Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/20910 |
Resumo: | Thyroid cancer is the most common endocrine neoplasia, and its incidence has been increasing in recent years. A better understanding of the molecular events involved in the progression of thyroid cancer may aid in the identification of patients with low and high-risk carcinomas. Among the mediators capable of modulating immune processes, such as cell differentiation, we highlight ATP, ADP, AMP, and adenosine, whose extracellular concentrations are controlled by the activity of the ectonucleoside triphosphate 5'-diphosphohydrolase (E- NTPDase), E-5'-nucleotidase (E-5’-NT) ectoenzymes and adenosine deaminase (ADA), and which act on specific receptors, forming the purinergic system. It is well known the relationship between reactive oxygen species (ROS) and cancer, in which ROS can contribute to the neoplastic transformation of cells. ROS are normally produced by metabolic oxidative processes and the molecules often damaged by them are lipids, proteins, and DNA. Antioxidant defense systems work cooperatively to relieve oxidative stress caused by increased production of ROS. Any change in one of these systems can break that balance and cause cell damage and, ultimately, malignant transformation. In addition, butyrylcholinesterase (BChE) appears to play important non-cholinergic roles as it is capable of intervening in cellular processes such as proliferation, differentiation, and apoptosis, suggesting a possible influence on tumorigenesis. The objective of this work is a better understanding of the molecular processes that occur during the progression of thyroid cancer, in order to identify possible new therapeutic targets. Therefore, we investigated the purinergic signaling profile in patients with thyroid cancer through platelet determination of E-NTPDase and E-5’-NT enzyme activities, as well as platelet and serum determination of ADA activity, by spectrophotometry. We also investigated the oxidative profile, through the determination of ROS levels and the biological damage caused by reactive species in lipids and proteins by the determination of lipid peroxidation and carbonylation levels of proteins. In addition, we verified the antioxidant profile of thyroid cancer patients by determining the levels of total thiols (T-SHs) and reduced glutathione (GSH). The serum activity of BChE was also performed. We observed a significant reduction in E-NTPDase activity, both in ATP and ADP hydrolysis. These results suggest an increase in ATP concentration as a consequence of a self-protection mechanism, and ADP, favoring thromboembolic changes. However, a significant increase in E-5’-NT activity has been observed, which, together with the reduction of ADA activity in both platelets and serum, leads to an increase in the extracellular concentration of adenosine, which may be involved in the tumor progression. Analyzing the oxidative profile, we observed a significant increase in the levels of ROS, which, together with the absence of a concomitant increase in antioxidant defenses represented by T-SHs and GSH levels, generate a pro-oxidant environment that justifies the elevated levels of thiobarbituric acid reactives substances (TBARS). The significant increase in BChE activity may be related to the stage of tumor progression, since patients in the study had pronounced nodules indicating a more advanced stage of cancer. The results demonstrated that, during the progression of thyroid cancer, alterations occur both in the activity of the enzymes of the purinergic and cholinergic systems as well as in the oxidative profile of these patients. Therefore, such parameters may represent future targets for the therapy and monitoring of the evolution of this neoplasm. |
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2021-05-14T19:51:02Z2021-05-14T19:51:02Z2019-02-19http://repositorio.ufsm.br/handle/1/20910Thyroid cancer is the most common endocrine neoplasia, and its incidence has been increasing in recent years. A better understanding of the molecular events involved in the progression of thyroid cancer may aid in the identification of patients with low and high-risk carcinomas. Among the mediators capable of modulating immune processes, such as cell differentiation, we highlight ATP, ADP, AMP, and adenosine, whose extracellular concentrations are controlled by the activity of the ectonucleoside triphosphate 5'-diphosphohydrolase (E- NTPDase), E-5'-nucleotidase (E-5’-NT) ectoenzymes and adenosine deaminase (ADA), and which act on specific receptors, forming the purinergic system. It is well known the relationship between reactive oxygen species (ROS) and cancer, in which ROS can contribute to the neoplastic transformation of cells. ROS are normally produced by metabolic oxidative processes and the molecules often damaged by them are lipids, proteins, and DNA. Antioxidant defense