Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional Manancial UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/18109 |
Resumo: | Multiple myeloma (MM) is an incurable hematological disorder characterized by clonal population of bone marrow plasma cells proliferation, which secrete monoclonal antibodies or fragments thereof, causing failure in normal hematopoiesis. In addition to failures in responses mediated by altered antibodies, the patients show defects in their cellular immune responses, often with the occurrence of infections. The nucleotidases, ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) and 5'-nucleotidase (5'-NT), and adenosine deaminase (ADA), in their soluble forms or in the external surface of the cell membrane such lymphocytes, have shown to influence, directly or indirectly, the growth of tumor cells by modulating of signaling molecules such as ATP, ADP, AMP and adenosine, by various mechanisms involving the purinergic system. This system dynamically changes with the pathophysiologic context in which it is inserted and is also linked to cytokines production, affecting the growth, survival and apoptosis process in myeloma cells. The aim of this study was to evaluate the activities of NTPDase, 5'-NT and ADA enzymes carried out by spectrophotometry, present in the serum of patients with MM treated (n = 22) and untreated (n = 9), at least in the last 90 days (plateau phase), and of the control group (n=30), its correlation with the activity of caspases 1, 3 and 8 performed by fluorimetry, and the relationship with the concentration of various cytokines identified by flow cytometry. Moreover, we also evaluated the activity of E-NTPDase and E-ADA by spectrophotometry as well as the percentage of CD39+ and CD73+ expression in lymphocytes, identified by flow cytometry, of MM patients treated (n = 32) and untreated (n = 10) (plateau phase) and of the control group (n=85). The obtained results demonstrated a reduction in the nucleotidases activity (5'-NT and NTPDase) and increased in ADA activity in serum from patients with MM. Serum levels of IL-6 and IL-10 cytokines were between 80% and 100% higher, respectively, in MM patients and may be related to immunosuppressive and anti-apoptotic effects. The anti-apoptotic effects appear to be increased since the activity of caspases 1, 3 and 8 were reduced approximately 70% in patients with MM and were positively correlated with the activities of NTPDase and 5'-NT. Evaluation of E-NTPDase activity and percentage of CD39+ lymphocytes was not modified in patients with MM, while there was a reduction in the percentage of CD73+ lymphocytes in the patients treated. Also, the E-ADA activity in lymphocytes presented increased in both groups of MM patients as well as in the serum, indicating a possible compensation against an increase of extracellular adenosine. Thus, it can be concluded that patients with MM exhibit a modulation in purinergic signaling resulting from changes in activities or percentage of expression of enzymes responsible for the system, that are directly or indirectly related to the concentration of certain cytokines and the activity of caspases. The effect of the modulation of the purinergic system may affect the immune response in these patients and may be involved in the relapse of the disease and / or resistance to treatment, and susceptibility to infections. |
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2019-09-02T14:47:03Z2019-09-02T14:47:03Z2016-08-25http://repositorio.ufsm.br/handle/1/18109Multiple myeloma (MM) is an incurable hematological disorder characterized by clonal population of bone marrow plasma cells proliferation, which secrete monoclonal antibodies or fragments thereof, causing failure in normal hematopoiesis. In addition to failures in responses mediated by altered antibodies, the patients show defects in their cellular immune responses, often with the occurrence of infections. The nucleotidases, ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) and 5'-nucleotidase (5'-NT), and adenosine deaminase (ADA), in their soluble forms or in the external surface of the cell membrane such lymphocytes, have shown to influence, directly or indirectly, the growth of tumor cells by modulating of signaling molecules such as ATP, ADP, AMP and adenosine, by various mechanisms involving the purinergic system. This system dynamically changes with the pathophysiologic context in which it is inserted and is also linked to cytokines production, affecting the growth, survival and apoptosis process in myeloma