified hearts hint at positive inotropy in response to A1 receptors. Since the latter is only evidenced in modified lines, it is possible A1-mediated inotropy may be abnormal or supraphysiological. In Chapter 4 the impact of genetic 'deletion' of A1ARs and/or adenosine deaminase (ADA) on intrinsic tolerance to ischaemia were studied. Data demonstrate that genetic deletion of A1 receptors significantly limits the ability of the mouse myocardium to withstand injury during ischaemic insult. Thus, providing strong support for a role of A1ARs in determining intrinsic tolerance to ischaemia-reperfusion. ADA KO mice confirm protection afforded by endogenous adenosine and the notion of adenosine metabolism modification as a protective strategy. Interestingly, effects of A1AR KO differ from A1AR overexpression or A1AR agonism in that the latter decrease contractile diastolic dysfunction while A1AR KO selectively increase systolic dysfunction and increase oncosis without altering diastolic injury. This challenges current dogma regarding the action of A1 adenosine receptors on ischaemic injury. In Chapter 5 the effects of adenosine metabolism inhibition (via adenosine deaminase (ADA) and adenosine kinase (AK) inhibitors) were studied. Inhibition of adenosine deaminase with the drug EHNA, and adenosine phosphorylation with iodotubercidin significantly protected mouse hearts from ischaemia-reperfusion, reducing contractile dysfunction and cardiac enzyme efflux. However, inhibitors failed to improve the outcome of the aged myocardium. 8-SPT and 5-HD reduced the protective effects of EHNA and iodotubercidin demonstrating thus; cardioprotection via ADA and AK appears to rely on adenosine receptor activation and involves a mitoK ATP dependent mechanism. Since aging is of considerable importance with regard to outcomes of ischaemic heart disease, experiments in Chapter 6 focused on effects of aging (and gender) on cardiovascular function and injury during ischaemia-reperfusion. In assessing post ischaemic outcomes in hearts from young adult (2-4 months), mature adult (8 months), middle aged (12 months), aged (18 months) and senescent (24-28 months) C57/BL/6J mice, data reveal a substantial age-related decline in ischaemic tolerance (which appears selective for myocardial vs. vascular injury). The decline in ischaemic tolerance is expressed primarily within the initial 12 months in both males and females with relatively little further decline with continued aging. There is evidence of a modest improvement in tolerance in senescence vs. aged hearts possibly reflecting selection of a protected phenotype in senescent populations. In addition, mature and middle-aged female hearts showed improved tolerance to ischaemia-reperfusion compared to males, supporting a role for hormonal changes. Effects of aging and purine metabolism were studied in Chapter 7. Data suggest impaired tolerance to ischaemia-reperfusion in older hearts may stem in part from shifts in myocardial purine catabolism. Data reveal reduced accumulation of salvageable and cardioprotective adenosine and enhanced accumulation of poorly salvaged (and potentially injurious) hypoxanthine and xanthine. These changes may potentially predispose the aged myocardium to ischaemic injury and radical generation via the xanthine oxidase reaction. The final data Chapter of this Thesis describes preliminary data regarding aging, signalling and adenosine mediated protection. It was found that protein kinase C (PKC) and A1 receptors mediate protection in young hearts and also that A1 receptors appear to mediate protection via a PKC LindependentLi signalling cascade. In addition, experiments in aged hearts (attempting to elucidate mechanisms behind impaired adenosinergic protection with age) suggest a PKC-independent A1-mediated protection path may be preserved with aging, since A1 receptors continue to offer some protection while PKC activation does not. It is possible the failure of exogenous adenosine to offer protection in aged hearts may result from a lesion at or downstream of PKC.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
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Freitas, Helder Teixeira de. "Papel da sinalização da adenosina na geração de células T regulatórias a partir de células T naive de cordão umbilical e na imunomodulação por células-tronco estromais mesenquimais de medula óssea." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17153/tde-19072018-135504/.
