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1.
Life Sci ; 234: 116784, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445026

RESUMO

Tobacco smoking is recognized as a life-threatening risk factor worldwide. Initiation of smoking primarily occurs during adolescence which is a critical developmental phase characterized by specific neurobehavioral alterations. The effect of adolescent nicotine exposure on vulnerability to opioid addiction has not been previously addressed. Furthermore, lateral paragigantocellularis (LPGi) is a key modulator of opiate effects. In this study we investigated the effect of adolescent nicotine treatment on development of morphine tolerance and dependence as well as LPGi neuronal responses to morphine during adulthood. Male Wistar rats received subcutaneous injections of either nicotine or saline during adolescence and then development of morphine tolerance and dependence was assessed during adulthood by tail-flick and withdrawal tests, respectively. In vivo single-unit recording was performed to examine the LPGi neuronal activities. Results indicated that adolescent nicotine exposure significantly facilitates the development of tolerance to analgesic effect of morphine and increases the expression of morphine withdrawal signs in adulthood. Also, it was observed that following adolescent nicotine treatment, the extent of morphine-induced excitation is attenuated in LPGi neurons of adult rats. Moreover, the onset of morphine-induced inhibition was increased in these animals. Neither the baseline, nor the regularity of firing was affected in our observations. It could be concluded that nicotine challenge during adolescence may enhance the future vulnerability to opioid addiction through induction of persistent neuroadaptations in LPGi neurons.


Assuntos
Tronco Encefálico/efeitos dos fármacos , Dependência de Morfina/etiologia , Neurônios/efeitos dos fármacos , Nicotina/efeitos adversos , Envelhecimento , Animais , Tronco Encefálico/citologia , Tronco Encefálico/fisiopatologia , Masculino , Dependência de Morfina/fisiopatologia , Neurônios/patologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Ratos Wistar , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/fisiopatologia
2.
Toxicol Lett ; 314: 43-52, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310794

RESUMO

Thioredoxin is an evolutionarily conserved antioxidant protein that plays a crucial role for fundamental cellular processes and embryonic development. Growing evidence support that Thioredoxin influences cellular response to chemicals insults, particularly those accompanying oxidative stress. The mechanisms underlying the functions of Thioredoxin1 in the embryonic development under the environmental toxicant exposure remain, however, largely unexplored. We report here that thioredoxin1 becomes differentially expressed in zebrafish embryos after exposure to 9 out of 11 environmental chemicals. In situ gene expression analysis show that thioredoxin1 is expressed in neurons, olfactory epithelia, liver and swim bladder under normal conditions. After MeHg exposure, however, thioredoxin1 is ectopically induced in the hair cells of the lateral line and in epithelia cells of the pharynx. Knockdown of Thioredoxin1 induces hydrocephalus and increases cell apoptosis in the brain ventricular epithelia cells. In comparison with 5% malformation in embryos injected with control morpholino, MeHg induces more than 77% defects in Thioredoxin1 knockdown embryos. Our data suggest that there is an association between hydrocephalus and Thioredoxin1 malfunction in embryonic development, and provide valuable information to elucidate the protective role of Thioredoxin1 against chemicals disruption.


Assuntos
Encéfalo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hidrocefalia/induzido quimicamente , Tiorredoxinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica no Desenvolvimento , Hidrocefalia/embriologia , Hidrocefalia/genética , Hidrocefalia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
3.
Cell Biochem Funct ; 37(6): 432-442, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31318458

