RESUMO
Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.
Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Glioblastoma , MicroRNAs , RNA Longo não Codificante , RNA Mensageiro , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/mortalidade , Glioblastoma/metabolismo , RNA Longo não Codificante/genética , Prognóstico , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mapas de Interação de Proteínas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/metabolismo , Perfilação da Expressão Gênica , Biologia Computacional/métodos , Bases de Dados Genéticas , RNA Endógeno CompetitivoRESUMO
Astaxanthin (AST) is a lipid-soluble carotenoid with antioxidant and anti-inflammatory properties. Previous reports demonstrated the promising effects of AST on spinal cord injury (SCI)-induced inflammation and sensory-motor dysfunction. Macrophage migration inhibitory factor (MIF), as a cytokine, plays a critical role in the inflammatory phase of SCI. The aim of this study was to evaluate the effects of AST on post-SCI levels of MIF in serum and spinal cord. The possible correlation between MIF and mechanical pain threshold was also assessed. Adult male rats were subjected to a severe compression spinal injury and 30 min later were treated with AST (Intrathecal, 2 nmol) or vehicle. Neuropathic pain was assessed by von Frey filaments before the surgery, and then on days 7, 14, 21, and 28 post-SCI. Western blot and ELISA were used to measure the serum level and spinal expression of MIF following SCI in the same time points. AST treatment significantly attenuated the SCI-induced dysregulations in the serum levels and tissue expression of MIF. A negative correlation was observed between mechanical pain threshold and serum MIF level (r = -0.5463, P < 0.001), as well as mechanical pain threshold and spinal level of MIF (r = -0.9562; P < 0.001). AST ameliorates SCI-induced sensory dysfunction, probably through inhibiting MIF-regulated inflammatory pathways.
Assuntos
Fatores Inibidores da Migração de Macrófagos , Traumatismos da Medula Espinal , Animais , Antioxidantes/farmacologia , Lipídeos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Ratos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologiaRESUMO
The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell-conditioned medium (CM) therapy has emerged as an alternative candidate. Here, we investigated the effect of CM derived from human embryonic MSCs on experimental ischemic stroke. Wistar rats underwent ischemic stroke by the right middle cerebral artery occlusion (MCAO). CM was infused either one time (1 hr post-MCAO) or three times (1, 24, and 48 hr post-MCAO) through guide cannula into the left lateral ventricle. Neurological functions were evaluated using Bederson's test and modified Neurological Severity Score on Days 1, 3, and 7 following MCAO. Infarction volumes and cerebral edema were measured on Days 3 and 7. growth-associated protein-43, synaptophysin, cAMP response element-binding protein, and phosphorylated-cAMP response element-binding protein levels were also assessed in peri-ischemic cortical tissue on Day 7 postsurgery. Our results indicated that three times injections of CM could significantly reduce body weight loss, mortality rate, infarct volumes, cerebral edema, and improve neurological deficits in MCAO rats. Moreover, three injections of CM could restore decreased levels of synaptic markers in MCAO rats up to its normal levels observed in the sham group. Our data suggest that using the CM obtained from embryonic stem cells-MSCs could be a potent therapeutic approach to attenuate cerebral ischemia insults which may be partly mediated through modulation of synaptic plasticity.
Assuntos
Encéfalo/patologia , Meios de Cultivo Condicionados/farmacologia , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Mesenquimais/metabolismo , Acidente Vascular Cerebral/patologia , Sinapses/patologia , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Infarto Encefálico/complicações , Infarto Encefálico/patologia , Linhagem Celular , Edema/complicações , Edema/patologia , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Injeções Intraventriculares , Masculino , Neurogênese/efeitos dos fármacos , Ratos Wistar , Sinapses/efeitos dos fármacosRESUMO
Exploring the regulatory effects of estrogen on different body organs via its receptors is largely of interest. Recently, the expression, signaling and the clinical significance of ERα36, the newly identified isoform of ERα, mediating non-genomic signaling of estrogen, have been studied in a wide range of organs and tumors. ERα36 is expressed highly in the CNS and actively involved in neuroprotection. It is also suggested to be an important estrogen receptor involved in preserving bone in postmenopausal women. On the oncological side, although ERα36 has usually been considered to be an oncogenic molecule, results from some studies paradoxically imply its protective role in certain tumors. Collectively, it seems that ERα36 is highly involved in cell type-specific functions of estrogen through its MAPK/ERK signaling, which is dependent on ERα36 expression levels, ligand concentrations and disease stage. The response is also dependent on the levels of ERα66 and ERß. These factors influence the ERK kinetic and determine the ultimate mitogenic or antimitogenic signaling of estrogen, leading to cell survival or cell death. In this review, we summarize the recent organ-specific, cellular and molecular events and the mechanisms involved in estrogen effects mediated through the ERα36/ ERα66 with a particular focus on carcinomas where more clinical information has recently emerged.
