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1.
J Psycholinguist Res ; 51(6): 1209-1229, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35988112

RESUMO

Formalization of the semantics of generics has been considered extremely challenging for their inherent vagueness and context-dependence that hinder a single fixed truth condition. The present study suggests a way to formalize the semantics of generics by constructing flexible acceptance conditions with comparative probabilities. Findings from our in-depth psycholinguistic experiment show that two comparative probabilities-cue validity and prevalence-indeed construct the flexible acceptance conditions for generics in a systematic manner that can be applied to a diverse types of generics: Acceptability of IS_A relational generics is mostly determined by prevalence without interaction with cue validity; feature-describing generics are endorsed acceptable with high cue validity, albeit mediated by prevalence; and acceptability of feature-describing generics with low cue validity is mostly determined by prevalence irrespective of cue validity. Such systematic patterns indicate a great potential for the formalization of the semantics of generics.


Assuntos
Semântica , Humanos , Probabilidade
2.
BMC Bioinformatics ; 21(1): 29, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992184

RESUMO

BACKGROUND: Event extraction from the biomedical literature is one of the most actively researched areas in biomedical text mining and natural language processing. However, most approaches have focused on events within single sentence boundaries, and have thus paid much less attention to events spanning multiple sentences. The Bacteria-Biotope event (BB-event) subtask presented in BioNLP Shared Task 2016 is one such example; a significant amount of relations between bacteria and biotope span more than one sentence, but existing systems have treated them as false negatives because labeled data is not sufficiently large enough to model a complex reasoning process using supervised learning frameworks. RESULTS: We present an unsupervised method for inferring cross-sentence events by propagating intra-sentence information to adjacent sentences using context trigger expressions that strongly signal the implicit presence of entities of interest. Such expressions can be collected from a large amount of unlabeled plain text based on simple syntactic constraints, helping to overcome the limitation of relying only on a small number of training examples available. The experimental results demonstrate that our unsupervised system extracts cross-sentence events quite well and outperforms all the state-of-the-art supervised systems when combined with existing methods for intra-sentence event extraction. Moreover, our system is also found effective at detecting long-distance intra-sentence events, compared favorably with existing high-dimensional models such as deep neural networks, without any supervised learning techniques. CONCLUSIONS: Our linguistically motivated inference model is shown to be effective at detecting implicit events that have not been covered by previous work, without relying on training data or curated knowledge bases. Moreover, it also helps to boost the performance of existing systems by allowing them to detect additional cross-sentence events. We believe that the proposed model offers an effective way to infer implicit information beyond sentence boundaries, especially when human-annotated data is not sufficient enough to train a robust supervised system.


Assuntos
Mineração de Dados/métodos , Bactérias , Processamento de Linguagem Natural , Publicações
3.
J Korean Med Sci ; 28(3): 366-73, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23487582

RESUMO

In this study, we explored the potentiality of human arginine decarboxylase (ADC) to enhance the survival of mesenchymal stem cells (MSCs) against unfavorable milieu of host tissues as the low survival of MSCs is the issue in cell transplantation therapy. To address this, human MSCs overexpressing human ADC were treated with H2O2 and the resultant intracellular events were examined. First, we examined whether human ADC is overexpressed in human MSCs. Then, we investigated cell survival or death related events. We found that the overexpression of human ADC increases formazan production and reduces caspase 3 activation and the numbers of FITC, hoechst, or propidium iodide positive cells in human MSCs exposed to H2O2. To elucidate the factors underlying these phenomena, AKT, CREB, and BDNF were examined. We found that the overexpression of human ADC phosphorylates AKT and CREB and increases BDNF level in human MSCs exposed to H2O2. The changes of these proteins are possibly relevant to the elevation of agmatine. Collectively, our data demonstrate that the overexpression of human ADC stimulates pro-survival factors to protect human MSCs against H2O2 toxicity. In conclusion, the present findings support that ADC can enhance the survival of MSCs against hostile environment of host tissues.