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As células T regulatórias (Tregs) são essenciais para a manutenção da tolerância periférica, prevenção de doenças autoimunes e limitantes nas doenças inflamatórias crônicas. Além disso, essas células exercem um papel fundamental no controle da rejeição de transplantes. Diferentes protocolos mostraram que é possível obter Tregs a partir de células T naive CD4+ in vitro. Para tal, é consenso que o TGF-? e a interleucina-2 (IL-2) são capazes de direcionar as células T naive CD4+ a se tornarem regulatórias após um estímulo antigênico (anti-CD3/CD28). Nosso grupo recentemente notou que, durante a imunomodulação de linfócitos T pelas células estromais mesenquimais (CTMs), estas eram capazes de produzir adenosina que, por sua vez, participa do processo de imunorregulação. Outros trabalhos indicam que as CTMs suprimem a proliferação dos linfócitos T pela geração de Tregs e que as CTMs induzem a geração de Tregs através da regulação negativa da via TCR e da via AKTmTOR. Evidências apontam que a adenosina pode atuar regulando negativamente a via mTOR. Portanto, acredita-se que a adenosina possa participar do processo de geração de Tregs através da modulação da via mTOR. Além disso, estudos recentes indicam que a ativação de receptores de adenosina, mais especificamente A2a, com agentes agonistas, leva ao aumento da produção de células Tregs, enquanto que a utilização de agentes antagonistas destes receptores leva à diminuição da diferenciação de Tregs. Porém, estes estudos mostram a geração de Tregs a partir de células T naive de camundongos. Visto a grande importância das Tregs no contexto imunológico, a produção eficiente de Tregs in vitro tem importância fundamental para o desenvolvimento de novos protocolos terapêuticos para o tratamento de doenças autoimunes e no combate à rejeição de transplantes. Assim, o objetivo central deste trabalho foi avaliar a participação de agonistas e antagonistas de receptores de adenosina na indução de células T regulatórias geradas in vitro (iTreg) pela ativação de células T CD4+ naive isoladas de sangue de cordão umbilical (SCU) humano. Para isso, células mononucleares foram isoladas de bolsas de SCU e as células T naive foram isoladas imunomagnéticamente. Essas células foram ativadas com beads ligadas a anticorpos anti-CD2/CD3/CD28 e cultivadas por cinco dias na presença de IL-2 e diferentes concentrações de drogas agonistas e antagonistas de receptores de adenosina. Em seguida, foram avaliados os principais marcadores de células T regulatorias por meio de citometria de fluxo e o meio de cultura foi coletado ao final da geração para quantificação de citocinas. Além disso, o RNA total foi extraído de todas as condições de cultivo para a análise da expressão de genes envolvidos na geração e desenvolvimento das Tregs, por PCR quantitativo. O potencial de supressão de células T efetoras também foi avaliado.Regulatory T cells (Tregs) are essential for the maintenance of peripheral tolerance, prevention of autoimmune and limiting diseases in chronic inflammatory diseases. In addition, these cells play a key role in the control of transplant rejection. Different protocols have shown that it is possible to obtain Tregs from naive CD4+ T cells in vitro. To this end, there is consensus that TGF-? and interleukin-2 (IL-2) are capable of directing the naive CD4 + T cells to become regulatory following an antigenic stimulus (anti-CD3/CD28).. Our group recently noted that during the immunomodulation of T lymphocytes by mesenchymal stromal cells (MSCs), they were able to produce adenosine which in turn participates in the immunoregulation process. Other studies indicate that MSCs suppress the proliferation of T lymphocytes by generation of Tregs and that MSCs induce generation of Tregs by downregulation of the TCR pathway and the AKT-mTOR pathway. Evidence indicates that adenosine may act by downregulating the mTOR pathway. Therefore, it is believed that adenosine may participate in the generation of Tregs by modulating the mTOR pathway. In addition, recent studies indicate that activation of adenosine receptors, more specifically A2a, with agonist agents, leads to increased production of Treg cells, whereas the use of antagonistic agents of these receptors leads to a decrease in Treg differentiation.. However, these studies show the generation of Tregs from naive T cells of mice. In view of the great importance of Tregs in the immunological context, the efficient production of Tregs in vitro is of fundamental importance for the development of new therapeutic protocols for the treatment of autoimmune diseases and in the fight against transplant rejection. Thus, the central objective of this study was to evaluate the participation of adenosine receptor agonists and antagonists in induction of regulatory T cells generated in vitro (iTreg) by the activation of naive CD4+ T cells isolated from human umbilical cord blood (SCU). For this, mononuclear cells were isolated from SCU and naive T cells were immunomagnetic isolated. These cells were activated with beads bound to anti-CD2/CD3/CD28 antibodies and cultured for five days in the presence of IL-2 and different concentrations of agonist drugs and antagonists of adenosine receptors. Next, the major regulatory T-cell markers were assessed by flow cytometry and the culture medium was collected at the end of the generation for quantification of cytokines. In addition, total RNA was extracted from all culture conditions for the analysis of the expression of genes involved in the generation and development of Tregs by quantitative PCR. The potential for suppression of effector T cells was also evaluated.
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Rodenko, Boris. "A new entry to adenosine analogues via purine nitration combinatorial synthesis of antiprotozoal agents and adenosine receptor ligands /." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/71739.
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Yonally, Sarah K. "The mitochondrial F{207}F{206} ATP synthase : multienzyme associations and membrane locations /." view abstract or download file of text, 2006. http://proquest.umi.com/pqdweb?did=1188872031&sid=1&Fmt=2&clientId=11238&RQT=309&VName=PQD.
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Thesis (Ph. D.)--University of Oregon, 2006.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 63-68). Also available for download via the World Wide Web; free to University of Oregon users.
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Brown, Ruth Elizabeth. "Investigations of adenosine as a vascular modulator." Thesis, Queen Mary, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397335.
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Khan, Zeenatul. "Adenosine diphosphoribosyl transferase in granulocyte-monocyte differentiation." Thesis, Brunel University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.255772.