systems work cooperatively to relieve oxidative stress caused by increased production of ROS. Any change in one of these systems can break that balance and cause cell damage and, ultimately, malignant transformation. In addition, butyrylcholinesterase (BChE) appears to play important non-cholinergic roles as it is capable of intervening in cellular processes such as proliferation, differentiation, and apoptosis, suggesting a possible influence on tumorigenesis. The objective of this work is a better understanding of the molecular processes that occur during the progression of thyroid cancer, in order to identify possible new therapeutic targets. Therefore, we investigated the purinergic signaling profile in patients with thyroid cancer through platelet determination of E-NTPDase and E-5’-NT enzyme activities, as well as platelet and serum determination of ADA activity, by spectrophotometry. We also investigated the oxidative profile, through the determination of ROS levels and the biological damage caused by reactive species in lipids and proteins by the determination of lipid peroxidation and carbonylation levels of proteins. In addition, we verified the antioxidant profile of thyroid cancer patients by determining the levels of total thiols (T-SHs) and reduced glutathione (GSH). The serum activity of BChE was also performed. We observed a significant reduction in E-NTPDase activity, both in ATP and ADP hydrolysis. These results suggest an increase in ATP concentration as a consequence of a self-protection mechanism, and ADP, favoring thromboembolic changes. However, a significant increase in E-5’-NT activity has been observed, which, together with the reduction of ADA activity in both platelets and serum, leads to an increase in the extracellular concentration of adenosine, which may be involved in the tumor progression. Analyzing the oxidative profile, we observed a significant increase in the levels of ROS, which, together with the absence of a concomitant increase in antioxidant defenses represented by T-SHs and GSH levels, generate a pro-oxidant environment that justifies the elevated levels of thiobarbituric acid reactives substances (TBARS). The significant increase in BChE activity may be related to the stage of tumor progression, since patients in the study had pronounced nodules indicating a more advanced stage of cancer. The results demonstrated that, during the progression of thyroid cancer, alterations occur both in the activity of the enzymes of the purinergic and cholinergic systems as well as in the oxidative profile of these patients. Therefore, such parameters may represent future targets for the therapy and monitoring of the evolution of this neoplasm.O câncer de tireoide é a neoplasia endócrina mais comum, cuja incidência vem aumentando nos últimos anos. A melhor compreensão dos eventos moleculares envolvidos na progressão do câncer de tireoide pode auxiliar na identificação de pacientes com carcinomas de baixo e alto risco. Dentre os mediadores capazes de modular processos imunes, tais como a diferenciação celular, destacam-se o ATP, o ADP, o AMP e a adenosina, cujas concentrações extracelulares são controladas pela atividade das ectoenzimas ectonucleosídeo trifosfato 5'- difosfoidrolase (E-NTPDase), E-5’-nucleotidase (E-5’-NT) e adenosina desaminase (ADA), e que agem em receptores específicos, formando o sistema purinérgico. É bem conhecida a relação entre as espécies reativas de oxigênio (EROs) e câncer, na qual as EROs podem contribuir para a transformação neoplásica de células. As EROs são normalmente produzidas por processos oxidativos metabólicos e as moléculas frequentemente danificadas por elas são lipídios, proteínas e o DNA. Os sistemas de defesa antioxidante trabalham cooperativamente para aliviar o estresse oxidativo causado pela produção aumentada das EROs. Qualquer alteração em um desses sistemas pode quebrar esse equilíbrio e causar dano celular e, em última instância, transformação maligna. Além disso, a butirilcolinesterase (BChE) parece desempenhar funções não-colinérgicas importantes, pois é capaz de intervir em processos celulares como a proliferação, diferenciação e apoptose, o que sugere uma possível influência na tumorigênese. O objetivo desse trabalho é a melhor compreensão dos processos moleculares que ocorrem durante a progressão do câncer de tireoide, visando a identificação de possíveis novos alvos terapêuticos. Para tanto, investigamos o perfil de sinalização purinérgica em pacientes com câncer de tireoide através da determinação, em plaquetas, da atividade das enzimas E-NTPDase e E-5’-NT, além da determinação em plaquetas e no soro da atividade da E-ADA, por espectrofotometria, além do perfil oxidativo, através da dosagem dos níveis de EROs e da avaliação da intensidade do dano biológico causado por eles em lipídios e proteínas, através da determinação da peroxidação lipídica