Metabolic networks in aging and age-related diseases
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10773/28463 |
Resumo: | Aging is a natural physiological process, but its specific causes are not entirely understood at the molecular level. During aging, the levels of the redox cofactor Nicotinamide Adenine Dinucleotide (NAD) decrease. This molecule is essential for energy production by the cell and is also a substrate to a range of enzymes that regulate gene expression and cell survival. To gain insight into the metabolic networks of age-related disorders, we took a combined bioinformatics and molecular approach. We used text-mining methods to extract protein interaction data from 1500 PubMed abstracts containing keywords related to proteostasis, aging and age-related diseases. Protein networks were obtained with Cytoscape and were submitted to parameter-based analysis. An enrichment analysis using the cytoscape plug-in ClueGo was followed. Parameter analysis revealed APP as the most central and influential protein in the network and enrichment analysis depicted a predominance of terms related to Immune system along with Cancer and Cell Cycle regulation. As a cellular model, we have used a NAD metabolism inhibitor in SH-SY5Y neuroblastoma cells to mimic the NAD decline during aging. At different time points (8h, 24h, and 48h) we measured cell viability along with the expression levels of NAMPT and NAPRT, the rate-limiting enzymes from the NAD biosynthetic nicotinamide salvage pathway and the Preiss handler pathway respectively. Our results show a 50% decrease in cell viability at 48h along with a decrease in NAPRT protein expression. No alterations in NAMPT protein levels were recorded in any measured time point. It is possible that other NAD biosynthesis pathways are activated, so further studies intended to elucidate question are required. |
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Metabolic networks in aging and age-related diseasesNAD+NAMPTNAPRTFK866AgingAging-related diseasesProteostasisEGASCytoscapeClueGoProtein NetworksAging is a natural physiological process, but its specific causes are not entirely understood at the molecular level. During aging, the levels of the redox cofactor Nicotinamide Adenine Dinucleotide (NAD) decrease. This molecule is essential for energy production by the cell and is also a substrate to a range of enzymes that regulate gene expression and cell survival. To gain insight into the metabolic networks of age-related disorders, we took a combined bioinformatics and molecular approach. We used text-mining methods to extract protein interaction data from 1500 PubMed abstracts containing keywords related to proteostasis, aging and age-related diseases. Protein networks were obtained with Cytoscape and were submitted to parameter-based analysis. An enrichment analysis using the cytoscape plug-in ClueGo was followed. Parameter analysis revealed APP as the most central and influential protein in the network and enrichment analysis depicted a predominance of terms related to Immune system along with Cancer and Cell Cycle regulation. As a cellular model, we have used a NAD metabolism inhibitor in SH-SY5Y neuroblastoma cells to mimic the NAD decline during aging. At different time points (8h, 24h, and 48h) we measured cell viability along with the expression levels of NAMPT and NAPRT, the rate-limiting enzymes from the NAD biosynthetic nicotinamide salvage pathway and the Preiss handler pathway respectively. Our results show a 50% decrease in cell viability at 48h along with a decrease in NAPRT protein expression. No alterations in NAMPT protein levels were recorded in any measured time point. It is possible that other NAD biosynthesis pathways are activated, so further studies intended to elucidate question are required.O envelhecimento é um processo fisiológico natural, contudo as suas causas específicas não são totalmente compreendidas ao nível molecular. Durante o envelhecimento, os níveis do cofator redox Nicotinamida Adenina Dinucleotídeo (NAD+) diminuem. Esta molécula é essencial para a produção de energia por parte da célula e também é um substrato para uma variedade de enzimas que regulam a expressão genética e a sobrevivência celular. Para obter informações sobre as redes metabólicas de doenças relacionadas com o envelhecimento, adotamos uma combinação de abordagens bioinformática e molecular. Utilizamos métodos de extração de texto para extrair dados de interação proteica de 1500 resumos de artigos da PubMed contendo palavras-chave relacionadas com proteostase, envelhecimento e doenças relacionadas com o envelhecimento. As