Assuntos
Estrogênios/metabolismo , Neoplasias/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Apoptose , Produtos Biológicos/farmacologia , Humanos , Neuroproteção , Isoformas de Proteínas/metabolismo , Receptores de Estrogênio/química , Receptores Acoplados a Proteínas G/metabolismo , Caracteres SexuaisRESUMO
According to the intrinsic plasticity of stem cells, controlling their fate is a critical issue in cell-based therapies. Recently, a growing body of evidence has suggested that substrate stiffness can affect the fate decisions of various stem cells. Epidermal neural crest stem cells as one of the main neural crest cell derivatives hold great promise for cell therapies due to presenting a high level of plasticity. This study was conducted to define the influence of substrate stiffness on the lineage commitment of these cells. Here, four different polyacrylamide hydrogels with elastic modulus in the range of 0.7-30 kPa were synthesized and coated with collagen and stem cells were seeded on them for 24 hr. The obtained data showed that cells can attach faster to hydrogels compared with culture plate and cells on <1 kPa stiffness show more neuronal-like morphology as they presented several branches and extended longer neurites over time. Moreover, the transcription of actin downregulated on all hydrogels, while the expression of Nestin, Tubulin, and PDGFR-α increased on all of them and SOX-10 and doublecortin gene expression were higher only on <1 kPa. Also, it was revealed that soft hydrogels can enhance the expression of glial cell line-derived neurotrophic factor, neurotrophin-3, and vascular endothelial growth factor in these stem cells. On the basis of the results, these cells can respond to the substrate stiffness in the short term culture and soft hydrogels can alter their morphology and gene expression. These findings suggested that employing proper substrate stiffness might result in cells with more natural profiles similar to the nervous system and superior usefulness in therapeutic applications.
Assuntos
Técnicas de Cultura de Células/métodos , Meios de Cultura/farmacologia , Módulo de Elasticidade/fisiologia , Crista Neural/citologia , Células-Tronco , Resinas Acrílicas , Animais , Células Cultivadas , Proteína Duplacortina , Expressão Gênica/efeitos dos fármacos , Hidrogéis , Masculino , Ratos , Ratos Wistar , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/fisiologiaRESUMO
PURPOSE: The regulatory effects of estradiol on pituitary homeostasis have been well documented. However, the expression patterns of ERα66 and ERα36 and their correlations with the clinical course of postoperative prolactinoma tumors remain unclear. METHODS: The expression of ERα36, ERα66, Ki67, p53, and CD31 were determined by immunohistochemistry in 62 prolactinoma patients. Snap-frozen tumors and normal pituitaries were also examined by western blotting for estrogen receptor detection. RESULTS: A broad expression of ERα36 was identified in normal pituitaries. The median scores of ERα36 and ERα66 expression were 8 and 6 in normal pituitaries and 4 and 0 in tumors, respectively. Four phenotypes of ERα36 and ERα66 expression were explored in tumors with regard to sex, invasiveness, dopamine resistance, and recurrence. Low ERα36 expression was associated with tumor invasion and increased Ki67. Low ERα66 expression was associated with tumor invasion, dopamine-agonist resistance, and enhanced tumor size. Multivariable logistic regression analysis showed that low ERα36 expression is an independent risk factor for invasiveness. The significant inverse association of ERα66 with invasiveness, dopamine resistance, and tumor size remained significant after adjustment for sex as a potential confounder. After controlling for sex, the low ERα66/low ERα36 phenotype was 6.24 times more prevalent in invasive tumors than in noninvasive tumors. Although the decreasing trend of CD31 expression from surrounding nontumoral lactotroph adenomas to tumors was similar to that of the estrogen receptors, a significant correlation was not observed here. CONCLUSION: The decreasing trends of ERα36 and ERα66 expression from normal pituitaries to tumors are associated with aggressive clinical behavior.