e dos níveis de carbonilação de proteínas. Adicionalmente, verificamos o perfil antioxidante dos pacientes com câncer de tireoide, através da determinação dos níveis de tióis totais (T-SHs) e glutationa reduzida (GSH). A atividade sérica da BChE também foi determinada. Observamos uma significativa redução da atividade da E-NTPDase, tanto na hidrólise do ATP quanto na do ADP. Esses resultados sugerem um aumento da concentração de ATP como consequência de um mecanismo de autoproteção, e ADP, favorecendo alterações tromboembólicas. Contudo, foi observado um significativo aumento da atividade da E-5’-NT, que associada à redução da atividade da ADA, tanto nas plaquetas quanto no soro, conduzem ao aumento da concentração extracelular de adenosina, a qual pode estar envolvida no processo de progressão tumoral. Quanto ao perfil oxidativo, observamos um significativo aumento dos níveis de EROs, que associado a ausência de um aumento concomitante das defesas antioxidantes representadas pelo níveis de T-SHs e GSH, geram um ambiente pró-oxidante que justifica o aumento dos níveis de substâncias reativas ao ácido tiobarbitúrico (TBARS) observados. O aumento significativo da atividade da BChE pode estar relacionado ao estágio de progressão tumoral, visto que os pacientes do estudo apresentavam nódulos pronunciados indicando um estágio mais avançado do câncer. Os resultados descritos demonstram que, durante a progressão do câncer de tireoide, ocorrem alterações tanto na atividade das enzimas do sistema purinérgico e colinérgico quanto no perfil oxidativo desses pacientes. Portanto, tais parâmetros podem representar futuros alvos para a terapia e monitoramento da evolução dessa neoplasia.porUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em Ciências FarmacêuticasUFSMBrasilCiências da SaúdeAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessCâncer de tireoideSistema purinérgicoEstresse oxidativoButirilcolinesteraseThyroid cancerPurinergic systemOxidative stressButyrylcholinesteraseCNPQ::CIENCIAS DA SAUDE::FARMACIACâncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativoThyroid cancer: evaluation of purinergic system enzyme activities, butyrylcholinesterase and oxidative profileinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisLeal, Daniela Bitencourt Rosahttp://lattes.cnpq.br/3639683273462361Moreira, Cleci MenezesXXXXXXXXXXXXXXXFleck, JulianaXXXXXXXXXXXXXXXXXXBauermann, Liliane de FreitasXXXXXXXXXXXXXXXSchetinger, Maria Rosa ChitolinaXXXXXXXXXXXXXXXXXXhttp://lattes.cnpq.br/4911392125230611Cavalheiro, Patrícia Bernardes400300000005600ebd6d0bc-4e14-43fd-8d4e-ad9ebe640af24dd4e59f-61cf-47f3-95a2-fc2b3d1dcb1a42b89fc7-1153-4da6-b5b3-8f2f688fad001061f325-eb1b-462a-889e-04c8f0051208fd911925-2f77-4c9b-90e0-fe5f4b3b868498300743-ff68-46b6-b7c0-7145a94b913dreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
dc.title.alternative.eng.fl_str_mv |
Thyroid cancer: evaluation of purinergic system enzyme activities, butyrylcholinesterase and oxidative profile |
title |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
spellingShingle |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo Cavalheiro, Patrícia Bernardes Câncer de tireoide Sistema purinérgico Estresse oxidativo Butirilcolinesterase Thyroid cancer Purinergic system Oxidative stress Butyrylcholinesterase CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
title_full |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
title_fullStr |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
title_full_unstemmed |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
title_sort |
Câncer de tireoide: avaliação da atividade de enzimas do sistema purinérgico, butirilcolinesterase e perfil oxidativo |
author |
Cavalheiro, Patrícia Bernardes |
author_facet |
Cavalheiro, Patrícia Bernardes |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Leal, Daniela Bitencourt Rosa |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3639683273462361 |
dc.contributor.referee1.fl_str_mv |
Moreira, Cleci Menezes |
dc.contributor.referee1Lattes.fl_str_mv |
XXXXXXXXXXXXXXX |
dc.contributor.referee2.fl_str_mv |
Fleck, Juliana |
dc.contributor.referee2Lattes.fl_str_mv |
XXXXXXXXXXXXXXXXXX |
dc.contributor.referee3.fl_str_mv |
Bauermann, Liliane de Freitas |
dc.contributor.referee3Lattes.fl_str_mv |
XXXXXXXXXXXXXXX |
dc.contributor.referee4.fl_str_mv |
Schetinger, Maria Rosa Chitolina |
dc.contributor.referee4Lattes.fl_str_mv |
XXXXXXXXXXXXXXXXXX |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/4911392125230611 |
dc.contributor.author.fl_str_mv |
Cavalheiro, Patrícia Bernardes |
contributor_str_mv |
Leal, Daniela Bitencourt Rosa Moreira, Cleci Menezes Fleck, Juliana Bauermann, Liliane de Freitas Schetinger, Maria Rosa Chitolina |
dc.subject.por.fl_str_mv |
Câncer de tireoide Sistema purinérgico Estresse oxidativo Butirilcolinesterase |
topic |
