Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da Uninove |
Texto Completo: | http://bibliotecatede.uninove.br/handle/tede/3306 |
Resumo: | Two processes are crucial for the development and progression of bladder cancer (BC), angiogenesis and immune escape, which are related through key molecules specially induced in a hypoxic environment controlled by HIF-1 α. Indoleamine 2,3-dioxygenase-1 (IDO1) is an immunomodulating enzyme induced by interferon-gamma (IFN-γ ) that has been linked to angiogenesis in some neoplasms. It is possible that its activity is modulated during hypoxia, affecting local inflammation and the production of new vessels. The aim of the study was to verify whether the situation of hypoxia with alteration of HIF1α alters the expression of IFN-γ and IDO1 and whether the activity of IDO1 influences angiogenesis in BC. In an in vitro phase, T24 cells were subjected to different times of hypoxia with and without oxygen recovery. CoCl2 was also used as a stabilizer for HIF-1 α without hypoxia. HIF-1α, VEGF-A, IFN-γ and IDO1 were analyzed by ELISA or qRT-PCR, and IDO1 activity by Lkynurenine measurement (HPLC). In another phase, HUVEC cells were incubated with a high concentration of L-kynurenine and/or with a low concentration of tryptophan for analysis of vascular tubes. In the in vivo phase, CB-bearing animals were treated with 1-methyl-tryptophan (IDO1 inhibitor) to assess angiogenesis (CD31 immunohistochemistry). As a result, hypoxia increased IFN-γ, while IDO expression and activity significantly decreased. The decrease in IDO1 expression correlated negatively with VEGF-A expression. The simulation of an environment with a high concentration of L-kynurenine and a low concentration of tryptophan decreased the formation of vascular tubes. In an animal model, IDO1 inhibition increased blood vessel formation. In conclusion, in BC, during hypoxia there is an increase in IFN-γ, but there is a decrease in IDO1 expression and activity, effects possibly mediated by HIF-1α. The low activity of IDO1 during hypoxia favors angiogenesis in BC. |
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Dellê, Humbertohttp://lattes.cnpq.br/7435662740477057Dellê, Humbertohttp://lattes.cnpq.br/7435662740477057Dalboni, Maria Aparecidahttp://lattes.cnpq.br/9818040147487320Rodrigues, Maria Fernanda Setúbal Destrohttp://lattes.cnpq.br/7153553682954852Moreno, Ana Carolina Ramoshttp://lattes.cnpq.br/3582028585601108Silva, Aline da2024-04-08T19:04:50Z2021-12-10Silva, Aline da. Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga. 2021. 77 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo.http://bibliotecatede.uninove.br/handle/tede/3306Two processes are crucial for the development and progression of bladder cancer (BC), angiogenesis and immune escape, which are related through key molecules specially induced in a hypoxic environment controlled by HIF-1 α. Indoleamine 2,3-dioxygenase-1 (IDO1) is an immunomodulating enzyme induced by interferon-gamma (IFN-γ ) that has been linked to angiogenesis in some neoplasms. It is possible that its activity is modulated during hypoxia, affecting local inflammation and the production of new vessels. The aim of the study was to verify whether the situation of hypoxia with alteration of HIF1α alters the expression of IFN-γ and IDO1 and whether the activity of IDO1 influences angiogenesis in BC. In an in vitro phase, T24 cells were subjected to different times of hypoxia with and without oxygen recovery. CoCl2 was also used as a stabilizer for HIF-1 α without hypoxia. HIF-1α, VEGF-A, IFN-γ and IDO1 were analyzed by ELISA or qRT-PCR, and IDO1 activity by Lkynurenine measurement (HPLC). In another phase, HUVEC cells were incubated with a high concentration of L-kynurenine and/or with a low concentration of tryptophan for analysis of vascular tubes. In the in vivo phase, CB-bearing animals were treated with 1-methyl-tryptophan (IDO1 inhibitor) to assess angiogenesis (CD31 immunohistochemistry). As a result, hypoxia increased IFN-γ, while IDO expression and activity significantly decreased. The decrease in IDO1 expression correlated negatively with VEGF-A expression. The simulation of an environment with a high concentration of L-kynurenine and a low concentration of tryptophan decreased the formation of vascular tubes. In an animal model, IDO1 inhibition increased blood vessel formation. In