Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Nat Chem Biol ; 15(5): 453-462, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30911178

RESUMO

Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184-an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL)-as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog. We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.


Assuntos
Benzodioxóis/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Endocanabinoides/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Longevidade/efeitos dos fármacos , Monoacilglicerol Lipases/antagonistas & inibidores , Piperidinas/farmacologia , Animais , Benzodioxóis/química , Caenorhabditis elegans/metabolismo , Endocanabinoides/metabolismo , Inibidores Enzimáticos/química , Estrutura Molecular , Monoacilglicerol Lipases/metabolismo , Piperidinas/química
2.
J Vis Exp ; (204)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38465935

RESUMO

Feeding is an essential biological process for an organism's growth, reproduction, and survival. This assay aims to measure the food intake of Caenorhabditis elegans (C. elegans), an important parameter when studying the genetics of aging or metabolism. In most species, feeding is determined by measuring the difference between the amount of food provided and the amount left after a given time interval. The method presented here uses the same strategy to determine the feeding of C. elegans. It measures the amount of bacteria, the food source of C. elegans, cleared within 72 h. This method uses 96-well microtiter plates and has allowed the screening of hundreds of drugs for their ability to modulate food intake at a speed and depth not possible in other animal models. The strength of this assay is that it allows to measure feeding and lifespan simultaneously and directly measures the disappearance of food and, thus, is based on the same principles used for other organisms, facilitating species-to-species comparison.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Envelhecimento , Longevidade , Bactérias/metabolismo , Ingestão de Alimentos
3.
Nat Commun ; 9(1): 5272, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30532051

RESUMO

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Ingestão de Alimentos/genética , Hiperfagia/genética , Animais , Antipsicóticos/toxicidade , Fator de Ligação a CCAAT/genética , Quimioterapia Adjuvante , Proteínas de Ligação a DNA/genética , Ingestão de Alimentos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Hiperfagia/induzido quimicamente , Hiperfagia/tratamento farmacológico , Hipotálamo/metabolismo , Camundongos , Fenótipo , Fatores de Transcrição/genética , Vemurafenib/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA