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1.
Cell Death Dis ; 11(7): 578, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709881

RESUMO

APOE4 is a major risk factor for sporadic Alzheimer's disease; however, it is unclear how it exerts its pathological effects. Others and we have previously shown that autophagy is impaired in APOE4 compared to APOE3 astrocytes, and demonstrated differences in the expression of mitochondrial dynamics proteins in brains of APOE3 and APOE4 transgenic mice. Here, we investigated the effect of APOE4 expression on several aspects of mitochondrial function and network dynamics, including fusion, fission, and mitophagy, specifically in astrocytes. We found that APOE3 and APOE4 astrocytes differ in their mitochondrial dynamics, suggesting that the mitochondria of APOE4 astrocytes exhibit reduced fission and mitophagy. APOE4 astrocytes also show impaired mitochondrial function. Importantly, the autophagy inducer rapamycin enhanced mitophagy and improved mitochondrial functioning in APOE4 astrocytes. Collectively, the results demonstrate that APOE4 expression is associated with altered mitochondrial dynamics, which might lead to impaired mitochondrial function in astrocytes. This, in turn, may contribute to the pathological effects of APOE4 in Alzheimer's disease.


Assuntos
Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Dinâmica Mitocondrial , Apolipoproteína E3/metabolismo , Astrócitos/ultraestrutura , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Linhagem Celular , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Sirolimo/farmacologia , Ubiquitinação/efeitos dos fármacos
2.
J Neurotrauma ; 35(21): 2581-2590, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29495919

RESUMO

Neurotrauma causes immediate elevation of extracellular glutamate (Glu) levels, which creates excitotoxicity and facilitates inflammation, glial scar formation, and consequently neuronal death. Finding factors that reduce the inflammatory response and glial scar formation, and increase neuronal survival and neurite outgrowth, are of major importance for improving the outcome after spinal cord injury (SCI). In the present study, we evaluated a new treatment aiming to remove central nervous system (CNS) Glu into the systemic blood circulation by intravenous (IV) administration of blood Glu scavengers (BGS) such as the enzyme recombinant glutamate-oxaloacetate transaminase 1 (rGOT1) and its co-substrate. In this study we induced in mice an SCI (hemisection), and 1 h post-injury started administering BGS treatment for 5 consecutive days. The treatment reduced the expression levels of p-p38, which regulates apoptosis and increased the expression of p-Akt, which mediates cell survival. Moreover, this treatment decreased pro-inflammatory cytokine expression and microglia activation, reduced astrocytes' reactivity, and facilitated expression of radial glia markers such as Pax6 and nestin. BGS treatment increased the survival of neurons at lesion site and enabled axonal regeneration into the injury site. These effects were correlated with improved functional recovery of the left paretic hindlimb. Thus, early pharmacological intervention with BGS following SCI may be neuroprotective and create a pro-regenerative environment by modulating glia cell response. In light of our results, the availability of the method to remove excess Glu from CNS without the need to deliver drugs across the blood-brain barrier (BBB) and with minimal or no adverse effects may provide a major therapeutic asset.


Assuntos
Aspartato Aminotransferase Citoplasmática/farmacologia , Ácido Glutâmico/sangue , Ácido Glutâmico/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismos da Medula Espinal/sangue , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia
3.
Cell Death Dis ; 9(2): 47, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29352243

RESUMO

ErbB2, a member of the ErbB family of receptor tyrosine kinases, is an essential player in the cell's growth and proliferation signaling pathways. Amplification or overexpression of ErbB2 is observed in ∼30% of breast cancer patients, and often drives cellular transformation and cancer development. Recently, we have shown that ErbB2 interacts with the nuclear-cytoplasmic shuttling protein nucleolin, an interaction which enhances cell transformation in vitro, and increases mortality risk and disease progression rate in human breast cancer patients. Given these results, and since acquired resistance to anti-ErbB2-targeted therapy is a major obstacle in treatment of breast cancer, we have examined the therapeutic potential of targeting the ErbB2-nucleolin complex. The effect of the nucleolin-specific inhibitor GroA (AS1411) on ErbB2-positive breast cancer was tested in vivo, in a mouse xenograft model for breast cancer; as well as in vitro, alone and in combination with the ErbB2 kinase-inhibitor tyrphostin AG-825. Here, we show that in vivo treatment of ErbB2-positive breast tumor xenografts with GroA reduces tumor size and leads to decreased ErbB2-mediated signaling. Moreover, we found that co-treatment of breast cancer cell lines with GroA and the ErbB2 kinase-inhibitor tyrphostin AG-825 enhances the anti-cancer effects exerted by GroA alone in terms of cell viability, mortality, migration, and invasiveness. We, therefore, suggest a novel therapeutic approach, consisting of combined inhibition of ErbB2 and nucleolin, which has the potential to improve breast cancer treatment efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzotiazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Oligodesoxirribonucleotídeos/farmacologia , Fosfoproteínas/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Tirfostinas/farmacologia , Animais , Aptâmeros de Nucleotídeos , Benzotiazóis/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Oligodesoxirribonucleotídeos/administração & dosagem , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Tirfostinas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto , Nucleolina
4.
Oncotarget ; 7(40): 65320-65334, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27542246

RESUMO

ErbB2 is an important member of the ErbB family, which activates growth and proliferation signaling pathways. ErbB2 is often overexpressed in various malignancies, especially in breast cancer, and is a common target for anti-cancer drugs. Breast cancer is currently one of the leading mortality causes in women, and acquired resistance to ErbB2-targeted therapies is a major obstacle in its treatment. Thus, understanding ErbB2-mediated signaling is crucial for further development of anti-cancer therapeutics and disease treatment. Previously, we have reported that the ErbB receptors interact with the major nucleolar protein nucleolin. In addition to its function in the nucleoli of cells, nucleolin participates in various cellular processes at the cytoplasm and cell-surface. Deregulated nucleolin is frequently overexpressed on the membrane of cancer cells. Here, we show that nucleolin increases colony formation and anchorage-independent growth of ErbB2-overexpressing cells. Importantly, this enhanced tumorigenicity also occurs in human ErbB2-positive breast cancer patients; namely, nucleolin overexpression in these patients is associated with reduced patient survival rates and increased disease-risk. ErbB2-nucleolin complexes are formed endogenously in both normal and cancer cells, and their effect on tumorigenicity is mediated through activation of ErbB2 signaling. Accordingly, nucleolin inhibition reduces cell viability and ErbB2 activation in ErbB2-positive cancer cells.


Assuntos
Neoplasias da Mama/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptor ErbB-2/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Carcinogênese , Adesão Celular , Processos de Crescimento Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Terapia de Alvo Molecular , Fosfoproteínas/genética , Ligação Proteica , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genética , Receptor ErbB-2/genética , Transdução de Sinais , Análise de Sobrevida , Nucleolina
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