redes de proteínas foram obtidas com o Cytoscape e submetidas a uma análise baseada em parâmetros. Seguiu-se uma análise de enriquecimento usando o ClueGo um plug-in do Cytoscape. A análise de parâmetros revelou APP como a proteína mais central e influente na rede e a análise de enriquecimento retratou uma predominância de termos relacionados com o sistema imunológico, juntamente com a regulação do ciclo celular. Como modelo celular, usamos um inibidor do metabolismo do NAD+ em células de neuroblastoma SH-SY5Y para imitar o declínio do NAD+ durante o envelhecimento. Em diferentes momentos (8h, 24h, 48h e 72h), medimos a viabilidade celular juntamente com os níveis de expressão de NAMPT e NAPRT, as enzimas limitadoras de taxa das vias Salvage de Nicotinamida e Preiss-Handler, respetivamente, ambas vias de produtoras de NAD+. Os Nossos resultados mostram uma diminuição de 50% na viabilidade celular às 48h, juntamente com uma diminuição na expressão proteica de NAPRT. Não foram registadas alterações nos níveis de proteína NAMPT em nenhum momento. É possível que outras vias de biossíntese do NAD+ estejam ativas, de maneira que outros estudos com o objetivo de elucidar esta questão são necessários.2020-05-08T22:54:42Z2019-01-01T00:00:00Z2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/28463engLucas, Vasco de Almeidainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T11:55:03Zoai:ria.ua.pt:10773/28463Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:01:00.153866Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Metabolic networks in aging and age-related diseases |
title |
Metabolic networks in aging and age-related diseases |
spellingShingle |
Metabolic networks in aging and age-related diseases Lucas, Vasco de Almeida NAD+ NAMPT NAPRT FK866 Aging Aging-related diseases Proteostasis EGAS Cytoscape ClueGo Protein Networks |
title_short |
Metabolic networks in aging and age-related diseases |
title_full |
Metabolic networks in aging and age-related diseases |
title_fullStr |
Metabolic networks in aging and age-related diseases |
title_full_unstemmed |
Metabolic networks in aging and age-related diseases |
title_sort |
Metabolic networks in aging and age-related diseases |
author |
Lucas, Vasco de Almeida |
author_facet |
Lucas, Vasco de Almeida |
author_role |
author |
dc.contributor.author.fl_str_mv |
Lucas, Vasco de Almeida |
dc.subject.por.fl_str_mv |
NAD+ NAMPT NAPRT FK866 Aging Aging-related diseases Proteostasis EGAS Cytoscape ClueGo Protein Networks |
topic |
NAD+ NAMPT NAPRT FK866 Aging Aging-related diseases Proteostasis EGAS Cytoscape ClueGo Protein Networks |
description |
Aging is a natural physiological process, but its specific causes are not entirely understood at the molecular level. During aging, the levels of the redox cofactor Nicotinamide Adenine Dinucleotide (NAD) decrease. This molecule is essential for energy production by the cell and is also a substrate to a range of enzymes that regulate gene expression and cell survival. To gain insight into the metabolic networks of age-related disorders, we took a combined bioinformatics and molecular approach. We used text-mining methods to extract protein interaction data from 1500 PubMed abstracts containing keywords related to proteostasis, aging and age-related diseases. Protein networks were obtained with Cytoscape and were submitted to parameter-based analysis. An enrichment analysis using the cytoscape plug-in ClueGo was followed. Parameter analysis revealed APP as the most central and influential protein in the network and enrichment analysis depicted a predominance of terms related to Immune system along with Cancer and Cell Cycle regulation. As a cellular model, we have used a NAD metabolism inhibitor in SH-SY5Y neuroblastoma cells to mimic the NAD decline during aging. At different time points (8h, 24h, and 48h) we measured cell viability along with the expression levels of NAMPT and NAPRT, the rate-limiting enzymes from the NAD biosynthetic nicotinamide salvage pathway and the Preiss handler pathway respectively. Our results show a 50% decrease in cell viability at 48h along with a decrease in NAPRT protein expression. No alterations in NAMPT protein levels were recorded in any measured time point. It is possible that other NAD biosynthesis pathways are activated, so further studies intended to elucidate question are required. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-01-01T00:00:00Z 2019 2020-05-08T22:54:42Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10773/28463 |
url |
http://hdl.handle.net/10773/28463 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799137665433468928 |