Assuntos
Biomarcadores/metabolismo , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hipofisárias/metabolismo , Prolactinoma/metabolismo , Isoformas de Proteínas/metabolismo , Adulto , Western Blotting , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prolactinoma/genética , Isoformas de Proteínas/genéticaRESUMO
Accumulating evidence has reached the consensus that the balance of phosphorylation state of signaling molecules is a pivotal point in the regulation of cell signaling. Therefore, characterizing elements (kinases-phosphatases) in the phosphorylation balance are at great importance. However, the role of phosphatase enzymes is less investigated than kinase enzymes. PP2A is a member of serine/threonine protein phosphatase that its imbalance has been reported in neurodegenerative diseases. Therefore, we reviewed the superfamily of phosphatases and more specifically PP2A, its regulation, and physiological functions participate in CNS. Thereafter, we discussed the latest findings about PP2A dysregulation in Alzheimer and Parkinson diseases and possible interplay between this phosphatase and insulin signaling pathways. Finally, activating/inhibitory modulators for PP2A activity as well as experimental methods for PP2A study have been reviewed.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Insulina/metabolismo , Doença de Parkinson/metabolismo , Proteína Fosfatase 2/metabolismo , Transdução de Sinais , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Humanos , Resistência à Insulina , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doença de Parkinson/patologia , Fosforilação , Proteína Fosfatase 2/análiseRESUMO
Methamphetamine (METH) is a highly potent and addictive psychostimulant that is frequently abused worldwide. Although the biggest challenge to the efficient treatment of drug dependence is relapse, its mechanism is completely unclear. Plenty of evidence suggests that inflammation contributes to drug-induced reward especially in brain regions that are involved in the reward system, but there is no document about relapse. Cannabidiol (CBD) is a nonpsychoactive cannabinoid that has powerful anti-inflammatory and immunosuppressive properties. A previous research in our laboratory has demonstrated that CBD prevents reinstatement of METH even in 24-hour rapid eye movement (REM) sleep-deprived (RSD) rats. The aim of this study was to assess whether CBD prevents reinstatement of METH through change of gene expression of cytokines such as interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor α (TNF-α) in extinguished rats. Real-time polymerase chain reaction (PCR) was used in this research to assay gene expression of cytokines. We found that stress- and drug-induced reinstatement of METH enhanced mRNA expression of cytokines in the prefrontal cortex (PFC) and hippocampus. Furthermore, CBD treatment significantly reduced the mRNA expression of cytokines in the PFC and hippocampus, but CBD treatment in RSD rats increased expression of cytokines in the hippocampus. It seems that enhancement of cytokines leads to change in neurotransmission and so triggers reinstatement of METH.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Encéfalo/efeitos dos fármacos , Canabidiol/farmacologia , Inflamação/fisiopatologia , Metanfetamina/farmacologia , Estresse Fisiológico , Animais , Anticonvulsivantes/farmacologia , Encéfalo/fisiopatologia , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: The role of gut microbiota in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), via the gut-brain axis has recently been demonstrated; hence, modification of the intestinal microbiota composition by probiotic biotherapy could be a therapeutic target for these conditions. The aim of this study was to assess the effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) on inflammatory and memory processes in lipopolysaccharide (LPS)-induced rats, one of the animal models used in peripherally induced neuroinflammation and neurodegeneration. METHODS: Rats were randomly divided into four groups (Control, LPS, Probiotic + LPS, and Probiotic). All experimental groups were orally administrated maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 14 consecutive days and then were injected with saline or LPS (1 mg/kg, intraperitoneally [i.p.], single dose) 20 hours later. Memory retention ability and systemic and neuroinflammatory markers were assessed 4 hours after the injections. RESULTS: Systemic exposure to LPS resulted in significant elevation of both the circulating and hippocampal levels of proinflammatory cytokines, which decreased remarkably following probiotic pretreatment. Oral bacteriotherapy with a combination of L. helveticus R0052 and B. longum R0175 also attenuated the decremental effect of LPS on memory through brain-derived neurotrophic factor (BDNF) expression at the molecular level; however, this effect was not significant in the passive avoidance test at the behavioral level. CONCLUSIONS: These results suggest that the management of gut microbiota with this probiotic formulation could be a promising intervention to improve neuroinflammation-associated disorders such as AD.