Assuntos
Apoptose/efeitos dos fármacos , Carboxiliases/metabolismo , Peróxido de Hidrogênio/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carboxiliases/genética , Caspase 3/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
J Toxicol Environ Health A ; 71(4): 289-99, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18253895

RESUMO

The herbicide paraquat is a suspected etiologic factor in the development of Parkinson's disease (PD). Paraquat was therefore used to reproduce Parkinsonian syndromes in lab animals, in which it produces dopaminergic pathogenesis. However, the factors or mechanisms by which paraquat kills dopaminergic neurons are not fully understood. Based on reported evidence that paraquat increases p53 protein levels and inhibits mitochondrial function, it was hypothesized that paraquat induces cell death in dopaminergic neurons through a mechanism in which p53 and mitochondrial apoptotic pathway are linked. To explore this possibility, dopaminergic SY5Y cells were treated with paraquat for 48 h and p53 responses were investigated, as well as biomarkers of the mitochondrial intrinsic pathway of apoptosis. Paraquat significantly increased protein levels of p53 and one of its target genes, Bax. By 24 h, paraquat decreased mitochondrial complex I activity and mitochondrial transmembrane potential and induced the release of cytochrome c from mitochondria. In addition, paraquat increased the activities of caspases 9 and 3. Finally, nuclear condensation and DNA fragmentation occurred 48 h after treatment. The decrease of mitochondrial functions, the release of cytochrome c, the increase of caspase 9 and 3 activities, and DNA damage that were produced by paraquat were inhibited by a specific p53 inhibitor, pifithrin-alpha. These findings support the conclusion that paraquat produced apoptosis in SY5Y cells through the mitochondrial intrinsic pathway associated with p53.


Assuntos
Herbicidas/toxicidade , Mitocôndrias/efeitos dos fármacos , Paraquat/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Dano ao DNA , Humanos , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/fisiologia , Proteína X Associada a bcl-2/metabolismo
5.
J Toxicol Environ Health A ; 70(21): 1849-57, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17934957

RESUMO

Paraquat (PQ) is suspected to be an environmental risk factor for Parkinson's disease (PD). A strong correlation between exposure to paraquat and the occurrence of PD was reported in Canada, Taiwan, and the United States. This correlation is supported by in vivo work showing that paraquat produces dopaminergic pathogenesis. In particular, paraquat forms abnormal protein aggregates in dopaminergic neurons of mice. However, it is not clear how paraquat produces this pathology. Given that proteasome dysfunction induces aberrant protein aggregation, it was hypothesized that paraquat induces proteasome dysfunction. To explore this possibility, proteasome activity and some factors possibly contributing to proteasome dysfunction were investigated in dopaminergic SY5Y cells treated with paraquat. Furthermore, levels of alpha-synuclein and ubiquitin-conjugated proteins were measured to test whether paraquat induces protein accumulation in SY5Y cells. Results showed that at a concentration of paraquat that reduced viability by about 60% at 48 h (0.5 mM) loss of proteasome activity occurred. In addition, the cells showed decreased ATP levels and reduced mitochondrial complex V activity. These changes were significant 24 h after treatment with paraquat. Furthermore, paraquat-treated cells showed decreased protein levels of proteasome 19S subunits, but not 20S alpha or beta subunits, suggesting that the effects observed were not the result of general cytotoxicity. Paraquat also increased levels of alpha-synuclein and ubiquitinated proteins, suggesting that paraquat-induced proteasome dysfunction leads to aberrant protein accumulation. Taken together, these findings support the hypothesis that paraquat impairs proteasome function in SY5Y cells.