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Atterbury, Alison. "Development of adenosine signalling in the cerebellum." Thesis, University of Warwick, 2010. http://wrap.warwick.ac.uk/35147/.
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The release and clearance of adenosine are reasonably well-documented in the mature CNS but relatively little is known about how adenosine signalling changes during postnatal development. The activation of presynaptic A1 receptors (A1R) at cerebellar parallel fibre terminals is known to inhibit synaptic transmission and the expression of A1R has been observed in mature rat cerebellar slices. However its distribution during development or in relation to parallel fibre–Purkinje cell (PF-PC) synapses has not previously been described. In the mature cerebellum blockade of presynaptic A1R at PF-PC synapses enhances synaptic transmission suggesting an inhibitory adenosine tone and an extracellular purine tone is detectable with microelectrode biosensors under basal conditions. The active release of adenosine can be stimulated with trains of activity in the molecular layer of mature slices although this does not appear to be a source of the basal extracellular adenosine tone. This study used immunohistochemistry to determine the distribution of A1R at PFPC synapses in cerebellar slices at postnatal day 3 prior to PF-PC synapse formation, postnatal days 8-14 and postnatal days 21-28. This study also used cerebellar slices from rats at postnatal days 9-14 to investigate the pharmacological profile of the immature rat PF-PC synapse with electrophysiology and microelectrode biosensors. The immunohistochemistry suggests that A1R are widely distributed across Purkinje cell bodies and their dendrites and within the granule layer of the cerebellum and that its expression does not change during development. The same staining patterns were also observed prior to PF-PC synapse formation. Application of adenosine resulted in a variable A1R-mediated inhibition at immature PF-PC synapses. This did not appear to be gender-specific or correlated with age of rat and the synapses otherwise appeared identical in their properties. The comparison of log concentration-response curves generated for an A1R agonist suggested that some A1R may have a lower efficacy at this stage of development. Blockade of presynaptic A1R at immature PF-PC synapses suggested that an inhibitory adenosine tone is low or absent at this stage of development and is not the result of a low A1R expression or developmental differences in A1R efficacy. Inhibition of adenosine clearance via adenosine deaminase, adenosine kinase and equilibrative transporters had little effect on synaptic transmission suggesting that little adenosine is moving between the intracellular and extracellular spaces under basal conditions in immature slices. Active adenosine release measured by electrophysiology and microelectrode biosensors could be stimulated with hypoxia in immature slices but this was delayed and slower in comparison to the release observed in mature slices. Adenosine could not be actively released at immature PFPC synapses in response to electrical stimulation in the molecular layer.
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Larner, Carrie Jayne Byrom. "Selective targeting of the adenosine A2A receptor." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608592.
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Varley, David Robert. "The synthesis of novel analogues of adenosine." Thesis, University of Exeter, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307291.
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Hussey, Martin John. "Adenosine Aâ‚‚A receptors and peripheral nociception." Thesis, University of Surrey, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441903.
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Gurden, Mark Francis. "Studies on the classification of adenosine receptors." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386645.
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Hern, Jonathan A. "Studies on the human adenosine A₁ receptor." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445552/.
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The adenosine A} receptor (AR) is an important G protein-coupled receptor (GPCR) distributed widely throughout the human body and influences many bodily functions. The work presented here investigates in detail the complex heterogeneous nature of agonist binding to the human AR in order to explore receptor-receptor interactions that might be present in oligomeric receptor complexes. The equilibrium and kinetic binding properties of two cell lines expressing the AR at different densities were characterised in detail. This characterisation was compared with that of a series of 47 cell lines expressing different levels of either the AjR-GFP or AR-GFP-Gaj fusion proteins. Equilibrium radioligand saturation and competition experiments provided evidence for a re lationship between the fraction of high affinity agonist binding sites and the level of receptor expression. Cell lines expressing lower levels of the AR showed a greater relative ability to bind agonists with high affinity, and to promote formation of the activated agonist-receptor-G protein ternary complex. The association of Hjagonist to the AjR was biphasic and determined by two different molec ular processes. The association rate constant of the fast component was entirely dependent on the concentration of Hjagonist, whereas dependence of the slow component on concentration was inconclusive. The dissociation of a Hjinverse agonist from the AR was rapid, mono-exponential, complete, and insensitive to GTP. In contrast, the kinetics of H agonist dissociation were complex. Disso ciation of H agonist from the AR-G protein complex was biphasic and dependent on the nature of ligand used to prevent H agonist rebinding. Greater H agonist dissociation was observed in the presence of competing agonist than competing inverse agonist, a novel finding called "agonist- induced agonist dissociation," and was dependent on agonist efficacy. The mechanism behind this is unknown, but appears to involve interactions between high affinity receptor-G protein complexes, possibly in the form of receptor oligomerisation. These interactions are absent at low expression levels and progressively increase with level of expression. Agonist-induced agonist dissociation was observed even in the presence of a high concentration of GTP. Separation of cell membrane fractions by their buoyant density clearly showed the AR-GFP and AR-GFP-Gaj fusion proteins were not found in lower density caveolin-enriched "raft" frac tions. These observations have implications for the nature of the immediate receptor environment and whether the AR and other components of the receptor signalling complex are actively con centrated in regions of the cell membrane. The work presented here describes novel properties of agonist and antagonist binding at the human adenosine Aj receptor and to AjR-GFP and AR-GFP-Go fusion proteins. The ligand dependence of the kinetics of agonist dissociation provides direct evidence for receptor-receptor interactions, such as receptor oligomerisation.