Assuntos
Bifidobacterium longum , Inflamação/induzido quimicamente , Lactobacillus helveticus , Lipopolissacarídeos/toxicidade , Probióticos/uso terapêutico , Actinas/genética , Actinas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Microbioma Gastrointestinal , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/prevenção & controle , Masculino , Polissacarídeos , Distribuição Aleatória , Ratos , Ratos Wistar , Regulação para CimaRESUMO
In recent years, the beneficial impact of targeted gut microbiota manipulation in various neurological disorders has become more evident. Therefore, probiotics have been considered as a promising approach to modulate brain gene expression and neuronal pathways even in some neurodegenerative diseases. The purpose of this study was to determine the effect of probiotic biotherapy with combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the expression levels of proteins critical to neuronal apoptosis in hippocampus of lipopolysaccharide (LPS)-exposed rats. Four groups of animals (Control, LPS, Probiotic + LPS, and Probiotic) were treated with maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 2 weeks by gavage. On the 15th day, a single intraperitoneal dose of saline or LPS (1 mg/kg) was injected and 4 h later, protein assessment was performed by western blotting in hippocampal tissues. LPS significantly increased the Bax, Bax/Bcl-2 ratio, and cleaved caspase-3 expression along with decreased the Bcl-2 and procaspase-3 protein levels. However, probiotic pretreatment (L. helveticus R0052 + B. longum R0175) significantly downregulated the Bax and Bax/Bcl-2 ratio accompanied with upregulated Bcl-2 expression. Prophylactic treatment with these bacteria also attenuated LPS-induced caspase-3 activation by remarkably increasing the expression of procaspase-3 while reducing the level of cleaved caspase-3 in target tissues. Our data indicate that probiotic formulation (L. helveticus R0052 + B. longum R0175) alleviated hippocampal apoptosis induced by LPS in rats via the gut-brain axis and suggest that this probiotic could play a beneficial role in some neurodegenerative conditions.
Assuntos
Apoptose , Bifidobacterium longum/crescimento & desenvolvimento , Hipocampo/patologia , Lactobacillus helveticus/crescimento & desenvolvimento , Lipopolissacarídeos/toxicidade , Probióticos/administração & dosagem , Animais , Western Blotting , Caspase 3/análise , Hipocampo/efeitos dos fármacos , Placebos/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/análise , Ratos , Proteína X Associada a bcl-2/análiseRESUMO
Methamphetamine (MA), a highly abused psychostimulant, exerts neurotoxic effects on the dopaminergic system via several neurotoxicity mechanisms in the long-term administration. Since the effect of MA on the signaling insulin pathway is less studied, the current study was designed to evaluate the effect of escalating an MA regimen on different insulin signaling elements in substantia nigra (SN) and striatum of a rat. Increasing MA doses (1-14 mg/kg) were administrated intraperitoneally twice a day for 14 days in rats. In the control group, normal saline was injected in the same volume. On days 1, 14, 28, and 60 after MA discontinuation, molecular assessments were performed. Insulin receptor (IR) and insulin receptor substrate (IRS) 1 and 2 gene expression were evaluated using real-time polymerase chain reaction, and protein levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phospho-PI3K, Akt, phospho-Akt, glycogen synthase kinase 3ß (GSK3ß), and phospho-GSK3ß were measured by the Western blot analysis in SN and striatum. Messenger RNA levels of IR and insulin receptor substrate 2 were increased in SN, 1 day after the last injection. Although no changes were observed in PI3K, phospho-PI3K, Akt, phospho-Akt, and GSK3ß levels, increase in the level of inactive form of GSK3ß (phosphorylated on serine 9) was indicated in SN on day 28. In striatum, decreases in IR and phospho-Akt were demonstrated, without any change in other elements. Repeated escalating regimen of MA activated the insulin signaling pathway and inhibited GSK3ß activity in SN. This response, which did not occur in striatum, may act as an adaptive mechanism to prevent MA-induced neurotoxicity in dopaminergic cell bodies.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Insulina/metabolismo , Metanfetamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Substância Negra/metabolismo , Análise de Variância , Animais , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Expressão Gênica , Injeções Intraperitoneais , Proteínas Substratos do Receptor de Insulina/genética , Masculino , Metanfetamina/administração & dosagem , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Insulina/genéticaRESUMO