RESUMO

Advanced glycation end products (AGEs) are naturally occurring molecules that start to accumulate from embryonic developmental stages and form as part of normal ageing. When reducing sugars interact with and modify proteins or lipids, AGE production occurs. AGE formation accelerates in chronic hyperglycemic conditions, and high AGE levels have been associated with the pathogenesis of various diseases. In addition, enhanced levels of AGEs have been linked to delayed wound healing as seen in patients with diabetes mellitus. Research has provided numerous ways in which a high AGE concentration results in impaired wound healing, including oxidative stress, structural and functional changes to proteins important in wound repair, an enhanced inflammatory response by activation of transcription factors, and possible exaggerated apoptosis of cells necessary to the wound repair process. Apoptosis is a naturally occurring cell death process that is significant for normal tissue functioning and plays an important role in wound repair by preventing a prolonged inflammatory response and excessive scar formation. Abnormal apoptosis affects wound healing, resulting in slow healing wounds. This review will summarize the role of AGEs in wound healing, focusing on the mechanisms by which AGEs lead to apoptosis in various cell types. The review provides the way forward for medical research and molecular studies as it focuses on the mechanisms by which AGEs induce apoptosis in various cell types, including fibroblasts, osteoblasts, neuronal cells, and endothelial cells. Reviewing the mechanisms of AGE-linked apoptosis is important in understanding the impact of high AGE levels in delayed wound healing in diabetic patients due to abnormal apoptosis of cells necessary to the wound healing process.


Assuntos
Apoptose , Produtos Finais de Glicação Avançada/metabolismo , Cicatrização , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neurônios/metabolismo , Neurônios/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia
4.
Life Sci ; 232: 116611, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260683

RESUMO

PURPOSE: To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. METHODS: Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. RESULTS: 50 µg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. CONCLUSION: DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
5.
Yonsei Med J ; 60(7): 640-650, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250578

RESUMO

PURPOSE: Alzheimer's disease (AD) is the most common neurodegenerative disease, with a rising prevalence worldwide. Long noncoding RNAs (lncRNAs) have been found to play important roles in the development and treatment of AD. However, the exact role of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in neuronal damage in AD is largely unknown. MATERIALS AND METHODS: The AD model was established in SH-SY5Y and SK-N-SH cells via treatment with amyloid ß1-42 (Aß). The expression of NEAT1 and microRNA-107 (miR-107) was measured by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were detected by MTT assay, immunocytochemistry, and flow cytometry. The expression of phosphorylated tau protein (p-Tau) was measured by Western blot. The interaction between NEAT1 and miR-107 was explored by bioinformatics analysis, luciferase activity, and RNA immunoprecipitation assays. RESULTS: NEAT1 expression was enhanced in Aß-treated SH-SY5Y and SK-N-SH cells, and its knockdown attenuated Aß-induced inhibition of viability and promotion of apoptosis and p-Tau levels. NEAT1 was indicated as a decoy of miR-107. miR-107 abundance was reduced in Aß-treated cells, and its overexpression reversed Aß-induced injury. Moreover, interference of miR-107 abated silencing of NEAT1-mediated inhibition of neuronal damage in Aß-treated SH-SY5Y and SK-N-SH cells. CONCLUSION: LncRNA NEAT1 aggravated Aß-induced neuronal damage by sponging miR-107, indicating a novel avenue for treatment of AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , MicroRNAs/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/toxicidade , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Humanos , Neurônios/patologia
6.
Cell Mol Biol Lett ; 24: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168302

RESUMO

Background: Accumulating evidence has shown that altered microRNA (miR) modulation is implicated in the pathologies of ischemic stroke. However, it is unclear whether and how hsa-miR-19a-3p mediates cerebral ischemic injury. Herein, we investigated the functional role of miR-19a-3p in cerebral ischemic injury and explored its underlying regulatory mechanism. Methods: In vivo ischemic/reperfusion (I/R) neuronal injury and in vitro oxygen-glucose deprivation (OGD) were established. Expression of miR-19a-3p was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Glucose uptake, lactate production, and apoptosis were determined. ADIPOR2 was predicted as a target of miR-19a-3p in silico and experimentally validated by qRT-PCR, Western blot analysis and luciferase assay assays. Results: MiR-19a expression was significantly downregulated and upregulated in rat neurons and astrocytes, respectively (P < 0.01). A significantly elevated level of miR-19a-3p was found in I/R and OGD models in comparison to sham/control groups (P < 0.01). Expression of the glycolysis enzyme markers LDHA, PKM2, HK2, Glut1 and PDK1, apoptosis-related factors levels, apoptosis, glucose uptake, and lactate production were significantly repressed by both I/R and OGD (P < 0.01 in each case). Moreover, miR-19a-3p mimic aggravated, while miR-19a-3p inhibitor alleviated, the above observations. Adipor2 was predicted and confirmed to be a direct target of miR-19a. Furthermore, restoration of Adipor2 reversed miR-19a-3p-induced effects. Conclusions: Collectively, our results indicate that elevated miR-19a-3p mediates cerebral ischemic injury by targeting ADIPOR2. MiR-19a-3p attenuation thus might offer hope of a novel therapeutic target for ischemic stroke injury treatment.


