Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/205756 |
Resumo: | Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPHinduced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < −1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability. |
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Silva, Bruna Santos daLeffa, Douglas TeixeiraSilva, Walter Orlando Beys daTorres, Iraci Lucena da SilvaRovaris, Diego LuizVictor, Marcelo MoraesRohde, Luis Augusto PaimMota, Nina RothOliveira, Carla deOliveira, Markus BergerYates, Jonh R.Sabnis, RenukaPeña, Ramón DíazCampos, Alexandre RosaGrevet, Eugenio HorácioSanti, LucéliaBau, Claiton Henrique DottoContini, Veronica2020-02-13T04:21:20Z20192158-3188http://hdl.handle.net/10183/205756001109544Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPHinduced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < −1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.application/pdfengTranslational psychiatry. New York. Vol. 9, no. 1 (Nov. 2019), 308, 13 p.MetilfenidatoTranstorno do déficit de atenção com hiperatividadeProteômicaIntegrative proteomics and pharmacogenomics analysis of methylphenidate treatment responseEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001109544.pdf.txt001109544.pdf.txtExtracted Texttext/plain61097http://www.lume.ufrgs.br/bitstream/10183/205756/2/001109544.pdf.txtb17510a8e307c542728e75cd15dde714MD52ORIGINAL001109544.pdfTexto completo (inglês)application/pdf939546http://www.lume.ufrgs.br/bitstream/10183/205756/1/001109544.pdf7a655cc2898054ed7f6c0d7dc9dc8dd3MD5110183/2057562020-12-13 05:11:35.319522oai:www.lume.ufrgs.br:10183/205756Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2020-12-13T07:11:35Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
title |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
spellingShingle |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response Silva, Bruna Santos da Metilfenidato Transtorno do déficit de atenção com hiperatividade Proteômica |
title_short |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
title_full |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
title_fullStr |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
title_full_unstemmed |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
title_sort |
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response |
author |
Silva, Bruna Santos da |
author_facet |
Silva, Bruna Santos da Leffa, Douglas Teixeira Silva, Walter Orlando Beys da Torres, Iraci Lucena da Silva Rovaris, Diego Luiz Victor, Marcelo Moraes Rohde, Luis Augusto Paim Mota, Nina Roth Oliveira, Carla de Oliveira, Markus Berger Yates, Jonh R. Sabnis, Renuka Peña, Ramón Díaz Campos, Alexandre Rosa Grevet, Eugenio Horácio Santi, Lucélia Bau, Claiton Henrique Dotto Contini, Veronica |
author_role |
author |
author2 |
Leffa, Douglas Teixeira Silva, Walter Orlando Beys da Torres, Iraci Lucena da Silva Rovaris, Diego Luiz Victor, Marcelo Moraes Rohde, Luis Augusto Paim Mota, Nina Roth Oliveira, Carla de Oliveira, Markus Berger Yates, Jonh R. Sabnis, Renuka Peña, Ramón Díaz Campos, Alexandre Rosa Grevet, Eugenio Horácio Santi, Lucélia Bau, Claiton Henrique Dotto Contini, Veronica |
author2_role |
author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Silva, Bruna Santos da Leffa, Douglas Teixeira Silva, Walter Orlando Beys da Torres, Iraci Lucena da Silva Rovaris, Diego Luiz Victor, Marcelo Moraes Rohde, Luis Augusto Paim Mota, Nina Roth Oliveira, Carla de Oliveira, Markus Berger Yates, Jonh R. Sabnis, Renuka Peña, Ramón Díaz Campos, Alexandre Rosa Grevet, Eugenio Horácio Santi, Lucélia Bau, Claiton Henrique Dotto Contini, Veronica |
dc.subject.por.fl_str_mv |
Metilfenidato Transtorno do déficit de atenção com hiperatividade Proteômica |
topic |
Metilfenidato Transtorno do déficit de atenção com hiperatividade Proteômica |
description |
Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPHinduced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < −1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019 |
dc.date.accessioned.fl_str_mv |
2020-02-13T04:21:20Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10183/205756 |
dc.identifier.issn.pt_BR.fl_str_mv |
2158-3188 |
dc.identifier.nrb.pt_BR.fl_str_mv |
001109544 |
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2158-3188 001109544 |
url |
http://hdl.handle.net/10183/205756 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Translational psychiatry. New York. Vol. 9, no. 1 (Nov. 2019), 308, 13 p. |
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info:eu-repo/semantics/openAccess |
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openAccess |
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