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Moscoso, Castro Maria 1988. "Study of the involvement of adenosine A2A receptors in the pathophysiology of schizophrenia." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/565401.
Full textAbstract:
The adenosinergic system is a neuromodulatory complex acting on four receptor subtypes with varying distributions throughout the central nervous system. This system contributes to homeostasis and regulates several physiological functions including sleep, motor function, synaptic plasticity or cognition. Adenosine can exert an upstream modulation of several neurotransmitter systems, including dopamine and glutamate, both implicated in the pathophysiology of neuropsychiatric diseases and particularly in psychosis. Schizophrenia is considered a psychotic disease characterized by a chronic and debilitating course that can be triggered by different genetic, developmental and environmental factors. The disease is manifested with three symptom domains including positive, negative and cognitive symptoms and has important treatment limitations. Preclinical and clinical data suggest that adenosine dysfunction may contribute to the pathophysiology of schizophrenia. Hence, the main focus of this thesis is to study the responses induced by the complete deletion of adenosine A2A receptors in the pathophysiology of the disease, paying special attention to the cognitive symptom domain. The use of biochemical and behavioural approaches has allowed us to assess the validity of A2A receptor KO as a possible animal model for the study of schizophrenia.El sistema adenosinèrgic és un neuromodulador que actua sobre quatre subtipus de receptors amb diferents distribucions en el sistema nerviós central. Aquest sistema contribueix a l’homeòstasi i a la vegada regula diverses funcions fisiològiques com per exemple la son, la funció motora, la plasticitat sinàptica o la cognició. L’adenosina pot exercir un control “upstream” sobre diferents sistemes de neurotransmissió, incloent la dopamina i el glutamat, neurotransmissors implicats en la fisiopatologia de les malalties neuropsiquiàtriques, especialment en la psicosis. L’esquizofrènia es considera una malaltia psicòtica que cursa de forma crònica i debilitant provocada per la interacció de diferents factors genètics, ambientals i del desenvolupament. La malaltia es manifesta en tres dominis de símptomes, incloent símptomes positius, negatius i cognitius, i actualment té importants limitacions terapèutiques. Estudis preclínics i clínics suggereixen que la disfunció en el sistema d’adenosina pot contribuir a la patofisiologia de l’esquizofrènia. Per tant, l’objectiu principal d’aquesta tesi és l’estudi dels efectes induïts per la supressió completa dels receptors A2A d’adenosina en la fisiopatologia de la malaltia, parant especial atenció al domini de símptomes cognitius. L’ús de mètodes bioquímics i comportamentals ens ha permès avaluar la validesa dels KO pel receptor A2A d’adenosina com a possible model animal per a l’estudi de l’esquizofrènia.
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Junqueira, Ana FlÃvia Torquato de AraÃjo. "Estudo do efeito do inibidor da enzima adenosina desaminase, EHNA, sobre a enterite induzida pela toxina a do Clostridium difficile em alÃa ileal isolada de camundongos." Universidade Federal do CearÃ, 2008. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1305.
