RESUMO
Microglial cells clear the brain of pathogens and harmful debris, including amyloid-ß (Aß) deposits that are formed during Alzheimer's disease (AD). We studied the expression of Msr1, Ager and Cd36 receptors involved in Aß uptake and expression of Cd33 protein, which is considered a risk factor in AD. The effect of silver nanoparticles (AgNPs) and cadmium telluride quantum dots (CdTeQDs) on the expression of the above receptors and Aß uptake by microglial cells was investigated. Absorption of Aß and NPs was confirmed by confocal microscopy. AgNPs, but not CdTeQDs, caused a decrease in Aß accumulation. By using a specific inhibitor-polyinosinic acid-we demonstrated that Aß and AgNPs compete for scavenger receptors. Real-time PCR showed up-regulation of Cd33 and Cd36 gene expression after treatment with CdTeQDs for 24 h. Analysis of the abundance of the receptors on the cell surface revealed that AgNP treatment significantly reduced the presence of Msr1, Cd33, Ager and Cd36 receptors (6 and 24 h), whereas CdTeQDs increased the levels of Msr1 and Cd36 (24 h). To summarize, we showed that AgNP uptake competes with Aß uptake by microglial cells and consequently can impair the removal of the aggregates. In turn, CdTeQD treatment led to the accumulation of proinflammatory Cd36 protein on the cell surface.
RESUMO
Oxidative stress, perturbations in the cellular thiol level and redox balance, affects many cellular functions, including signaling pathways. This, in turn, may cause the induction of autophagy or apoptosis. The NRF2/KEAP1 signaling pathway is the main pathway responsible for cell defense against oxidative stress and maintaining the cellular redox balance at physiological levels. The relation between NRF2/KEAP1 signaling and regulation of apoptosis and autophagy is not well understood. In this hypothesis article we discuss how KEAP1 protein and its direct interactants (such as PGAM5, prothymosin α, FAC1 (BPTF), and p62) provide a molecular foundation for a possible cross-talk between NRF2/KEAP1, apoptosis, and autophagy pathways. We present a hypothesis for how NRF2/KEAP1 may interfere with the cellular apoptosis-regulatory machinery through activation of the ASK1 kinase by a KEAP1 binding partner-PGAM5. Based on very recent experimental evidence, new hypotheses for a cross-talk between NF-κB and the NRF2/KEAP1 pathway in the context of autophagy-related "molecular hub" protein p62 are also presented. The roles of KEAP1 molecular binding partners in apoptosis regulation during carcinogenesis and in neurodegenerative diseases are also discussed.
Assuntos
Apoptose , Autofagia , Estresse Oxidativo , Transdução de Sinais/fisiologia , Compostos de Sulfidrila/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Motivos de Aminoácidos , Animais , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 5/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Oxirredução , Fosfoproteínas Fosfatases , Fosforilação , Ligação Proteica , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Sequestossoma-1 , Timosina/análogos & derivados , Timosina/genética , Timosina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , UbiquitinaçãoRESUMO
Currently used dietary recommendations and requirements are generalized. It applies to both healthy and ailing individuals. These recommendations are meant to avert leading chronic illnesses such as: type 2 diabetes mellitus, obesity, hyperlipidemia, cardiovascular diseases and hypertension. In the future it might be possible to give dietary advice tailored to every - sick and healthy - individual. Nutrigenomics and nutrigenetics are two fields derived from nutrition science and genetics. Their main goal is to elucidate the influence of interactions between genes and diet on individuals' health. This paper shows the examples of metabolic response changes according to diet and chosen gene polymorphisms. It will enable an effective prevention or management of chronic diseases by accurate diet and lifestyle matched to an individual's genetic makeup. It could be useful especially to define predisposition for type 2 diabetes mellitus in young children. It will be possible to change their diet and lifestyle so that they could avoid this chronic disease. There will also be a possibility to detect early the beginning of the illness and choose/select proper treatment. It is important because type 2 diabetes mellitus frequency is up to 90% of all cases of diabetes mellitus. It's often diagnosed too late and a lot of patients have already developed complications caused by this disease. Successful dietotherapy will also be available in such disease entities as dyslipidemias, hypertension and micro- , macronutrients and vitamins defficiences.