cells. The aim of this study was to evaluate the activities of NTPDase, 5'-NT and ADA enzymes carried out by spectrophotometry, present in the serum of patients with MM treated (n = 22) and untreated (n = 9), at least in the last 90 days (plateau phase), and of the control group (n=30), its correlation with the activity of caspases 1, 3 and 8 performed by fluorimetry, and the relationship with the concentration of various cytokines identified by flow cytometry. Moreover, we also evaluated the activity of E-NTPDase and E-ADA by spectrophotometry as well as the percentage of CD39+ and CD73+ expression in lymphocytes, identified by flow cytometry, of MM patients treated (n = 32) and untreated (n = 10) (plateau phase) and of the control group (n=85). The obtained results demonstrated a reduction in the nucleotidases activity (5'-NT and NTPDase) and increased in ADA activity in serum from patients with MM. Serum levels of IL-6 and IL-10 cytokines were between 80% and 100% higher, respectively, in MM patients and may be related to immunosuppressive and anti-apoptotic effects. The anti-apoptotic effects appear to be increased since the activity of caspases 1, 3 and 8 were reduced approximately 70% in patients with MM and were positively correlated with the activities of NTPDase and 5'-NT. Evaluation of E-NTPDase activity and percentage of CD39+ lymphocytes was not modified in patients with MM, while there was a reduction in the percentage of CD73+ lymphocytes in the patients treated. Also, the E-ADA activity in lymphocytes presented increased in both groups of MM patients as well as in the serum, indicating a possible compensation against an increase of extracellular adenosine. Thus, it can be concluded that patients with MM exhibit a modulation in purinergic signaling resulting from changes in activities or percentage of expression of enzymes responsible for the system, that are directly or indirectly related to the concentration of certain cytokines and the activity of caspases. The effect of the modulation of the purinergic system may affect the immune response in these patients and may be involved in the relapse of the disease and / or resistance to treatment, and susceptibility to infections.O mieloma múltiplo (MM) é uma doença hematológica incurável caracterizada pela proliferação de população clonal de plasmócitos na medula óssea, que secretam anticorpos monoclonais ou fragmentos destes, ocasionando na falha da hematopoiese normal. Em adição às falhas nas respostas mediadas pelos anticorpos alterados, os pacientes demonstram defeitos nas suas respostas imunes celulares, sendo frequente a ocorrência de infecções. As nucleotidases, ecto-nucleosídeo trifosfato difosfoidrolase (NTPDase) e 5'-nucleotidase (5'-NT), e a adenosina desaminase (ADA), nas suas formas solúveis ou na superfície externa da membrana das células como nos linfócitos, têm demonstrado influenciar, direta ou indiretamente, o crescimento das células tumorais através da modulação de moléculas sinalizadoras como ATP, ADP, AMP e adenosina, através de vários mecanismos envolvendo o sistema purinérgico. Este sistema muda dinamicamente com o contexto fisiopatológico em que está inserido e está também ligado à produção de citocinas, afetando o crescimento, a sobrevivência e o processo de apoptose em células do mieloma. O objetivo deste estudo foi avaliar as atividades das enzimas NTPDase, 5’-NT e ADA, realizadas por espectrofotometria, presentes no soro de pacientes com MM tratados (n= 22) e não tratados (n=9), pelo menos nos últimos 90 dias (fase de platô), e do grupo controle (n=30), a sua correlação com as atividades das caspases 1, 3 e 8 realizadas por fluorimetria, e a relação com a concentração de diversas citocinas identificadas por citometria de fluxo. Além disso, também foram avaliadas as atividades de E-NTPDase e E-ADA por espectrofotometria, bem como o percentual de expressão de CD39+ e CD73+ em linfócitos, identificados através da citometria de fluxo, de pacientes com MM tratados (n=32) e não tratados (n=10) (fase de platô) e do grupo controle (n=85). Os resultados obtidos demonstraram uma redução na atividade de nucleotidases (NTPDase e 5'-NT) e um aumento da atividade de ADA no soro de pacientes com MM. Os níveis séricos das citocinas IL-6 e IL-10 estavam entre 80% e 100% mais elevados, respectivamente, em pacientes com MM e podem estar relacionados com efeitos imunossupressores e antiapoptóticos. Os efeitos antiapoptóticos parecem estar aumentados uma vez que as atividades das caspases 1, 3 e 8 estavam aproximadamente 70% reduzidas nos pacientes com MM e foram positivamente correlacionadas com as atividades de NTPDase e 5'-NT. A avaliação da atividade de E-NTPDase e percentagem de linfócitos CD39+ não foi modificada nos pacientes com MM, enquanto houve uma redução no percentual de linfócitos CD73+ nos pacientes tratados. Ainda, a atividade de E-ADA nos linfócitos apresentou-se aumentada em ambos os grupos de pacientes com MM, assim como no soro, indicando uma possível compensação frente a um aumento de adenosina extracelular. Dessa forma, pode-se concluir que os pacientes com MM apresentam uma modulação na sinalização purinérgica decorrente de alterações nas atividades ou percentual de expressão das enzimas responsáveis por este sistema, que estão relacionadas direta ou indiretamente com a concentração de algumas citocinas e atividade das caspases. O efeito da modulação do sistema purinérgico pode afetar a resposta imune destes pacientes e pode estar envolvido com a recaída da doença e/ou resistência aos tratamentos, além de suscetibilidade a infecções.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessMieloma múltiploSinalização purinérgicaCitocinasCaspasesMultiple myelomaPurinergic signalingCytokinesCaspasesCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAAvaliação da sinalização purinérgica em pacientes com Mieloma MúltiploEvaluation of purinergic signaling in patients with Multiple Myelomainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisSilva, José Edson Paz dahttp://lattes.cnpq.br/1177504021154172Leal, Daniela Bitencourt Rosahttp://lattes.cnpq.br/3639683273462361Gonçalves, Jamile Fabbrinhttp://lattes.cnpq.br/3517679241506587Fleck, Julianahttp://lattes.cnpq.br/1497762896019410Magni, Danieli Valneshttp://lattes.cnpq.br/5452391689473129Beck, Sandra Trevisanhttp://lattes.cnpq.br/4435727183593265http://lattes.cnpq.br/2894132193582102Soares, Pâmela de Brum201000000000600f31cbb2c-a6b3-42b5-99ec-4f7ceeff61499046a864-1b8b-42d9-9662-04294f2d472b273fd05e-83b4-4374-81a7-26d005e91f4bb9e596dc-2655-4915-af79-daed878f33d91061f325-eb1b-462a-889e-04c8f0051208d3d4d481-e218-40ca-929c-28186a18f541025f490a-3470-49b5-881a-288b5218bd7ereponame:Repositório Institucional Manancial UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGCF_2016_SOARES_PAMELA.pdfTES_PPGCF_2016_SOARES_PAMELA.pdfTese de Doutoradoapplication/pdf1840747http://repositorio.ufsm.br/bitstream/1/18109/1/TES_PPGCF_2016_SOARES_PAMELA.pdfeed2ddb65ea33daee3a94ce31d1ec882MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
dc.title.alternative.eng.fl_str_mv |
Evaluation of purinergic signaling in patients with Multiple Myeloma |
title |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
spellingShingle |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo Soares, Pâmela de Brum Mieloma múltiplo Sinalização purinérgica Citocinas Caspases Multiple myeloma Purinergic signaling Cytokines Caspases CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
title_full |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
title_fullStr |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
title_full_unstemmed |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
title_sort |
Avaliação da sinalização purinérgica em pacientes com Mieloma Múltiplo |
author |
Soares, Pâmela de Brum |
author_facet |
Soares, Pâmela de Brum |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Silva, José Edson Paz da |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/1177504021154172 |
dc.contributor.advisor-co1.fl_str_mv |
Leal, Daniela Bitencourt Rosa |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/3639683273462361 |
dc.contributor.referee1.fl_str_mv |
Gonçalves, Jamile Fabbrin |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/3517679241506587 |
dc.contributor.referee2.fl_str_mv |
Fleck, Juliana |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/1497762896019410 |
dc.contributor.referee3.fl_str_mv |
Magni, Danieli Valnes |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/5452391689473129 |
dc.contributor.referee4.fl_str_mv |
Beck, Sandra Trevisan |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/4435727183593265 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/2894132193582102 |
dc.contributor.author.fl_str_mv |
Soares, Pâmela de Brum |
contributor_str_mv |
Silva, José Edson Paz da Leal, Daniela Bitencourt Rosa Gonçalves, Jamile Fabbrin Fleck, Juliana Magni, Danieli Valnes Beck, Sandra Trevisan |
dc.subject.por.fl_str_mv |
Mieloma múltiplo Sinalização purinérgica Citocinas Caspases |
topic |