Full textAbstract:
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoO Clostridium difficile tem como principal fator de virulÃncia a toxina A (TxA), a qual provoca inflamaÃÃo e destruiÃÃo tecidual aguda em intestinos de animais experimentais e de pacientes com a doenÃa induzida por esta bactÃria. Em locais de injÃria tecidual, adenosina à produzida em altas concentraÃÃes, onde exerce uma sÃrie de efeitos antiinflamatÃrios, limitados por sua rÃpida degradaÃÃo pela enzima adenosina desaminase. O objetivo deste trabalho foi investigar o efeito da inibiÃÃo da enzima adenosina desaminase pelo EHNA (eritro-9-(2-hidrÃxi-3-nonil)-adenina) sobre a enterite induzida pela TxA do C. difficile em alÃa ileal de camundongos. Para isto, injetamos EHNA (90 μmol/kg) ou PBS i.p. 30 minutos antes da administraÃÃo de TxA (10 a 100 μg) ou PBS na alÃa ileal isolada. Os animais foram sacrificados 3 horas depois da induÃÃo da enterite e as alÃas foram retiradas para estudo. As razÃes peso/comprimento da alÃa e volume de secreÃÃo/comprimento da alÃa foram calculadas e amostras de tecido foram coletadas para histopatologia, dosagem de atividade de mieloperoxidase (MPO), dosagem de TNF-α, IL-1β e IL-10 por ELISA, imunohistoquÃmica para TNF-α, IL-1β, NOS induzÃvel e PTX3, e PCR para TNF-α, IL-1β e PTX3. A injeÃÃo de TxA (10 a 100 μg) nas alÃas ileais aumentou significativamente (p<0,05) as razÃes peso/comprimento da alÃa e volume de secreÃÃo/comprimento da alÃa com resultados consistentes a partir de 50 μg. A TxA promoveu significativa (p<0,05) destruiÃÃo tecidual, edema, infiltraÃÃo de cÃlulas inflamatÃrias, aumento das citocinas TNF-α e IL-1β, e elevaÃÃo de iNOS e PTX3. Todos esses parÃmetros foram significativamente revertidos com o uso do EHNA (p<0,05). Em adiÃÃo, a TxA nÃo alterou os nÃveis de IL-10 em relaÃÃo ao controle, mas o prÃ-tratamento com EHNA promoveu uma elevaÃÃo nos nÃveis desta citocina. Assim, concluÃmos que na enterite induzida pela TxA em camundongos o EHNA demonstrou um potente efeito antiinflamatÃrio, reduzindo consideravelmente a lesÃo tecidual, a migraÃÃo neutrofÃlica, a expressÃo e os nÃveis de citocinas prÃinflamatÃrias (TNF-α, IL-1β) e produzindo um aumento nos nÃveis de IL-10. AlÃm disso, a administraÃÃo de TxA induziu um aumento na expressÃo da proteÃna PTX3 e no nÃmero de cÃlulas imunomarcadas para iNOS no tecido ileal, ambos revertidos pelo EHNA
The main factor of virulence in Clostridium difficile is toxin A (TxA), which can induce inflammation and acute tissue injury in the bowels of animals and humans affected by this organism. The high concentration of adenosine generated upon injury produces a number of antiinflammatory effects limited by rapid degradation by adenosine deaminase. The objective of this study was to determine the effect of EHNA (erythro-9-(2-hydroxy-3-nonyl)-adenine) inhibition of adenosine deaminase upon TxA-induced ileal loop enteritis in mice. EHNA (90 μmol/kg) or PBS was injected i.p. 30 minutes prior to TxA (10-100 μg) or PBS instillation into the ligated ileal loop. The animals were euthanized 3 hours after enteritis induction and the ileal loops were retrieved for analysis. The weight/length ratio and the secretion volume/length ratio were calculated and tissue samples were submitted to histopathological study, myeloperoxidase assay (MPO), measurement of TNF-α, IL-1β and IL-10 levels with ELISA, immunohistochemical tests for TNF-α, IL-1β, inducible NOS and PTX3, and PCR assay for TNF-α, IL-1β and PTX3. The instillation of TxA (10-100 μg) into the ileal loop significantly increased (p<0.05) the weight/length ratio and the secretion volume/length ratio with consistent results above 50 μg. TxA induced a significant amount (p<0.05) of histological damage, edema and inflammatory cell infiltration and increased the production of TNF-α, IL-1β, iNOS and PTX3. All changes were significantly reverted by treatment with EHNA (p<0.05). Moreover, IL-10 levels remained unchanged in animals treated with TxA, but increased in animals receiving EHNA. In conclusion, in mice with TxA-induced enteritis EHNA produced considerable antiinflammatory effects, reducing tissue injury, neutrophil migration, the expression and levels of proinflammatory cytokines (TNF-α and IL-1β) and producing an increase in IL-10 levels. In addition, TxA instillation increased PTX3 expression and the number of cells immunolabeled for iNOS in the ileal tissue, both of which were reverted by EHNA
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TARGA, Martina. "ADENOSINE RECEPTORS IN RESPIRATORY DISORDERS AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MALIGNANT PLEURAL MESOTHELIOMA." Doctoral thesis, Università degli studi di Ferrara, 2012. http://hdl.handle.net/11392/2388779.
Full textAbstract:
Adenosine is a purine nucleoside that is commonly expressed in the body and involved in a wide range of
physiological processes. The effects of adenosine are mediated through specific G-protein coupled cell
surface receptors, named A1, A2A, A2B and A3 adenosine receptors (ARs). It is now well recognized that
extracellular levels of adenosine markedly increase under metabolically stressful conditions and in the last
two decades it has become clear that adenosine is a mediator involved in the pathogenesis of lung
inflammatory disorders and in cancer.
Indeed adenosine induces bronchoconstriction in animal models and in patients with airway diseases such as
asthma and chronic obstructive pulmonary diseases (COPD). COPD is defined as an inflammatory
respiratory disease, largely caused by exposure to tobacco smoke. The disease is characterized by a
progressive and incompletely reversible airflow obstruction. The key elements of COPD are exposure to
cigarette smoke, airway inflammation, and airflow obstruction that is not fully reversible.
In addition, an high concentration of adenosine have been reported in cancer tissues, where it appears to be
implicated in the growth of tumors, and in the regulation of cell death and proliferation. The development of
pleural-based abnormalities such as malignant pleural mesothelioma (MPM), is caused by inhalation of
asbestos fibers.
To study the interaction between adenosine and pulmonary diseases, the presence and functionality of ARs
were explored in human healthy subjects in comparison with COPD patients by using lung tissues and
bronchoalveolar lavage (BAL). The aim of this study was to investigate the expression, affinity and density
of ARs in peripheral lung parenchyma and in BAL from age-matched smokers with COPD and smokers with
normal lung function. The data, obtained in lung samples from COPD patients, suggest a downregulation of
A2BARs and an upregulation of A2A and A3ARs. A correlation among ARs expression and clinical
parameters such as FEV1/FVC ratio, an established index of airflow obstruction, was observed. Moreover
the subcellular location of A2BARs in BAL macrophages of patients with COPD and healthy smokers was
investigated, revealing a significant decrease in A2BARs expression in BAL from COPD patients compared
to an age-matched group of control smokers with normal lung function. This reduction was associated with a
decrease in A2BARs mRNA expression, suggesting a regulation at the transcriptional level.
ARs were also studied in MPM patients by using membranes or primary cultures from pleura of MPM
patients in comparison with healthy tissues or cells. Furthermore, to better understand the interaction
between adenosine and MPM, the presence and the functionality of ARs were explored in healthy
mesothelial cells (HMC) and malignant mesothelioma cells (MMC). ARs were analyzed by using RT-PCR,
western blotting and saturation binding assays. HMC were treated with crocidolite asbestos, which is the
principal risk factor of MPM. The dual effect of ARs stimulation on healthy and cancer cell growth was
studied by means of proliferation, apoptosis and cytotoxicity assays. The main result was that A3ARs were
up-regulated in MPM when compared with healthy mesothelial pleura. Stimulation of A3ARs decreases
proliferation and exerts cytotoxic and pro-apoptotic effect on MMC and on HMC exposed to asbestos and
TNF-�, but not in control HMC.
These data support the potential for modulating ARs function in pulmonary diseases such as inflammation
and cancer. In particular, the modulation of A2BARs by using selective antagonists in alveolar macrophages
as a new potential pharmacological tool could be used in the COPD disease. Moreover, the stimulation of
A3ARs by selective agonists could be involved as novel pharmacological treatment for malignant pleural
mesothelioma.
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Thevenin, Damien. "Roles of transmembrane domains in the folding and assembly of the adenosine A2A receptor." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 170 p, 2007. http://proquest.umi.com/pqdweb?did=1260822171&sid=2&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Coy, David Laughlin. "The activation and chemomechanical stoichiometry of cargo-loaded kinesin /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/10530.
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Lau, Siu-ling. "Characterization of adenosine transport in rat cardiomyocytes, H9c2 /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31494894.
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Wright, Denis Matthew John, and mikewood@deakin edu au. "Potential antiarrhythmic and cardioprotective agents based on adenosine." Deakin University. School of Biological and Chemical Sciences, 1998. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20050915.160941.
Full textAbstract:
N-Ethylcarboxamidoadenosine (12) was synthesised from adenosine (1) and the 6-chloro-2,3-O-isopropylidene-AT-ethylcarboxamidoadenosine (25) was synthesised from inosine (19).
Employing molecular modelling techniques and the results from previous structure activity relationships it was possible to design and synthesise a N6-substituted N-ethylcarboxamidoadenosines which possessed an oxygen in the N6-substituent either in the form of an epoxide (which was obtained by cpoxidising an alkene with m-CPBA or dimethyldioxirane) or in the form of a cyclic ether as was the case for N6-((tetrahydro-2H--pyran--2-yl)methyl-N-ethylcarboxamidoadenosine (78). These compounds were tested for their biological activity at the A1 adenosine receptor by their ability to inhibit cAMP accumulation in DDT, MF2 cells. The EC50 values obtained indicated that the N6-(norborn-5-en-2-yl)-N-ethylcarboxamidoadenosines were the most potent. Of theseN6-(S-endo-norbrn-5-en-2-yI)-N-ethylcarboxaniidoadenosine (56) was the most potent (0.2 nM). N6-(exo-norborn-5-en-2-yl)-2-iodo-N-ethylcarboxamidoadenosine (79) was synthesised from guanosine (22) and was also evaluated for its potency at the A, receptor (24.8 ± 1.5 nM). At present 79 is being evaluated for its selectivity for the A1 receptor compared to the other three receptor subtypes (A2a, A2b, A3). A series of N6-(benzyl)-N-ethylcarboxamidoadenosines were synthesised with substitutions at the 4-position of the phenyl ring. Another series of compounds were
synthesised which replaced the methylene spacer between the N6H and the N6-aromatic
or lipophilic substituent The replacement groups -were carbonyl and trans-2-
cyclopropyl moieties. The N6-acyl compounds were obtained by reacting 2,3-O-
di(tert-butyldimethylsilyl)-AT-ethylcarboxamidoadenosinc (59) with the appropriate acid chloride and then deprotecting with lelrabutylammonium fluoride in
tetrahydrofuran. The compound N6-(4-(1,2-dihydroxy)ethyl)benzyl-N-
ethylcarboxamidoadenosine (125) was synthesised by the reaction of 4-(1,2-0-
isopropylidene-ethyl)benzyl aminc (123) with 6-chloro-2,3-0-isopropylidene-N-
ethylcarboxamidoadenosine (25). Compound 123 was synthesised from an
epoxidation of vinylbenzyl phthalimide (118) followed by an acidic ring opening to
yield the diol which was isopropylidenated to yield 4-(l,2-O-isopropylidene-
elhyl)benzyl phlhalimide (122), It was hoped that the presence of the diol
functionality in 125 would increase water solubility whilst maintaining potency at the
A3 receptor.