Assuntos
Herbicidas/toxicidade , L-Lactato Desidrogenase/efeitos dos fármacos , Paraquat/toxicidade , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroblastoma/enzimologia , Neuroblastoma/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Células Tumorais Cultivadas
6.
Nat Commun ; 7: 13129, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27779191

RESUMO

X-linked adrenoleukodystrophy (X-ALD), caused by an ABCD1 mutation, is a progressive neurodegenerative disorder associated with the accumulation of very long-chain fatty acids (VLCFA). Cerebral inflammatory demyelination is the major feature of childhood cerebral ALD (CCALD), the most severe form of ALD, but its underlying mechanism remains poorly understood. Here, we identify the aberrant production of cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol (25-HC) in the cellular context of CCALD based on the analysis of ALD patient-derived induced pluripotent stem cells and ex vivo fibroblasts. Intriguingly, 25-HC, but not VLCFA, promotes robust NLRP3 inflammasome assembly and activation via potassium efflux-, mitochondrial reactive oxygen species (ROS)- and liver X receptor (LXR)-mediated pathways. Furthermore, stereotaxic injection of 25-HC into the corpus callosum of mouse brains induces microglial recruitment, interleukin-1ß production, and oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner. Collectively, our results indicate that 25-HC mediates the neuroinflammation of X-ALD via activation of the NLRP3 inflammasome.


Assuntos
Adrenoleucodistrofia/metabolismo , Corpo Caloso/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adrenoleucodistrofia/induzido quimicamente , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/patologia , Animais , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Expressão Gênica , Hidroxicolesteróis/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Inflamassomos/metabolismo , Inflamação , Injeções Intraventriculares , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/agonistas , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Técnicas Estereotáxicas , Esteroide Hidroxilases/deficiência , Esteroide Hidroxilases/genética , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismo , Substância Branca/patologia
7.
J Toxicol Environ Health A ; 68(22): 1939-61, 2005 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-16263688

RESUMO

Paraquat (PQ) is a cationic nonselective bipyridyl herbicide widely used to control weeds and grasses in agriculture. Epidemiologic studies indicate that exposure to pesticides can be a risk factor in the incidence of Parkinson's disease (PD). A strong correlation has been reported between exposure to paraquat and PD incidence in Canada, Taiwan, and the United States. This correlation is supported by animal studies showing that paraquat produces toxicity in dopaminergic neurons of the rat and mouse brain. However, it is unclear how paraquat triggers toxicity in dopaminergic neurons. Based on the prooxidant properties of paraquat, it was hypothesized that paraquat may induce oxidative stress-mediated toxicity in dopaminergic neurons. To explore this possibility, dopaminergic SH-SY5Y cells were treated with paraquat, and several biomarkers of oxidativestress were measured. First, a specific dopamine transporter inhibitor GBR12909 significantly protected SY5Y cells against the toxicity of paraquat, indicating that paraquat exerts its toxicity by a mechanism involving the dopamine transporter (DAT). Second, paraquat increased intracellular levels of reactive oxygen species (ROS), but decreased the levels of glutathione. Third, paraquat inhibited glutathione peroxidase activity, but did not affect glutathione reductase activity. On the other hand, paraquat increased GST activity by 24 h, after which GST activity returned to the control value at 48 h. Fourth, paraquat dissipated mitochondrial transmembrane potential (MTP). Fifth, paraquat produced increases of malondialdehyde (MDA) and protein carbonyls, as well as DNA fragmentation, indicating oxidative damage to major cellular components. Sixth, paraquat increased the protein level of heme oxygenase-1 (HO-1). Taken together, these findings verify our hypothesis that paraquat produces oxidative stress-mediated toxicity in SH-SY5Y cells. Thus, current findings suggest that paraquat may induce the pathogenesis of dopaminergic neurons through oxidative stress.


Assuntos
Herbicidas/toxicidade , Estresse Oxidativo , Paraquat/toxicidade , Receptores Dopaminérgicos/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Herbicidas/farmacologia , Humanos , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/fisiologia , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/fisiologia , Neuroblastoma/patologia , Neurônios , Paraquat/farmacologia , Doença de Parkinson/fisiopatologia , Espécies Reativas de Oxigênio , Receptores Dopaminérgicos/efeitos dos fármacos , Células Tumorais Cultivadas/patologia
8.
Stem Cell Rev Rep ; 10(6): 761-71, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24974101

