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Biochim Biophys Acta Mol Cell Res ; 1866(3): 317-328, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30529222


Retinoic acid (RA) promotes differentiation in multiple neurogenic cell types by promoting gene reprogramming through retinoid receptors and also by inducing cytosolic signaling events. The nuclear RXR receptors are one of the main mediators of RA cellular effects, classically by joining the direct receptors of RA, the nuclear RAR receptors, in RAR/RXR dimers which act as transcription factors. Distinct RXR genes lead to RXRα, RXRß and RXRγ subtypes, but their specific roles in neuronal differentiation remain unclear. We firstly investigated both RXRs and RARs expression profiles during RA-mediated neuronal differentiation of human neuroblastoma cell line SH-SY5Y, and found varying levels of retinoid receptors transcript and protein contents along the process. In order to understand the roles of the expression of distinct RXR subtypes to RA signal transduction, we performed siRNA-mediated silencing of RXRα and RXRß during the first stages of SH-SY5Y differentiation. Our results showed that RXRα is required for RA-induced neuronal differentiation of SH-SY5Y cells, since its silencing compromised cell cycle arrest and prevented the upregulation of neuronal markers and the adoption of neuronal morphology. Besides, silencing of RXRα affected the phosphorylation of ERK1/2. By contrast, silencing of RXRß improved neurite extension and led to increased expression of tau and synaptophysin, suggesting that RXRß may negatively regulate neuronal parameters related to neurite outgrowth and function. Our results indicate distinct functions for RXR subtypes during RA-dependent neuronal differentiation and reveal new perspectives for studying such receptors as clinical targets in therapies aiming at restoring neuronal function.

Neuritos/metabolismo , Receptor X Retinoide alfa/fisiologia , Receptor X Retinoide beta/fisiologia , Animais , Pontos de Checagem do Ciclo Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Neuroblastoma/genética , Neuroblastoma/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/genética , Receptores do Ácido Retinoico/metabolismo , Receptores do Ácido Retinoico/fisiologia , Receptor X Retinoide alfa/metabolismo , Receptor X Retinoide beta/metabolismo , Receptores X Retinoide , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional , Tretinoína/metabolismo , Tretinoína/farmacologia , Células Tumorais Cultivadas
J Biochem ; 163(6): 515-523, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29365096


The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor, which activation amplifies and perpetuates inflammatory reactions. RAGE activation also strongly stimulates the production of reactive oxygen species, leading an imbalance of redox cellular state. The extent of liver damage caused by inflammation is crucial to the systemic response during proinflammatory episodes. To investigate the role of RAGE in liver damage caused by systemic inflammation, we evaluated the effect of RAGE blocking in oxidative stress parameters induced by systemic lipopolysaccharide (LPS) injection. Wistar rats received an intraperitoneal injection of RAGE antibody (50 mg/kg), 1 h prior intraperitoneal injection of LPS (5 mg/kg). Twenty-four hours later, the liver was isolated for analysis. The LPS-induced effect in protein oxidative damage, mitochondrial complex II activity, catalase activity, signal transducer and activator of transcription 3 phosphorylation and caspase 3 activation was prevented by prior treatment with RAGE antibody. However, RAGE blocking was not able to inhibit reactive oxygen species production and the impairment in non-enzymatic antioxidant capacity induced by LPS. The present results indicate that RAGE is an important mediator of liver oxidative damage induced by an acute systemic injection of LPS, although other mechanisms may also be responsible for liver function impairment during inflammation.

Anticorpos/imunologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Fígado/metabolismo , Estresse Oxidativo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/imunologia , Animais , Anticorpos/administração & dosagem , Anticorpos/farmacologia , Inflamação/imunologia , Inflamação/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo
Brain Behav Immun ; 62: 124-136, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28088642


Systemic inflammation induces transient or permanent dysfunction in the brain by exposing it to soluble inflammatory mediators. The receptor for advanced glycation endproducts (RAGE) binds to distinct ligands mediating and increasing inflammatory processes. In this study we used an LPS-induced systemic inflammation model in rats to investigate the effect of blocking RAGE in serum, liver, cerebrospinal fluid (CSF) and brain (striatum, prefrontal cortex, ventral tegmental area and substantia nigra). Intraperitoneal injection of RAGE antibody (50µg/kg) was followed after 1h by a single LPS (5mg/kg) intraperitoneal injection. Twenty-four hours later, tissues were isolated for analysis. RAGE antibody reduced LPS-induced inflammatory effects in both serum and liver; the levels of proinflammatory cytokines (TNF-α, IL-1ß) were decreased and the phosphorylation/activation of RAGE downstream targets (ERK1/2, IκB and p65) in liver were significantly attenuated. RAGE antibody prevented LPS-induced effects on TNF-α and IL-1ß in CSF. In striatum, RAGE antibody inhibited increases in IL-1ß, Iba-1, GFAP, phospho-ERK1/2 and phospho-tau (ser202), as well as the decrease in synaptophysin levels. These effects were caused by systemic RAGE inhibition, as RAGE antibody did not cross the blood-brain barrier. RAGE antibody also prevented striatal lipoperoxidation and activation of mitochondrial complex II. In conclusion, blockade of RAGE is able to inhibit inflammatory responses induced by LPS in serum, liver, CSF and brain.

Anticorpos/farmacologia , Corpo Estriado/efeitos dos fármacos , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/imunologia , Animais , Anticorpos/uso terapêutico , Corpo Estriado/metabolismo , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo