Development of zebrafish chemical screens to identify new modifiers of intestinal neutrophilic inflammation (Record no. 14349)

Metadata
000 -Etiqueta do registo
campo de controlo de comprimento fixo nam a22 4500
001 - Identificador do registo
Campo de controlo 14349
100 ## - Dados Gerais de Proc.
Dados gerais de processamento 20220321 pory50
200 ## - Título
Título próprio Development of zebrafish chemical screens to identify new modifiers of intestinal neutrophilic inflammation
Primeira menção de responsabilidade Nuno Valério Santos Silva
Outras menções de responsabilidade orient. Carolina Lage Crespo, António Jacinto
210 ## - Publicação, Distribuição
Lugar da edição, distribuição, etc. Lisboa
Nome do editor, distribuidor, etc. NOVA Medical School
Data da publicação, distribuição, etc. 2022
330 ## - Sumário ou Resumo
Texto da nota Inflammatory bowel diseases (IBD) with chronic infiltration of immune cells in thegastrointestinal tract are common and largely incurable. The therapeutic targeting ofIBD has been hampered by the complex causality of the disease, with environmentalinsults like cholesterol-enriched Western diets playing a critical role. In fact, current therapies are still far from optimal and have significant side effects. This encouragedus to look for alternative approaches like the use of dietary (poly)phenols (PP). PP are known for their anti-inflammatory properties in several chronic inflammatory disordersand are associated with low or absent side effects. However, due to the systemic processing of PP, the most representative molecules that reach the tissues and circulation are low-molecular-weight PP metabolites (LMWPM). Thus, the reported beneficial effects of PP are most likely due to these bioavailable molecules. Yet, the potential for LMWPM in IBD is still unexplored; and the identification of the most potent anti-inflammatory ones can constitute a lead for novel drug development and nutraceutical applications.We developedan easy-to-handle dietary cholesterol-basedin vivoassay that allows the screening of immune-modulatory therapeutics in transgeniczebrafish (ZF) models.ZF larvaewere fed with a highcholesterol diet(HCD),selectively inducingarobust and consistent infiltration of myeloid cells in larvaeintestines that is highly suitable for compound discovery efforts. The use of transgenicswith fluorescent reporter expression in neutrophils, allowedus tomonitor an acute inflammatory response in a whole organismcontext with a fully functional innate immune system. Moreover,semi-automatedimage acquisitionandquantitative image analysis allowedto categorizeanti-or pro-inflammatory compounds based on a leukocytic inflammationindex. Our HCD gut inflammation (HCD-GI) assayis simple, cost-and time-effective aswell as highly physiological.Moreover, analysisof common IBD therapeutics (Prednisolone and Mesalamine) proved the fidelity and clinical relevance of ourIBD-like intestinal inflammation model.Therefore, we took advantage of the HCD-GI assay and implemented a discovery platform to screen a portfolio of 30 LMWPMfor their immune-modulatory properties.We found 4 LMWPM with potent anti-inflammatory properties that strongly halted HCD-induced intestinal inflammation at physiologically relevant concentrations. One, ferulic acid, has been previously reported to have protective and anti-inflammatory functions in animalmodels of IBD.Finally, we developed tools to investigate intestinal functionality under chronic inflammatory states. Specifically, we developed an assay to quantify intestinal motility and peristalsis in ZF larvae after long-term HCD exposure, and a microgavageassay that can be used to investigate the effect of promising metabolites on intestinal barrier function.In conclusion, the HCD-GI discovery platform can facilitate and accelerate drug discovery efforts on IBD, by the identification of novel lead molecules with immune modulatory action on intestinal neutrophilic inflammation. We identified 4 LMWPM with anti-inflammatory potential,whose action is ready tobe investigated in functional assays underchronic feeding settings (out of the current thesis scope). These molecules constitute highly attractive and physiologicallyrelevant strategies worth it to be explored in the future for the nutritional and pharmacological management of IBD.
606 ## - Nome comum
Koha Internal code 3731
Elemento de entrada Inflammatory Bowel Diseases
606 ## - Nome comum
Koha Internal code 22302
Elemento de entrada Intestinal Neutrophilic Inflammation
606 ## - Nome comum
Koha Internal code 30
Elemento de entrada Academic Dissertation
606 ## - Nome comum
Koha Internal code 5724
Elemento de entrada Portugal
610 ## - Termos de Indexação
Termo usado como assunto Dissertação de Mestrado
610 ## - Termos de Indexação
Termo usado como assunto Investigação Biomédica
610 ## - Termos de Indexação
Termo usado como assunto NOVA Medical School
610 ## - Termos de Indexação
Termo usado como assunto Universidade NOVA de Lisboa
610 ## - Termos de Indexação
Termo usado como assunto 2022
700 ## - Responsabilidade principal
Koha Internal Code 22303
Palavra de ordem Silva
Outra parte do nome Nuno Valério Santos
702 ## - Responsabilidade secundária
Código de função Orientador de tese
Koha Internal Code 22304
Palavra de ordem Crespo
Outra parte do nome Carolina Lage
702 ## - Responsabilidade secundária
Koha Internal Code 21465
Palavra de ordem Jacinto
Outra parte do nome António
Código de função Orientador de tese
801 ## - Fonte de origem
País Portugal
Agência NMS
Regras de catalogação RPC
856 ## - Localização e acesso electrónico
URL http://hdl.handle.net/10362/134914
090 ## - Números de controlo do sistema (Koha)
Número biblioitem do Koha (gerado automaticamente) 14349
942 ## - Elementos de entrada adicionados (Koha)
Tipo de item no Koha Documento Eletrónico
Suprimido Disponível no OPAC
Holdings
Removido (estado) Perdido (estado) Data de aquisição Identificador de recurso uniforme Origem do registo (biblioteca) (codificado) Código da organização que empresta ou é detentora (biblioteca) Localização da prateleira Código de barras Cota Tipo de circulação (não pode ser emprestado) Tipo de item e material
Disponível Disponível 2022-03-21 http://hdl.handle.net/10362/134914 Biblioteca NMS|FCM Biblioteca NMS|FCM online 20220060 RUN Normal Documento Eletrónico