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Beauglehole, Anthony Robert, and anthony@adenrx com. "N3-substituted xanthines as irreversible adenosine receptor antagonists." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20080612.084330.
Full textAbstract:
8-Cyclopentyl-3-(3-(4-fluorosulfonylbenzoyl)oxy)propyl-propylxanthine (44, FSCPX) has been reported to exhibit potent and selective irreversible antagonism of the A1 adenosine receptor when using in vitro biological preparations. However, FSCPX (44) suffers from cleavage of the ester linkage separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine pharmacophore when used in in vivo biological preparations or preparations containing significant enzyme activity, presumably by esterases. Cleavage of the ester linkage renders FSCPX (44) inactive in terms of irreversible receptor binding. In order to obtain an irreversible A1 adenosine receptor antagonist with improved stability, and to further elucidate the effects of linker structure on pharmacological characteristics, several FSCPX (44) analogues incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety were targeted, where the labile ester linkage has been replaced by more stable functionalites. In particular, ether, alkyl, amide and ketone linkers were targeted, where the length of the alkyl chain was varied from between one to five atoms.
Synthesis of the target compounds was achieved via direct attachment of the N-3 substituent to the xanthine. These compounds were then tested for their biological activity at the A1 adenosine receptor via their ability to irreversibly antagonise the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX, ( 9) to the A1 adenosine receptor of DDT1 MF-2 cells. For comparison, the xanthines were also tested for their ability to inhibit the binding of [3H]-4-(2-[7-amino-2-{furyl} {1,2,4}- triazolo{2,3-a} {1,3,5}triazin-5-ylamino-ethyl)]phenol ([3H]ZM241385, 36) to the A2A adenosine receptor of PC-12 cells. The results suggest that the length and chemical composition of the linker separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine ring contribute to the potency and efficacy of the irreversible A1 adenosine receptor ligands. Like FSCPX (44, IC50 A1 = 11.8 nM), all derivatives possessed IC50 values in the low nM range under in vitro conditions. Compounds 94 (IC50 A1 = 165 nM), 95 (IC50 A1 = 112 nM) and 96 (IC50 A1 = 101 nM) possessing one, three and five methylene spacers within the linkage respectively, exhibited potent and selective binding to the A1 adenosine receptor versus the A2A adenosine receptor. Compound 94 did not exhibit any irreversible binding at A1 adenosine receptors, while 95 and 96 exhibit only weak irreversible binding at A1 adenosine receptors. Those compounds containing a benzylic carbonyl separating the 4-(fluorosulfonyl)phenyl moiety from the xanthine ring in the form of an amide (119, IC50 A1 = 24.9 nM, and 120, IC50 A1 = 21 nM) or ketone (151, IC50 A1 = 14 nM) proved to be the most potent, with compound 120 exhibiting the highest selectivity of 132-fold for the A receptor over the A2A receptor. compounds 119, 120 and 151 also strongly inhibited the binding of [3H]DPCPX irreversibly (82%, 83% and 78% loss of [3H]DPCPX binding at 100 nM respectively). compounds 120 and 151 are currently being evaluated for use in in vivo studies.
Structure-activity studies suggest that altering the 8-cycloalkyl group of A1 selective xanthines for a 3-substituted or 2,3-disubstituted styryl, combined with N-7 methyl substitution will produce a compound with high affinity and selectivity for the A2A adenosine receptor over the A1 adenosine receptor. Compound 167 (IC50 A2A = 264 nM) possessing 8-(m-chloro)styryl substitution and the reactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine ring via an amide linker in the 3-position (as for 119 and 120), exhibited relatively potent binding to the A2A adenosine receptor of PC-12 cells, with a 16-fold selectivity for that receptor over the A1 adenosine receptor. However, compound 167 exhibited only very weak irreversible binding at A2A adenosine receptors.