Mieloma múltiplo Sinalização purinérgica Citocinas Caspases Multiple myeloma Purinergic signaling Cytokines Caspases CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Multiple myeloma Purinergic signaling Cytokines Caspases |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Multiple myeloma (MM) is an incurable hematological disorder characterized by clonal population of bone marrow plasma cells proliferation, which secrete monoclonal antibodies or fragments thereof, causing failure in normal hematopoiesis. In addition to failures in responses mediated by altered antibodies, the patients show defects in their cellular immune responses, often with the occurrence of infections. The nucleotidases, ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) and 5'-nucleotidase (5'-NT), and adenosine deaminase (ADA), in their soluble forms or in the external surface of the cell membrane such lymphocytes, have shown to influence, directly or indirectly, the growth of tumor cells by modulating of signaling molecules such as ATP, ADP, AMP and adenosine, by various mechanisms involving the purinergic system. This system dynamically changes with the pathophysiologic context in which it is inserted and is also linked to cytokines production, affecting the growth, survival and apoptosis process in myeloma cells. The aim of this study was to evaluate the activities of NTPDase, 5'-NT and ADA enzymes carried out by spectrophotometry, present in the serum of patients with MM treated (n = 22) and untreated (n = 9), at least in the last 90 days (plateau phase), and of the control group (n=30), its correlation with the activity of caspases 1, 3 and 8 performed by fluorimetry, and the relationship with the concentration of various cytokines identified by flow cytometry. Moreover, we also evaluated the activity of E-NTPDase and E-ADA by spectrophotometry as well as the percentage of CD39+ and CD73+ expression in lymphocytes, identified by flow cytometry, of MM patients treated (n = 32) and untreated (n = 10) (plateau phase) and of the control group (n=85). The obtained results demonstrated a reduction in the nucleotidases activity (5'-NT and NTPDase) and increased in ADA activity in serum from patients with MM. Serum levels of IL-6 and IL-10 cytokines were between 80% and 100% higher, respectively, in MM patients and may be related to immunosuppressive and anti-apoptotic effects. The anti-apoptotic effects appear to be increased since the activity of caspases 1, 3 and 8 were reduced approximately 70% in patients with MM and were positively correlated with the activities of NTPDase and 5'-NT. Evaluation of E-NTPDase activity and percentage of CD39+ lymphocytes was not modified in patients with MM, while there was a reduction in the percentage of CD73+ lymphocytes in the patients treated. Also, the E-ADA activity in lymphocytes presented increased in both groups of MM patients as well as in the serum, indicating a possible compensation against an increase of extracellular adenosine. Thus, it can be concluded that patients with MM exhibit a modulation in purinergic signaling resulting from changes in activities or percentage of expression of enzymes responsible for the system, that are directly or indirectly related to the concentration of certain cytokines and the activity of caspases. The effect of the modulation of the purinergic system may affect the immune response in these patients and may be involved in the relapse of the disease and / or resistance to treatment, and susceptibility to infections. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016-08-25 |
dc.date.accessioned.fl_str_mv |
2019-09-02T14:47:03Z |
dc.date.available.fl_str_mv |
2019-09-02T14:47:03Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/18109 |
url |
http://repositorio.ufsm.br/handle/1/18109 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
201000000000 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
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dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Farmacêuticas |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional Manancial UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
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Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Repositório Institucional Manancial UFSM |
collection |
Repositório Institucional Manancial UFSM |
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MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional Manancial UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
ouvidoria@ufsm.br |
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1808854725206999040 |