Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response

Detalhes bibliográficos
Autor(a) principal: Silva, Bruna Santos da
Data de Publicação: 2019
Outros Autores: 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
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.
id UFRGS-2_aac19fee0f27e8b42e56f45d24c3f504
oai_identifier_str oai:www.lume.ufrgs.br:10183/205756
network_acronym_str UFRGS-2
network_name_str Repositório Institucional da UFRGS
repository_id_str
spelling 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
format article
status_str 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
identifier_str_mv 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.
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Institucional da UFRGS
instname:Universidade Federal do Rio Grande do Sul (UFRGS)
instacron:UFRGS
instname_str Universidade Federal do Rio Grande do Sul (UFRGS)
instacron_str UFRGS
institution UFRGS
reponame_str Repositório Institucional da UFRGS
collection Repositório Institucional da UFRGS
bitstream.url.fl_str_mv http://www.lume.ufrgs.br/bitstream/10183/205756/2/001109544.pdf.txt
http://www.lume.ufrgs.br/bitstream/10183/205756/1/001109544.pdf
bitstream.checksum.fl_str_mv b17510a8e307c542728e75cd15dde714
7a655cc2898054ed7f6c0d7dc9dc8dd3
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
repository.name.fl_str_mv Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)
repository.mail.fl_str_mv
_version_ 1815447707790082048