Assuntos
Apoptose , Isquemia Encefálica/patologia , Glucose/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção , Acidente Vascular Cerebral/patologia , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Sequência de Bases , Modelos Animais de Doenças , MicroRNAs/genética , Oxigênio , Ratos Sprague-Dawley , Receptores de Adiponectina/metabolismo , Regulação para Cima/genética
7.
Nat Commun ; 10(1): 2394, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160584

RESUMO

To understand the molecular processes that link Aß amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer's disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Agregação Patológica de Proteínas/metabolismo , Células Piramidais/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Atrofia , Caspase 3/metabolismo , Morte Celular , Cromatografia Líquida , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Hipocampo/patologia , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Células Piramidais/patologia , Tauopatias , Proteínas tau/metabolismo
8.
Vet Microbiol ; 233: 78-84, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31176416

RESUMO

Autophagy is a critical physiologic process contributing to the maintenance of cell homeostasis. Autophagy dysfunction has been directly linked to a growing number of neurodegenerative disorders, including prion diseases. However, little is known about the molecular mechanisms underlying autophagic failure and its connection with prion neuropathology. In a previous work we described alterations of this process in the central nervous system (CNS) of sheep naturally infected with classical scrapie, although specific neuronal populations such as Purkinje cells seemed to display an autophagy-related neuroprotective effect against prion toxicity. As atypical scrapie displays a lesion pattern different to the one observed in the classical form, using immunohistochemical analyses, we further investigated herein the role of autophagy in the CNS of sheep experimentally infected with atypical scrapie prions. While ATG5 protein showed a similar distribution in atypical scrapie to that observed in the classical form, expression of LC3-B and LC3-A did not change in any brain region. However, p62, a marker of impaired autophagy, was overexpressed in the most prion-affected areas, including Purkinje cells, which suggests that autophagic activity is deteriorated in the CNS of atypical scrapie and these cells are also susceptible to neurotoxicity and do not exhibit a general defensive mechanism based on autophagy. By comparing data from both clinical scrapie forms, we have demonstrated that autophagy impairment is highly dependent on the neuropathological lesion levels of the brain area analysed and may be implicated in prion neuropathology.


Assuntos
Autofagia , Encéfalo/patologia , Príons , Scrapie/patologia , Animais , Proteína 5 Relacionada à Autofagia/genética , Feminino , Proteínas Associadas aos Microtúbulos/genética , Neurônios/patologia , Células de Purkinje/patologia , Ovinos , Fatores de Transcrição/genética
9.
Cell Physiol Biochem ; 53(1): 76-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31192545