Overall, at this stage of biological testing, compound 120 appears to possess the most advantageous characteristics as an irreversible antagonist for the A1 adenosine receptor. This can be attributed to its high selectivity for the A1 adenosine receptor as compared to the A2A adenosine receptor. It also has relatively high potency for the A1 adenosine receptor, a concentration-dependent and selective inactivation of A1 adenosine receptors, and unbound ligand is easily removed (washed out) from biological membranes. These characteristics mean compound 151 has the potential to be a useful tool for the further study of the structure and function of the A1 adenosine receptor.
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Tandon, Anurag. "Adenosine and acetylcholine synthesis in a sympathetic ganglion." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28539.
Full textAbstract:
The role of adenosine in modulating synaptic transmission in the cat superior cervical ganglion was investigated in this thesis. The first study showed that perfusion of ganglia with exogenous adenosine increased their acetylcholine (ACh) content. The effect was reduced by blockade of nucleoside transport, as if adenosine's action was mediated at an intracellular site. Isotopic labelling of the extra ACh with radiolabelled choline showed that the additional transmitter was due to increased ACh synthesis, and associated with increased choline transport. After its formation, preganglionic stimulation could release the extra ACh, but not if vesamicol, a vesicular ACh transport inhibitor, was present. Thus, the extra ACh appears to require mobilization from a reserve pool of transmitter.Activity-dependent modulation of synaptic transmission is known to occur in sympathetic ganglia. One such form of adaptive behavior is the increase in ACh content ('rebound ACh') after high frequency preganglionic stimulation. The possibility that adenosine might play a role in the rebound phenomenon was examined in the second study. The accumulation of rebound ACh was sensitive to nucleoside transport inhibitors; dipyridamole reduced rebound ACh if it wzs present only after the stimulation, but not if it was present only during stimulation. After its synthesis, rebound ACh was released by preganglionic stimulation, but not if vesamicol was present, as if the extra transmitter had to be mobilized from a reserve pool. Because the dipyridamole-sensitive step occurred after the conditioning period, it seemed possible that a retrograde messenger triggered the post-stimulation change in ACh synthesis.
Thus, the final series of experiments tested whether a postsynaptic signal could alter presynaptic ACh synthesis. Antidromic stimulation increased ganglionic ACh synthesis, and, consequently, ACh content. Subsequent evoked ACh release was potentiated, as if the additional transmitter was releasable. The antidromic stimulation-induced increase in AZh content was blocked by dipyridamole suggesting that adenosine might be involved.
Overall, the results presented in this thesis are consistent with the notion that adenosine acts as a retrograde messenger after high frequency orthodromic stimulation to induce an increase in presynaptic ACh synthesis.
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Lau, Siu-ling, and 劉少玲. "Characterization of adenosine transport in rat cardiomyocytes, H9c2." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45010237.
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Donaghy, Kevin M. "Actions of adenosine and anoxia in rat brain." Thesis, Queen's University Belfast, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333806.
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Harper, Laura. "A[2A subscript] adenosine receptors, dopamine and reward." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408638.
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Dale, Clare Louise. "Fluorescent Aâ‚-adenosine agonists : a structure activity relationship." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440124.
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Dexter, Emily Jane. "The role of adenosine in mast cell degranulation." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314292.
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Watt, A. H. "Cardiac and respiratory effects of adenosine in man." Thesis, University of Aberdeen, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379168.
Full textAbstract:
Adenosine is a nucleoside with varied pharmacological effects but its actions in man are sparsely documented. Cardiac and respiratory effects of adenosine in man were examined. Adenosine was found to increase coronary flow in patients without significant coronary atheroma. Adenosine restored sinus rhythm in some patients with supraventricular tachycardia. In those in whom sinus rhythm was not restored the underlying rhythm was atrial flutter. In patients with complete heart block adenosine decreased ventricular rate in a dose-related fashion. In subjects in sinus rhythm adenosine produced a transient dose-related bradycardia which was followed by a more sustained increase in sinus rate. These latter effects were compared but were found not to differ in young and elderly subjects. A dose-related respiratory stimulant effect of adenosine, which had not previously been widely appreciated, was observed. The possible relevance of this observation to the ventilatory response to hypoxia is discussed. Adenosine-induced respiratory stimulation was found not to differ in young and elderly subjects. Dipyridamole, an inhibitor of adenosine transport, potentiated adenosine-induced respiratory stimulation and bradycardia but not the subsequent tachycardia. Aminophylline, a competitive adenosine antagonist at cell-surface receptors, abolished adenosine-induced bradycardia but did not alter the tachycardia or respiratory stimulation. Adenosine-induced bradycardia in man may be explained by an action of adenosine on cell-surface receptors at one site, whereas such an explanation does not accord with the observations on tachycardia and respiratory stimulation. Adenosine administered proximal to the carotid circulation in man stimulated respiration, but infusion distal to those vessels had no such effect. These observations are consistent with the hypothesis that adenosine stimulates respiration in man by an action on the carotid body. Possible physiological, pathophysiological and therapeutic implications of these observations are discussed.
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Mann, J. S. "Adenosine : A putative mediator of bronchoconstriction in asthma." Thesis, University of Southampton, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379583.
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