Long-term use of methamphetamine (MA) causes a broad range of cognitive deficits. Recently, it has been reported insulin signaling and mitochondrial biogenesis are involved in cognitive processes. This study aimed to examine whether MA induces cognitive deficits concomitant with insulin signaling impairment and mitochondrial dysfunctions and also intranasal (IN) insulin treatment can reverse cognitive deficits caused by MA. Rats were repeatedly treated with increasing doses of MA (1-10 mg/kg) twice a day for 10 days, and their cognitive functions were assessed using Y-maze, novel object recognition and passive avoidance tasks. The expression of components involved in insulin signaling (IR/IRS2/PI3K/Akt/GSK3ß) and mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) was measured in the hippocampus. Therapeutic effects of IN insulin delivery (0.5- IU/day, for 7 days after MA discontinuation) were also investigated in MA-treated animals. Our results showed that repeated MA exposure induced cognitive deficits, and led to insulin signaling impairment and mitochondrial dysfunction. Interestingly, IN insulin treatment reduced MA-induced cognitive impairments possibly through activating insulin signaling, particularly PI3K/Akt/GSK3ß pathway, and mitochondrial biogenesis. Thus, insulin and insulin signaling pathway can be considered as useful targets for the treatment of abnormalities associated with MA abuse.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/complicações , Transtornos Cognitivos/tratamento farmacológico , Redes Reguladoras de Genes/efeitos dos fármacos , Insulina/administração & dosagem , Metanfetamina/toxicidade , Administração Intranasal , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Growing evidence that cell-based therapies can improve recovery outcome in spinal cord injury (SCI) models substantiates their application for treatment of human with SCI. To address the effectiveness of these stem cells, potential candidates should be evaluated in proper SCI platform that allows direct real-time monitoring. In this study, the role of epidermal neural crest stem cells (EPI-NCSCs) was elucidated in an ex vivo model of SCI, and valproic acid (VPA) was administered to ameliorate the inhospitable context of injury for grafted EPI-NCSCs. Here the contusion was induced in organotypic spinal cord slice culture at day seven in vitro using a weight drop device and one hour post injury the GFP- expressing EPI-NCSCs were grafted followed by VPA administration. The evaluation of treated slices seven days after injury revealed that grafted stem cells survived on the injured slices and expressed GFAP, whereas they did not express any detectable levels of the neural progenitor marker doublecortin (DCX), which was expressed prior to transplantation. Immunoblotting data demonstrated that the expression of GFAP, BDNF, neurotrophin-3 (NT3), and Bcl2 increased significantly in stem cell treated slices. This study illustrated that the fate of transplanted stem cells has been directed to the glial lineage in the ex vivo context of injury and EPI-NCSCs may ameliorate the SCI condition through releasing neurotrophic factors directly and/or via inducing resident spinal cord cells.
Assuntos
Crista Neural/citologia , Crista Neural/metabolismo , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neuroglia/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Proteína Duplacortina , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Células-Tronco Neurais/fisiologia , Neuroglia/fisiologia , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/terapiaRESUMO
Astaxanthin (AST) is a potent lipid-soluble keto-carotenoid with auspicious effects on human health. It protects organisms against a wide range of diseases with excellent safety and tolerability. Various imperative biological activities in vitro and in vivo models have been suggested for AST. This review article is focused on the therapeutic potentials, biological activities and benefical health effects of AST. The pharmacological mechanisms of action of AST in the treatment and prevention of the peripheral and central nervous system diseases was also reviewed to provide new insights to researchers. Finally, we suggested a novel hypothesis for the mechanism of action of AST in neuropathic pain following spinal cord injury.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Humanos , Xantofilas/farmacologia , Xantofilas/uso terapêuticoRESUMO
Neurocognitive impairment in response to methamphetamine (MA) has been proven in a variety of experimental and clinical studies. Elucidation of the underlying mechanisms of MA-induced cognitive deficits and finding preventive/therapeutic approaches need best-suited animal models. In modeling repeated MA exposure, while some believes that escalating doses simulate drug abuse conditions, others believe this regimen confers a preconditioning protection. The present study aimed to compare the effects of three different regimens of repeated MA administration on memory and cognitive function of adult rats. Rats in two different experimental groups were treated with escalating paradigms consisted of twice-daily i.p. injections; 1-4 mg/kg over 7 days or 1-10 mg/kg over 10 days. The third group received twice-daily doses of 15 mg/kg every other day over 14 days. Spatial working memory, novel object recognition task and anxiety-like behavior were measured sequentially in all MA-treated rats and vehicle-treated controls started from day 8 after last injection. All MA regimens decreased rates of spontaneous alternation in Y-maze and increased anxiety-like response. Short-term recognition memory was unchanged across all MA-treated animals, while long-term memory was impaired in the second and third MA regimen. Though MA deleterious effect especially in recognition memory is somehow dose dependent, preconditioning effect of increasing doses may be ruled out at least in the case of parameters measured here.
Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Cognição/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Metanfetamina/administração & dosagem , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Ansiedade , Comportamento Animal/efeitos dos fármacos , Esquema de Medicação , Masculino , Ratos , Ratos WistarRESUMO
Methamphetamine (MA) produces long-lasting deficits in dopaminergic neurons in the long-term use via several neurotoxic mechanisms. The effects of MA on mitochondrial biogenesis is less studied currently. So, we evaluated the effects of repeated escalating MA regimen on transcriptional factors involved in mitochondrial biogenesis and glial-derived neurotrophic factor (GDNF) expression in substantia nigra (SN) and striatum of rat. In male Wistar rats, increasing doses of MA (1-14 mg/kg) were administrated twice a day for 14 days. At the 1st, 14th, 28th, and 60th days after MA discontinuation, we measured the PGC1α, TFAM and NRF1 mRNA levels, indicator of mitochondrial biogenesis, and GDNF expression in SN and striatum. Furthermore, we evaluated the glial fibrillary acidic protein (GFAP) and Iba1 mRNA levels, and the levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) using immunohistochemistry and real-time polymerase chain reaction (PCR). We detected increments in PGC1α and TFAM mRNA levels in SN, but not striatum, and elevations in GDNF levels in SN immediately after MA discontinuation. We also observed increases in GFAP and Iba1 mRNA levels in SN on day 1 and increases in Iba1 mRNA on days 1 and 14 in striatum. Data analysis revealed that the number of TH+ cells in the SN did not reduce in any time points, though TH mRNA levels was increased on day 1 after MA discontinuation in SN. These data show that repeated escalating MA induces several compensatory mechanisms, such as mitochondrial biogenesis and elevation in GDNF in SN. These mechanisms can reverse MA-induced neuroinflammation and prevent TH-immunoreactivity reduction in nigrostriatal pathway. J. Cell. Biochem. 118: 1369-1378, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Metanfetamina/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Fatores de Transcrição/genética , Animais , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Masculino , Metanfetamina/farmacologia , Mitocôndrias/genética , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Wistar , Substância Negra/metabolismo , Fatores de Transcrição/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Cell death subsequent to or concurrent with neuroinflammation results in some damages like neuron loss and spatial memory impairment. In this study, we demonstrated the temporal pattern of neuroinflammation, necroptotic, and apoptotic cell deaths in hippocampus and frontal cortex following intracerebroventricular administration of lipopolysaccharide (LPS). We evaluated receptor interacting protein kinase 1 (RIP1), RIP3, and two related metabolic enzymes including glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase (GLUD) as necroptosis factors. Apoptosis pathway, antioxidant status and inflammatory cytokines were also assessed. Based on the probable role of these brain regions in working memory performance, spontaneous alternation was evaluated through the Y-maze apparatus. RIP1, RIP3, and then GLUL and GLUD, as well as apoptosis markers, inflammatory regulators, and antioxidant defense demonstrated different time-dependent patterns in hippocampus and frontal cortex. Interestingly, in hippocampus but not in frontal cortex, necroptosis resumed apoptosis. Our results in behavioral section revealed that neuroinflammation along with apoptosis and necroptosis pathways could lead to reversible short-term memory impairment after LPS injection. In conclusion, it can be suggested that there is a region-specific response of cell deaths regulators activation in hippocampus and frontal cortex. In addition, elucidating the time profile of events in response to neuroinflammation would be of great help in mechanistic studies and understanding of pathways interaction. J. Cell. Biochem. 118: 4628-4638, 2017. © 2017 Wiley Periodicals, Inc.