conclusion, in BC, during hypoxia there is an increase in IFN-γ, but there is a decrease in IDO1 expression and activity, effects possibly mediated by HIF-1α. The low activity of IDO1 during hypoxia favors angiogenesis in BC.Dois fenômenos são determinantes para o desenvolvimento e progressão do câncer de bexiga (CB), a angiogênese e o escape imunológico, os quais se relacionam por meio de moléculas-chave especialmente induzidas em ambiente hipóxico controlado por HIF1alfa. A indoleamina 2,3-dioxigenase-1 (IDO1) é uma enzima imunomoduladora induzida por interferon-gama (IFNγ) que tem sido relacionada à angiogênese em algumas neoplasias. É possível que sua atividade seja modulada durante a hipóxia, repercutindo na inflamação local e na produção de novos vasos. O objetivo do estudo foi verificar se a situação de hipóxia com alteração de HIF-1α altera a expressão de IFNγ e IDO1 e se a atividade da IDO1 influencia a angiogênese no CB. Em uma fase in vitro, células T24 foram submetidas à diferentes tempos de hipóxia com e sem recuperação da oxigenação. Foi usado também o CoCl2 como estabilizador de HIF-1alfa sem hipóxia. HIF-1α, VEGF-A, IFN-γ e IDO1 foram analisados por ELISA ou qRT-PCR, e a atividade da IDO1 por meio da mensuração de L-quinurenina (HPLC). Em outra fase, células HUVEC foram incubadas com alta concentração de L-quinurenina e/ou com baixa concentração de triptofano para análise de tubos vasculares. Na fase in vivo, animais portadores de CB foram tratados com 1-metil-triptofano (inibidor da IDO1) para avaliação de angiogênese (imunohistoquímica para CD31). Como resultados, a hipóxia aumentou IFN-γ, enquanto a expressão e atividade de IDO diminuiu significativamente. A queda da expressão de IDO1 correlacionou-se negativamente com a expressão de VEGF-A. A simulação de um ambiente com alta concentração de L-quinurenina e baixa de triptofano diminuiu a formação de tubos vasculares. Em modelo animal, a inibição de IDO1 aumentou a formação de vasos sanguíneos. Como conclusão, em CB, durante a hipóxia há aumento de IFN-γ, porém há uma queda na expressão e atividade da IDO1, efeitos possivelmente mediados pelo HIF-1alfa. A baixa atividade da IDO1 durante a hipóxia favorece a angiogênese no CB.Submitted by Nadir Basilio (nadirsb@uninove.br) on 2024-04-08T19:04:50Z No. of bitstreams: 1 Aline da Silva.pdf: 1058577 bytes, checksum: 4de06b1d2674f0ed8d3272c63d448859 (MD5)Made available in DSpace on 2024-04-08T19:04:50Z (GMT). No. of bitstreams: 1 Aline da Silva.pdf: 1058577 bytes, checksum: 4de06b1d2674f0ed8d3272c63d448859 (MD5) Previous issue date: 2021-12-10application/pdfporUniversidade Nove de JulhoPrograma de Mestrado em MedicinaUNINOVEBrasilSaúdeangiogêneseIDOcâncer de bexigahipóxiaVEGFangiogenesisIDObladder cancerhypoxiaVEGFCIENCIAS DA SAUDEInfluência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexigaInfluence of tryptophan catabolism by indoleamine 2,3-dioxygenase on hypoxic angiogenesis induction in bladder cancerinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis8765449414823306929600info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da Uninoveinstname:Universidade Nove de Julho (UNINOVE)instacron:UNINOVEORIGINALAline da Silva.pdfAline da Silva.pdfapplication/pdf1058577http://localhost:8080/tede/bitstream/tede/3306/2/Aline+da+Silva.pdf4de06b1d2674f0ed8d3272c63d448859MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82165http://localhost:8080/tede/bitstream/tede/3306/1/license.txtbd3efa91386c1718a7f26a329fdcb468MD51tede/33062024-04-08 16:04:50.354oai:localhost: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Biblioteca Digital de Teses e Dissertaçõeshttp://bibliotecatede.uninove.br/PRIhttp://bibliotecatede.uninove.br/oai/requestbibliotecatede@uninove.br||bibliotecatede@uninove.bropendoar:2024-04-08T19:04:50Biblioteca Digital de Teses e Dissertações da Uninove - Universidade Nove de Julho (UNINOVE)false |
dc.title.por.fl_str_mv |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
dc.title.alternative.eng.fl_str_mv |
Influence of tryptophan catabolism by indoleamine 2,3-dioxygenase on hypoxic angiogenesis induction in bladder cancer |
title |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
spellingShingle |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga Silva, Aline da angiogênese IDO câncer de bexiga hipóxia VEGF angiogenesis IDO bladder cancer hypoxia VEGF CIENCIAS DA SAUDE |