RESUMO

BACKGROUND/AIMS: Diabetes causes damage to the enteric nervous system. The enteric nervous system consists of neurons and enteric glial cells (EGCs). The present study evaluated the effects of an ethyl-acetate fraction (EAF) from Trichilia catigua (T. catigua; 200 mg/kg) on the total population of enteric neurons (HuC/D-immunoreactive [IR]) and EGCs (S100-IR and glial fibrillary acidic protein [GFAP]-IR) in the total preparation and jejunal mucosa in diabetic rats. METHODS: The animals were distributed into four groups: normoglycemic rats (N), diabetic rats (D), normoglycemic rats that received the EAF (NC), and diabetic rats that received the EAF (DC). The jejunum was processed for immunohistochemistry to evaluate HuC/D, S100, and GFAP immunoreactivity. The expression of S100 and GFAP proteins was also quantified by Western blot. RESULTS: The D group exhibited a decrease in the number of neurons and EGCs, an increase in the area of cell bodies, an increase in S100 protein expression, a decrease in GFAP protein expression, and a decrease in S100-IR and GFAP-IR EGCs in the jejunal mucosa. The DC group exhibited a decrease in the number of neurons and EGCs, a decrease in the area of cell bodies, a decrease in S100 and GFAP protein expression, and a decrease in S100-IR and GFAP-IR EGCs in the jejunal mucosa. The NC group exhibited maintenance of the number of neurons and EGCs, an increase in the area of cell bodies, and a decrease in S100 and GFAP protein expression. CONCLUSION: The EAF from T. catigua partially conferred protection against diabetic neuropathy in the enteric nervous system.


Assuntos
Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/prevenção & controle , Jejuno/inervação , Meliaceae/química , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetatos/química , Animais , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/patologia , Sistema Nervoso Entérico/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/análise , Jejuno/efeitos dos fármacos , Jejuno/patologia , Masculino , Neuroglia/patologia , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Proteínas S100/análise
10.
Nat Neurosci ; 22(7): 1089-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235908

RESUMO

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.


Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Pericitos/fisiologia , Choque/fisiopatologia , Animais , Isquemia Encefálica/fisiopatologia , Capilares/fisiopatologia , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Citocinas/deficiência , Citocinas/uso terapêutico , Células Endoteliais/citologia , Feminino , Genes Reporter , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Choque/metabolismo , Choque/patologia
11.
Nat Commun ; 10(1): 2000, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043608

RESUMO

Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic's function in the brain. We show that nuclear Cic expression is strongest in astrocytes and neurons but weaker in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we demonstrate that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage effects are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal, and tumorigenicity. Our results identify Cic as an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.


Assuntos
Neoplasias Encefálicas/patologia , Células-Tronco Neurais/patologia , Oligodendroglioma/patologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Animais , Astrócitos/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Neurônios/patologia , Oligodendroglia/citologia , Oligodendroglia/patologia , Cultura Primária de Células , Prosencéfalo/citologia , Prosencéfalo/patologia , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Commun ; 10(1): 2046, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053723

RESUMO

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.


Assuntos
Transtorno Bipolar/genética , Dopamina/biossíntese , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Fator de Crescimento Insulin-Like II/genética , Esquizofrenia/genética , Tirosina 3-Mono-Oxigenase/genética , Adulto , Idoso , Animais , Transtorno Bipolar/patologia , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neurônios/patologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/patologia , Proteômica , Esquizofrenia/patologia , Transcriptoma/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
13.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075828

RESUMO

Despite the different antineoplastic mechanisms of action, peripheral neurotoxicity induced by all chemotherapy drugs (anti-tubulin agents, platinum compounds, proteasome inhibitors, thalidomide) is associated with neuron morphological changes ascribable to cytoskeleton modifications. The "dying back" degeneration of distal terminals (sensory nerves) of dorsal root ganglia sensory neurons, observed in animal models, in in vitro cultures and biopsies of patients is the most evident hallmark of the perturbation of the cytoskeleton. On the other hand, in highly polarized cells like neurons, the cytoskeleton carries out its role not only in axons but also has a fundamental role in dendrite plasticity and in the organization of soma. In the literature, there are many studies focused on the antineoplastic-induced alteration of microtubule organization (and consequently, fast axonal transport defects) while very few studies have investigated the effect of the different classes of drugs on microfilaments, intermediate filaments and associated proteins. Therefore, in this review, we will focus on: (1) Highlighting the fundamental role of the crosstalk among the three filamentous subsystems and (2) investigating pivotal cytoskeleton-associated proteins.