Assuntos
Apoptose , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Animais , Lobo Frontal/patologia , Hipocampo/patologia , Lipopolissacarídeos/toxicidade , Masculino , Especificidade de Órgãos , Ratos , Ratos Wistar , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Although grape has been recently the topic of many investigations, Maviz (a kind of dried one) has remained neglected. The aim of this study was to assess anti-Alzheimer activity of Maviz. METHODS: To reach this goal, total phenolic content (TPC) of ethanolic (Eth) and aqueous (Aq) extracts were determined and radical scavenging activity was assayed by 2,2-diphenyl-1-picrylhydrazyl. Chemical compositions of each extract were also determined via GC-Mass. Behavioral changes were studied via passive avoidance and Morris water maze in Aß-induced model of Alzheimer's disease. Catalase (CAT) and superoxide dismutase (SOD) determination were also done on rats' hippocampus. RESULTS: The results showed that seed Eth extract has a high level of TPC and radical scavenging activity. However, this extract had surprisingly no effect on memory and CAT and SOD activities. In contrast, fruit Aq and Eth extracts (containing furfurals as major compounds) inhibited memory impairment (P < 0.001) and elevated brain levels of CAT and SOD(P < 0.05). CONCLUSION: It seems that Maviz non-phenolic compounds-most probably 5-hydroxymethylfurfural and other similar derivatives-are responsible for these actions.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Frutas/química , Extratos Vegetais/administração & dosagem , Vitis/química , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/análise , Aprendizagem da Esquiva , Modelos Animais de Doenças , Alimentos em Conserva , Sequestradores de Radicais Livres/análise , Furaldeído/análogos & derivados , Furaldeído/análise , Furaldeído/farmacologia , Hipocampo/enzimologia , Irã (Geográfico) , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Fenóis/administração & dosagem , Fenóis/análise , Compostos Fitoquímicos/análise , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Ratos , Ratos Wistar , Sementes/químicaRESUMO
AIM: To evaluate the effects of long-term, moderate level noise exposure during crucial periods of rat infants on stereological parameters of medial geniculate body (MGB) and auditory cortex. MATERIALS AND METHODS: Twenty-four male offspring of 12 pregnant rats were divided into four groups: fetal-to-critical period group, which were exposed to noise from the last 10 days of fetal life till postnatal day (PND) 29; fetal period group that exposed to noise during the last 10 days of fetal life; critical period group, exposed to noise from PND 15 till PND 29, and control group. White noise at 90 dB for 2 h per day was used. STATISTICAL ANALYSIS USED: Variance for variables was performed using Proc GLM followed by mean comparison by Duncan's multiple range test. RESULTS: Numerical density of neurons in MGB of fetal-to-critical period group was lower than control group. Similar results were seen in numerical density of neurons in layers IV and VI of auditory cortex. Furthermore, no significant difference was observed in the volume of auditory cortex among groups, and only MGB volume in fetal-to-critical period group was higher than other groups. Estimated total number of neurons in MGB was not significantly different among groups. CONCLUSION: It seems necessary to prevent long-term moderate level noise exposure during fetal-to-critical neonatal period.
Assuntos
Córtex Auditivo/fisiologia , Desenvolvimento Fetal/fisiologia , Corpos Geniculados/fisiologia , Ruído , Animais , Animais Recém-Nascidos , Contagem de Células , Feminino , Masculino , Neurônios/fisiologia , Gravidez , RatosRESUMO
Sphingosine-1 phosphate (S1P), a bioactive sphingolipid metabolite, plays an essential role in cellular homeostasis. It is well evidenced that enzymes responsible for S1P production, as well as S1P receptors are expressed in the central nervous system (CNS), implying that S1P may contribute to CNS physiology. In current review, we will present the current knowledge about developmental and neuromodulatory functions of S1P in the brain. Considering neuroprotective effects of S1P, we also review the relation between S1P and cellular autophagy, mitochondrial function, oxidative stress and apoptosis as well as molecular pathways underlying neuroprotective effects of S1P. Given these pivotal functions, in the last section, we will summarize latest findings about possible contribution of S1P dysregulation in neurological disorders like Alzheimer's disease and multiple sclerosis.