RESUMO

Recently, cell-based therapy has been highlighted as an alternative to treating ischemic brain damage in stroke patients. The present study addresses the therapeutic potential of polysialic acid-neural cell adhesion molecule (PSA-NCAM)-positive neural precursor cells (NPC(PSA-NCAM+)) derived from human embryonic stem cells (hESCs) in a rat stroke model with permanent middle cerebral artery occlusion. Data showed that rats transplanted with NPC(PSA-NCAM+) are superior to those treated with phosphate buffered saline (PBS) or mesenchymal stem cells (MSCs) in behavioral performance throughout time points. In order to investigate its underlying events, immunohistochemical analysis was performed on rat ischemic brains treated with PBS, MSCs, and NPC(PSA-NCAM+). Unlike MSCs, NPC(PSA-NCAM+) demonstrated a potent immunoreactivity against human specific nuclei, doublecortin, and Tuj1 at day 26 post-transplantation, implying their survival, differentiation, and integration in the host brain. Significantly, NPC(PSA-NCAM+) evidently lowered the positivity of microglial ED-1 and astrocytic GFAP, suggesting a suppression of adverse glial activation in the host brain. In addition, NPC(PSA-NCAM+) elevated α-SMA(+) immunoreactivity and the expression of angiopoietin-1 indicating angiogenic stimulation in the host brain. Taken together, the current data demonstrate that transplanted NPC(PSA-NCAM+) preserve brain tissue with reduced infarct size and improve behavioral performance through actions encompassing anti-reactive glial activation and pro-angiogenic activity in a rat stroke model. In conclusion, the present findings support the potentiality of NPC(PSA-NCAM+) as the promising source in the development of cell-based therapy for neurological diseases including ischemic stroke.


Assuntos
Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/fisiologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Ácidos Siálicos/farmacologia , Acidente Vascular Cerebral/terapia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Proteína Duplacortina , Células-Tronco Embrionárias/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo
9.
Yonsei Med J ; 55(3): 689-99, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24719136

RESUMO

PURPOSE: Alzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. MATERIALS AND METHODS: We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 µL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. RESULTS: Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group. CONCLUSION: Our results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD.


Assuntos
Agmatina/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Estreptozocina/toxicidade , Animais , Modelos Animais de Doenças , Masculino , Ratos
10.
Toxicol Lett ; 199(3): 239-46, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20851755

RESUMO

Paraquat produces dopaminergic pathologies of Parkinson's disease, in which cyclooxygenase-2 (COX-2) is implicated. However, it is unclear whether paraquat induces toxicity within dopaminergic neurons through COX-2. To address this, human neuroblastoma SH-SY5Y cells were treated with paraquat and then the involving mechanism of COX-2 was investigated. We initially examined the involvement of COX-2 in paraquat-induced toxicity. Data suggest that COX-2 is implicated in paraquat-induced reduction of viability in SY5Y cells. Then, to confirm the presence of COX-2 in SY5Y cells, we examined COX-2 mRNA and protein levels, which are regulated by NF-κB. Data indicate that paraquat activates NF-κB and up-regulates COX-2. We then checked quinone-bound proteins as quinones produced by COX-2 bind to intracellular proteins. Paraquat obviously forms quinone-bound proteins, in particular, quinone-bound DJ-1 and this formation is attenuated by meloxicam. Finally, we investigated antioxidant system including nuclear factor erythroid-related factor 2 (Nrf2), gamma glutamylcysteine synthetase (γGCS), and glutathione (GSH) as DJ-1 is linked to Nrf2 and Nrf2 regulates γGCS expression and γGCS is a GSH synthesis enzyme. Paraquat decreases protein levels of Nrf2 and γGCS and intracellular GSH level and these decreases are alleviated by meloxicam. Therefore, collectively, our data indicate that paraquat induces COX-2 implicated toxicity in SY5Y cells. In conclusion, current findings support the idea that paraquat might produce toxicity in dopaminergic neurons through COX-2.