title_short |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
title_full |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
title_fullStr |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
title_full_unstemmed |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
title_sort |
Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga |
author |
Silva, Aline da |
author_facet |
Silva, Aline da |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Dellê, Humberto |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/7435662740477057 |
dc.contributor.referee1.fl_str_mv |
Dellê, Humberto |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/7435662740477057 |
dc.contributor.referee2.fl_str_mv |
Dalboni, Maria Aparecida |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/9818040147487320 |
dc.contributor.referee3.fl_str_mv |
Rodrigues, Maria Fernanda Setúbal Destro |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/7153553682954852 |
dc.contributor.referee4.fl_str_mv |
Moreno, Ana Carolina Ramos |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/3582028585601108 |
dc.contributor.author.fl_str_mv |
Silva, Aline da |
contributor_str_mv |
Dellê, Humberto Dellê, Humberto Dalboni, Maria Aparecida Rodrigues, Maria Fernanda Setúbal Destro Moreno, Ana Carolina Ramos |
dc.subject.por.fl_str_mv |
angiogênese IDO câncer de bexiga hipóxia VEGF |
topic |
angiogênese IDO câncer de bexiga hipóxia VEGF angiogenesis IDO bladder cancer hypoxia VEGF CIENCIAS DA SAUDE |
dc.subject.eng.fl_str_mv |
angiogenesis IDO bladder cancer hypoxia VEGF |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE |
description |
Two processes are crucial for the development and progression of bladder cancer (BC), angiogenesis and immune escape, which are related through key molecules specially induced in a hypoxic environment controlled by HIF-1 α. Indoleamine 2,3-dioxygenase-1 (IDO1) is an immunomodulating enzyme induced by interferon-gamma (IFN-γ ) that has been linked to angiogenesis in some neoplasms. It is possible that its activity is modulated during hypoxia, affecting local inflammation and the production of new vessels. The aim of the study was to verify whether the situation of hypoxia with alteration of HIF1α alters the expression of IFN-γ and IDO1 and whether the activity of IDO1 influences angiogenesis in BC. In an in vitro phase, T24 cells were subjected to different times of hypoxia with and without oxygen recovery. CoCl2 was also used as a stabilizer for HIF-1 α without hypoxia. HIF-1α, VEGF-A, IFN-γ and IDO1 were analyzed by ELISA or qRT-PCR, and IDO1 activity by Lkynurenine measurement (HPLC). In another phase, HUVEC cells were incubated with a high concentration of L-kynurenine and/or with a low concentration of tryptophan for analysis of vascular tubes. In the in vivo phase, CB-bearing animals were treated with 1-methyl-tryptophan (IDO1 inhibitor) to assess angiogenesis (CD31 immunohistochemistry). As a result, hypoxia increased IFN-γ, while IDO expression and activity significantly decreased. The decrease in IDO1 expression correlated negatively with VEGF-A expression. The simulation of an environment with a high concentration of L-kynurenine and a low concentration of tryptophan decreased the formation of vascular tubes. In an animal model, IDO1 inhibition increased blood vessel formation. In conclusion, in BC, during hypoxia there is an increase in IFN-γ, but there is a decrease in IDO1 expression and activity, effects possibly mediated by HIF-1α. The low activity of IDO1 during hypoxia favors angiogenesis in BC. |
publishDate |
2021 |
dc.date.issued.fl_str_mv |
2021-12-10 |
dc.date.accessioned.fl_str_mv |
2024-04-08T19:04:50Z |
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dc.identifier.citation.fl_str_mv |
Silva, Aline da. Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga. 2021. 77 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo. |
dc.identifier.uri.fl_str_mv |
http://bibliotecatede.uninove.br/handle/tede/3306 |
identifier_str_mv |
Silva, Aline da. Influência do catabolismo do triptofano via indoleamina 2,3-dioxigenase sobre a indução da angiogênese por hipóxia no câncer de bexiga. 2021. 77 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo. |
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http://bibliotecatede.uninove.br/handle/tede/3306 |
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