A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases

Detalhes bibliográficos
Autor(a) principal: Silva, Nuno Valério
Data de Publicação: 2021
Outros Autores: Carregosa, Diogo, Gonçalves, Catarina, Vieira, Otília V., Nunes dos Santos, Cláudia, Jacinto, António, Crespo, Carolina Lage
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/120613
Resumo: Funding: This work was funded by the Fundação para a Ciência e a Tecnologia (FCT; PTDC/BTM-SAL/29377/2017 to CC and AJ. Zebrafish were reproduced and maintained by the CEDOC Fish Facility, supported by Congento LISBOA-01-0145- FEDER-022170, co-financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund).
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spelling A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseasesdietary cholesteroldietary phenolic acidsdrug screening and discoveryinflammation and immunityinflammatory bowel diseaseinnate immunitymyeloid cellsDevelopmental BiologyCell BiologyFunding: This work was funded by the Fundação para a Ciência e a Tecnologia (FCT; PTDC/BTM-SAL/29377/2017 to CC and AJ. Zebrafish were reproduced and maintained by the CEDOC Fish Facility, supported by Congento LISBOA-01-0145- FEDER-022170, co-financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund).Inflammatory bowel diseases (IBD) with chronic infiltration of immune cells in the gastrointestinal tract are common and largely incurable. The therapeutic targeting of IBD has been hampered by the complex causality of the disease, with environmental insults like cholesterol-enriched Western diets playing a critical role. To address this drug development challenge, we report an easy-to-handle dietary cholesterol-based in vivo assay that allows the screening of immune-modulatory therapeutics in transgenic zebrafish models. An improvement in the feeding strategy with high cholesterol diet (HCD) selectively induces a robust and consistent infiltration of myeloid cells in larvae intestines that is highly suitable for compound discovery efforts. Using transgenics with fluorescent reporter expression in neutrophils, we take advantage of the unique zebrafish larvae clarity to monitor an acute inflammatory response in a whole organism context with a fully functional innate immune system. The use of semi-automated image acquisition and processing combined with quantitative image analysis allows categorizing anti- or pro-inflammatory compounds based on a leukocytic inflammation index. Our HCD gut inflammation (HCD-GI) assay is simple, cost- and time-effective as well as highly physiological which makes it unique when compared to chemical-based zebrafish models of IBD. Besides, diet is a highly controlled, selective and targeted trigger of intestinal inflammation that avoids extra-intestinal outcomes and reduces the chances of chemical-induced toxicity during screenings. We show the validity of this assay for a screening platform by testing two dietary phenolic acids, namely gallic acid (GA; 3,4,5-trihydroxybenzoic acid) and ferulic acid (FA; 4-hydroxy-3-methoxycinnamic acid), with well described anti-inflammatory actions in animal models of IBD. Analysis of common IBD therapeutics (Prednisolone and Mesalamine) proved the fidelity of our IBD-like intestinal inflammation model. In conclusion, the HCD-GI assay can facilitate and accelerate drug discovery efforts on IBD, by identification of novel lead molecules with immune modulatory action on intestinal neutrophilic inflammation. This will serve as a jumping-off point for more profound analyses of drug mechanisms and pathways involved in early IBD immune responses.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)iNOVA4Health - pólo NMSRUNSilva, Nuno ValérioCarregosa, DiogoGonçalves, CatarinaVieira, Otília V.Nunes dos Santos, CláudiaJacinto, AntónioCrespo, Carolina Lage2021-07-06T22:18:12Z2021-06-032021-06-03T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/120613eng2296-634XPURE: 32314089https://doi.org/10.3389/fcell.2021.674749info: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:RCAAP2024-03-11T05:03:05Zoai:run.unl.pt:10362/120613Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:44:23.850532Repositório 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 A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
title A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
spellingShingle A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
Silva, Nuno Valério
dietary cholesterol
dietary phenolic acids
drug screening and discovery
inflammation and immunity
inflammatory bowel disease
innate immunity
myeloid cells
Developmental Biology
Cell Biology
title_short A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
title_full A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
title_fullStr A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
title_full_unstemmed A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
title_sort A Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases
author Silva, Nuno Valério
author_facet Silva, Nuno Valério
Carregosa, Diogo
Gonçalves, Catarina
Vieira, Otília V.
Nunes dos Santos, Cláudia
Jacinto, António
Crespo, Carolina Lage
author_role author
author2 Carregosa, Diogo
Gonçalves, Catarina
Vieira, Otília V.
Nunes dos Santos, Cláudia
Jacinto, António
Crespo, Carolina Lage
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
Centro de Estudos de Doenças Crónicas (CEDOC)
iNOVA4Health - pólo NMS
RUN
dc.contributor.author.fl_str_mv Silva, Nuno Valério
Carregosa, Diogo
Gonçalves, Catarina
Vieira, Otília V.
Nunes dos Santos, Cláudia
Jacinto, António
Crespo, Carolina Lage
dc.subject.por.fl_str_mv dietary cholesterol
dietary phenolic acids
drug screening and discovery
inflammation and immunity
inflammatory bowel disease
innate immunity
myeloid cells
Developmental Biology
Cell Biology
topic dietary cholesterol
dietary phenolic acids
drug screening and discovery
inflammation and immunity
inflammatory bowel disease
innate immunity
myeloid cells
Developmental Biology
Cell Biology
description Funding: This work was funded by the Fundação para a Ciência e a Tecnologia (FCT; PTDC/BTM-SAL/29377/2017 to CC and AJ. Zebrafish were reproduced and maintained by the CEDOC Fish Facility, supported by Congento LISBOA-01-0145- FEDER-022170, co-financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund).
publishDate 2021
dc.date.none.fl_str_mv 2021-07-06T22:18:12Z
2021-06-03
2021-06-03T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/120613
url http://hdl.handle.net/10362/120613
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2296-634X
PURE: 32314089
https://doi.org/10.3389/fcell.2021.674749
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 Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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