Assuntos
Citoesqueleto/patologia , Tratamento Farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Animais , Modelos Animais de Doenças , Humanos , Filamentos Intermediários/patologia , Neurônios/patologia
14.
Int J Mol Sci ; 20(9)2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31083528

RESUMO

Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.


Assuntos
Citocinas/metabolismo , Luz , Mesencéfalo/patologia , Neurônios/patologia , Acidente Vascular Cerebral/patologia , Trombose/patologia , Animais , Apoptose , Infarto Encefálico/patologia , Quimiocinas/metabolismo , Estimulação Elétrica , Interleucinas/metabolismo , Masculino , Neurônios/metabolismo , Ratos Wistar , Acidente Vascular Cerebral/complicações , Trombose/complicações
15.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 63-68, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078154

RESUMO

To investigate the expressions and roles of semaphorin3A (Sema3A) and vascular endothelial growth factor 165 (VEGF165) in cultured rat cortical neurons and vascular endothelial cells after oxygen glucose deprivation (OGD) stimulation. Cultured cortical neurons (NC) and vascular endothelial cells (VEC) of Sprague Dawley (SD) rats (SPF grade) were randomly divided into control group and OGD treatment group. Western blot assay, immunofluorescent staining and immunohistochemical methods were used to determine the expressions of VEGF165, Sema3A and neuropilin-1 (Nrp-1) protein. Cell migration was determined by Transwell, while TUNEL assay was used to measure apoptosis. The expressions of Sema3A, Nrp-1 and VEGF165 in NC and VEC cells after OGD treatment were up-regulated, when compared with the control group. With transfection of Sema3A shRNA, apoptosis of neurons decreased significantly after 2 h of OGD treatment, but the apoptosis of VEC cells was not obvious. The migration rate of VEC cells in the treatment group was significantly increased, relative to that of the control group. Stimulation with OGD induces neuronal expression of VEGF165 and regulates the migration of vascular endothelial cells, thereby enhancing their participation in angiogenesis, which may involve Sema3A.


Assuntos
Córtex Cerebral/patologia , Células Endoteliais/metabolismo , Glucose/deficiência , Neurônios/metabolismo , Oxigênio/metabolismo , Semaforina-3A/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Movimento Celular , Forma Celular , Células Cultivadas , Células Endoteliais/patologia , Neurônios/patologia , Neuropilina-1/metabolismo , Substâncias Protetoras/metabolismo , Ratos Sprague-Dawley
16.
Folia Neuropathol ; 57(1): 16-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038184

RESUMO

The present investigation evaluates the protective effect of Ginkgetin aglycone (GA) against ischemic stroke-induced neuronal injury. Ischemic stroke was produced by the middle cerebral artery occlusion (MCAO) model and animals were a group that received GA 100 and 200 mg/kg, i.p. five days before the induction of MCAO. The effect of GA against stroke was determined by estimating the neurological deficit score and brain water content was also observed. Moreover terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay was done for determining the neuronal apoptosis and Western blot assay also performed for estimating the expression of several proteins. Results of the study suggest that the neurological deficit score and brain water content was found to be lower in the GA treated group than the ischemia/reperfusion (I/R) group of rats. Moreover the number of TUNEL positive cells was found to be lower in the GA treated group than in the I/R group of rats. There was a significant (p < 0.01) decrease in the oxidative stress parameters and cytokine in the tissue homogenate of the GA treated group compared to the I/R group of rats. Further treatment with GA attenuates altered expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase B (Akt), B-cell lymphoma 2 (Bcl-2), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa light chain enhancer of activated B cells (NF-B), toll-like receptor 4 (TLR-4), Janus kinase 2 (JAK-2) and sirtuin-1 (SIRT-1) protein in the brain tissues of stroke rats. In conclusion, data of the report reveal that treatment with Ginkgetin aglycone protects the neuronal injury against stroke in rats by reducing oxidative stress and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Biflavonoides/farmacologia , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Animais , Inflamação/metabolismo , Inflamação/patologia , Janus Quinase 2/efeitos dos fármacos , Janus Quinase 2/metabolismo , Masculino , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/metabolismo , Acidente Vascular Cerebral/metabolismo
17.
Oxid Med Cell Longev ; 2019: 6392763, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057691

RESUMO

The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and Friedreich's ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.