Câncer de tireoide Sistema purinérgico Estresse oxidativo Butirilcolinesterase Thyroid cancer Purinergic system Oxidative stress Butyrylcholinesterase CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
Thyroid cancer Purinergic system Oxidative stress Butyrylcholinesterase |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Thyroid cancer is the most common endocrine neoplasia, and its incidence has been increasing in recent years. A better understanding of the molecular events involved in the progression of thyroid cancer may aid in the identification of patients with low and high-risk carcinomas. Among the mediators capable of modulating immune processes, such as cell differentiation, we highlight ATP, ADP, AMP, and adenosine, whose extracellular concentrations are controlled by the activity of the ectonucleoside triphosphate 5'-diphosphohydrolase (E- NTPDase), E-5'-nucleotidase (E-5’-NT) ectoenzymes and adenosine deaminase (ADA), and which act on specific receptors, forming the purinergic system. It is well known the relationship between reactive oxygen species (ROS) and cancer, in which ROS can contribute to the neoplastic transformation of cells. ROS are normally produced by metabolic oxidative processes and the molecules often damaged by them are lipids, proteins, and DNA. Antioxidant defense systems work cooperatively to relieve oxidative stress caused by increased production of ROS. Any change in one of these systems can break that balance and cause cell damage and, ultimately, malignant transformation. In addition, butyrylcholinesterase (BChE) appears to play important non-cholinergic roles as it is capable of intervening in cellular processes such as proliferation, differentiation, and apoptosis, suggesting a possible influence on tumorigenesis. The objective of this work is a better understanding of the molecular processes that occur during the progression of thyroid cancer, in order to identify possible new therapeutic targets. Therefore, we investigated the purinergic signaling profile in patients with thyroid cancer through platelet determination of E-NTPDase and E-5’-NT enzyme activities, as well as platelet and serum determination of ADA activity, by spectrophotometry. We also investigated the oxidative profile, through the determination of ROS levels and the biological damage caused by reactive species in lipids and proteins by the determination of lipid peroxidation and carbonylation levels of proteins. In addition, we verified the antioxidant profile of thyroid cancer patients by determining the levels of total thiols (T-SHs) and reduced glutathione (GSH). The serum activity of BChE was also performed. We observed a significant reduction in E-NTPDase activity, both in ATP and ADP hydrolysis. These results suggest an increase in ATP concentration as a consequence of a self-protection mechanism, and ADP, favoring thromboembolic changes. However, a significant increase in E-5’-NT activity has been observed, which, together with the reduction of ADA activity in both platelets and serum, leads to an increase in the extracellular concentration of adenosine, which may be involved in the tumor progression. Analyzing the oxidative profile, we observed a significant increase in the levels of ROS, which, together with the absence of a concomitant increase in antioxidant defenses represented by T-SHs and GSH levels, generate a pro-oxidant environment that justifies the elevated levels of thiobarbituric acid reactives substances (TBARS). The significant increase in BChE activity may be related to the stage of tumor progression, since patients in the study had pronounced nodules indicating a more advanced stage of cancer. The results demonstrated that, during the progression of thyroid cancer, alterations occur both in the activity of the enzymes of the purinergic and cholinergic systems as well as in the oxidative profile of these patients. Therefore, such parameters may represent future targets for the therapy and monitoring of the evolution of this neoplasm. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019-02-19 |
dc.date.accessioned.fl_str_mv |
2021-05-14T19:51:02Z |
dc.date.available.fl_str_mv |
2021-05-14T19:51:02Z |
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/1/20910 |
url |
http://repositorio.ufsm.br/handle/1/20910 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
400300000005 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
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openAccess |
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Universidade Federal de Santa Maria Centro de Ciências da Saúde |
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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 |
Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
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UFSM |
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UFSM |
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