Assuntos
Ciclo-Oxigenase 2/fisiologia , Herbicidas/toxicidade , Paraquat/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa/análise , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , L-Lactato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/patologia , Proteínas Oncogênicas/análise , Proteínas Oncogênicas/metabolismo , Proteína Desglicase DJ-1 , Quinonas/metabolismo
11.
Toxicol Lett ; 191(2-3): 203-10, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19735704

RESUMO

Epidemiologic and laboratory studies suggest that paraquat can be an environmental etiologic factor in Parkinson's disease (PD). One mechanism by which paraquat may mediate cell death of dopaminergic neurons is by inducing endoplasmic reticulum (ER) stress, as suggested in a recent report. In this study, we further investigated this linkage by examining ER stress cascades. To this aim, human neuroblastoma cells (SH-SY5Y cells) were treated with paraquat and the signaling cascades through which ER stress results in apoptosis were examined. Then, it was examined whether ER stress is produced by paraquat. Paraquat increased ER stress biomarker proteins, glucose-regulated protein 78 (GRP78), ER degradation-enhancing alpha-mannosidae-like protein (EDEM), and C/EBP homologous protein (CHOP). Then, it was investigated which ER stress cascades are affected by paraquat. Paraquat activated inositol-requiring enzyme 1 (IRE1), apoptosis signal regulating kinase 1 (ASK1), and c-jun kinase (JNK). Also, paraquat activated calpain and caspase 3, but did not affect the levels of intracellular calcium and the activity of caspase 12. Finally, apoptotic DNA damage by paraquat was investigated and this damage was attenuated by salubrinal (ER stress inhibitor), thioredoxin (ASK1 inhibitor) and SP600125 (JNK inhibitor). Therefore, current data indicate that paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in SY5Y cells.


Assuntos
Apoptose/efeitos dos fármacos , Endorribonucleases/biossíntese , Herbicidas/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , MAP Quinase Quinase Quinase 5/biossíntese , Proteínas de Membrana/biossíntese , Paraquat/toxicidade , Proteínas Serina-Treonina Quinases/biossíntese , Western Blotting , Sinalização do Cálcio/fisiologia , Caspases/metabolismo , Linhagem Celular Tumoral , Corantes , Dano ao DNA , Chaperona BiP do Retículo Endoplasmático , Endorribonucleases/genética , Formazans/metabolismo , Proteínas de Choque Térmico/biossíntese , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , MAP Quinase Quinase Quinase 5/genética , Proteínas de Membrana/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição CHOP/biossíntese , Azul Tripano
12.
Hum Mol Genet ; 16(23): 2900-10, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17823202

RESUMO

Parkinson's disease (PD) may be caused by a complex interaction of environmental insults and genetic susceptibilities. Previous studies of DJ-1-deficient mice have noted dopaminergic dysfunction mainly in older mice. To simulate the interaction of genetic factors and environmental factors, we treated DJ-1-deficient mice with paraquat. Even in relatively young mice, this combination produced dopamine loss and motor dysfunction. To determine the potential mechanism for the dopaminergic dysfunction, we investigated the proteasome function and ubiquitinated protein levels. DJ-1-deficient mice treated with paraquat showed decreased proteasome activities and increased ubiquitinated protein levels. To further investigate the mechanism of proteasome dysfunction, ATP levels and subunit protein levels of 19S ATPase Rpt6 and 20S beta5 were measured and noted to be decreased in the ventral midbrain, but not in the striatum. Finally, a transcription factor, Nrf2 that has been previously shown to be regulated by DJ-1 and to regulate 20S beta5 levels was decreased. These pathologies were not observed in brain regions of normal mice treated with paraquat. In conclusion, this study raises the possibility that environmental and genetic factors might cooperatively involve the mechanisms underlying proteasome impairment in PD brains.


Assuntos
Dopamina/fisiologia , Proteínas Oncogênicas/deficiência , Paraquat/toxicidade , Transtornos Parkinsonianos/etiologia , Complexo de Endopeptidases do Proteassoma/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Herbicidas/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Oncogênicas/genética , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/psicologia , Peroxirredoxinas , Proteína Desglicase DJ-1 , Desempenho Psicomotor/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos
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