Assuntos
Antioxidantes/metabolismo , Apoptose , Autofagia , Metabolismo Energético , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo
18.
Chemosphere ; 229: 618-630, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102917

RESUMO

Bisphenol-A (BPA) is a representative exogenous endocrine disruptor, which is extensively composed in plastic products. Due to the capability of passing through the blood-brain barrier, evidence has linked BPA exposure with multiple neuropsychological dysfunctions, neurobehavioral disorders and neurodegenerative diseases. However, the underlying mechanism by which BPA induces neurodegeneration still remains unclear. Our study used human embryonic stem cells-derived human cortical neurons (hCNs) as a cellular model to investigate the adverse neurotoxic effects of BPA. hCNs were treated with 0, 0.1, 1 and 10 µM BPA for 14 days. Impacts of BPA exposure on cell morphology, cell viability and neural marker (MAP2) were measured for evaluating the neurodegeneration. The intracellular calcium homeostasis, reactive oxygen species (ROS) generation and organelle functions were also taken into consideration. Results revealed that chronic exposure of BPA damaged the neural morphology, induced neuronal apoptosis and decreased MAP2 expression at the level of both transcription and translation. The intracellular calcium levels were elevated in hCNs after BPA exposure through NMDARs-nNOS-PSD-95 mediating. Meanwhile, BPA led to oxidative stress by raising the ROS generation and attenuating the antioxidant defense in hCNs. Furthermore, BPA triggered ER stress and increased cytochrome c release by impairing the mitochondrial function. Ultimately, BPA triggered the cell apoptosis by regulating Bcl-2 family and caspase-dependent signaling pathway. Taken together, BPA exerted neurotoxic effects on hCNs by eliciting apoptosis, which might due to the intracellular calcium homeostasis perturbation and cell organellar dysfunction.


Assuntos
Compostos Benzidrílicos/toxicidade , Cálcio/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Neurônios/efeitos dos fármacos , Fenóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Proteína 4 Homóloga a Disks-Large/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
19.
Nat Neurosci ; 22(6): 875-886, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061493

RESUMO

Misfolded protein toxicity and failure of protein quality control underlie neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. Here, we identified Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1) as a key regulator of protein quality control, the loss of which protected against the proteotoxicity of mutant Cu/Zn superoxide dismutase or C9orf72 dipeptide repeat proteins. L3MBTL1 acts by regulating p53-dependent quality control systems that degrade misfolded proteins. SET domain-containing protein 8, an L3MBTL1-associated p53-binding protein, also regulated clearance of misfolded proteins and was increased by proteotoxicity-associated stresses in mammalian cells. Both L3MBTL1 and SET domain-containing protein 8 were upregulated in the central nervous systems of mouse models of amyotrophic lateral sclerosis and human patients with amyotrophic lateral sclerosis/frontotemporal dementia. The role of L3MBTL1 in protein quality control is conserved from Caenorhabditis elegans to mammalian neurons. These results reveal a protein quality-control pathway that operates in both normal stress response and proteotoxicity-associated neurodegenerative diseases.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Proteínas Cromossômicas não Histona/metabolismo , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Animais , Caenorhabditis elegans , Drosophila , Humanos , Camundongos , Neurônios/metabolismo , Neurônios/patologia
20.
Nat Commun ; 10(1): 2246, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113950

RESUMO

Epigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer's disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Elementos Facilitadores Genéticos , Neurônios/patologia , Córtex Pré-Frontal/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Moléculas de Adesão Celular/genética , Disfunção Cognitiva/genética , Estudos de Coortes , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/citologia , Regulação para Cima
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