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1.
Development ; 151(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38063853

RESUMO

High-sugar diets (HSDs) often lead to obesity and type 2 diabetes, both metabolic syndromes associated with stem cell dysfunction. However, it is unclear whether excess dietary sugar affects stem cells. Here, we report that HSD impairs stem cell function in the intestine and ovaries of female Drosophila prior to the onset of insulin resistance, a hallmark of type 2 diabetes. Although 1 week of HSD leads to obesity, impaired oogenesis and altered lipid metabolism, insulin resistance does not occur. HSD increases glucose uptake by germline stem cells (GSCs) and triggers reactive oxygen species-induced JNK signaling, which reduces GSC proliferation. Removal of excess sugar from the diet reverses these HSD-induced phenomena. A similar phenomenon is found in intestinal stem cells (ISCs), except that HSD disrupts ISC maintenance and differentiation. Interestingly, tumor-like GSCs and ISCs are less responsive to HSD, which may be because of their dependence on glycolytic metabolism and high energy demand, respectively. This study suggests that excess dietary sugar induces oxidative stress and damages stem cells before insulin resistance develops, a mechanism that may also occur in higher organisms.


Assuntos
Células-Tronco Adultas , Diabetes Mellitus Tipo 2 , Proteínas de Drosophila , Resistência à Insulina , Animais , Feminino , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Açúcares da Dieta/metabolismo , Células-Tronco Adultas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Obesidade
2.
Development ; 147(2)2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941704

RESUMO

WD40 proteins control many cellular processes via protein interactions. Drosophila Wuho (Wh, a WD40 protein) controls fertility, although the involved mechanisms are unclear. Here, we show that Wh promotion of Mei-p26 (a human TRIM32 ortholog) function maintains ovarian germ cell homeostasis. Wh and Mei-p26 are epistatically linked, with wh and mei-p26 mutants showing nearly identical phenotypes, including germline stem cell (GSC) loss, stem-cyst formation due to incomplete cytokinesis between GSCs and daughter cells, and overproliferation of GSC progeny. Mechanistically, Wh interacts with Mei-p26 in different cellular contexts to induce cell type-specific effects. In GSCs, Wh and Mei-p26 promote BMP stemness signaling for proper GSC division and maintenance. In GSC progeny, Wh and Mei-p26 silence nanos translation, downregulate a subset of microRNAs involved in germ cell differentiation and suppress ribosomal biogenesis via dMyc to limit germ cell mitosis. We also found that the human ortholog of Wh (WDR4) interacts with TRIM32 in human cells. Our results show that Wh is a regulator of Mei-p26 in Drosophila germ cells and suggest that the WD40-TRIM interaction may also control tissue homeostasis in other stem cell systems.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células Germinativas/metabolismo , Homeostase , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Sequência Conservada , Drosophila melanogaster/citologia , Evolução Molecular , Feminino , Fertilidade , Células Germinativas/citologia , Meiose , MicroRNAs/genética , MicroRNAs/metabolismo , Mitose , Modelos Biológicos , Mutação/genética , Ovário/citologia , Óvulo/citologia , Óvulo/metabolismo , Fenótipo , Ligação Proteica , Ribossomos/metabolismo , Transdução de Sinais
3.
Adv Protein Chem Struct Biol ; 108: 85-103, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28427565

RESUMO

Mental disorders or mood disorders are prevalent globally irrespective of region, race, and ethnic groups. Of the types of mood disorders, major depressive disorder (MDD) and bipolar disorder (BPD) are the most prevalent forms of psychiatric condition. A number of preclinical studies emphasize the essential role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders. Additionally, BDNF is the most common growth factor in the central nervous system along with their essential role during the neural development and the synaptic elasticity. A malfunctioning of this protein is associated with many types of mood disorders. The variant methionine replaces valine at 66th position is strongly related to BPD, and an individual with a homozygous condition of this allele is at a greater risk of developing MDD. There are very sparse reports suggesting the structural changes of the protein occurring upon the mutation. Consequently, in this study, we applied a computational pipeline to understand the effects caused by the mutation on the protein's structure and function. With the use of in silico tools and computational macroscopic methods, we identified a decrease in the alpha-helix nature, and an overall increase in the random coils that could have probably resulted in deformation of the protein.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos do Humor/genética , Mutação Puntual , Sequência de Aminoácidos , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sequência Conservada , Humanos , Metionina/genética , Simulação de Dinâmica Molecular , Mapas de Interação de Proteínas , Estrutura Secundária de Proteína , Valina/genética
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