Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.477
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360625

RESUMO

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.


Assuntos
Astrócitos/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Neuroglia/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Humanos
2.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445109

RESUMO

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the progressive disability of patients. A characteristic feature of the disease is the presence of focal demyelinating lesions accompanied by an inflammatory reaction. Interactions between autoreactive immune cells and glia cells are considered as a central mechanism underlying the pathology of MS. A glia-mediated inflammatory reaction followed by overproduction of free radicals and generation of glutamate-induced excitotoxicity promotes oligodendrocyte injury, contributing to demyelination and subsequent neurodegeneration. Activation of purinergic signaling, in particular P2X7 receptor-mediated signaling, in astrocytes and microglia is an important causative factor in these pathological processes. This review discusses the role of astroglial and microglial cells, and in particular glial P2X7 receptors, in inducing MS-related neuroinflammatory events, highlighting the importance of P2X7R-mediated molecular pathways in MS pathology and identifying these receptors as a potential therapeutic target.


Assuntos
Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Inflamação/metabolismo , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Animais , Humanos , Neuroglia/metabolismo , Transdução de Sinais/fisiologia
3.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445248

RESUMO

The functional neural circuits are partially repaired after an ischemic stroke in the central nervous system (CNS). In the CNS, neurovascular units, including neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes maintain homeostasis; however, these cellular networks are damaged after an ischemic stroke. The present review discusses the repair potential of stem cells (i.e., mesenchymal stem cells, endothelial precursor cells, and neural stem cells) and gaseous molecules (i.e., nitric oxide and carbon monoxide) with respect to neuroprotection in the acute phase and regeneration in the late phase after an ischemic stroke. Commonly shared molecular mechanisms in the neurovascular unit are associated with the vascular endothelial growth factor (VEGF) and its related factors. Stem cells and gaseous molecules may exert therapeutic effects by diminishing VEGF-mediated vascular leakage and facilitating VEGF-mediated regenerative capacity. This review presents an in-depth discussion of the regeneration ability by which endogenous neural stem cells and endothelial cells produce neurons and vessels capable of replacing injured neurons and vessels in the CNS.


Assuntos
Células Endoteliais/metabolismo , AVC Isquêmico/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Endoteliais/patologia , Humanos , AVC Isquêmico/patologia , Neuroglia/patologia , Neurônios/patologia , Células-Tronco/patologia
4.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360931

RESUMO

Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing to brain pathologies such Alzheimer's disease or multiple sclerosis. Intervention strategies targeting FA synthesis in glia represents a potential therapeutic opportunity for several CNS diseases.


Assuntos
Doenças do Sistema Nervoso Central/metabolismo , Sistema Nervoso Central , Ácidos Graxos/metabolismo , Neuroglia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Humanos , Neuroglia/metabolismo , Neuroglia/patologia
5.
Nat Commun ; 12(1): 4857, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381039

RESUMO

Physical exercise stimulates adult neurogenesis, yet the underlying mechanisms remain poorly understood. A fundamental component of the innate neuroregenerative capacity of zebrafish is the proliferative and neurogenic ability of the neural stem/progenitor cells. Here, we show that in the intact spinal cord, this plasticity response can be activated by physical exercise by demonstrating that the cholinergic neurotransmission from spinal locomotor neurons activates spinal neural stem/progenitor cells, leading to neurogenesis in the adult zebrafish. We also show that GABA acts in a non-synaptic fashion to maintain neural stem/progenitor cell quiescence in the spinal cord and that training-induced activation of neurogenesis requires a reduction of GABAA receptors. Furthermore, both pharmacological stimulation of cholinergic receptors, as well as interference with GABAergic signaling, promote functional recovery after spinal cord injury. Our findings provide a model for locomotor networks' activity-dependent neurogenesis during homeostasis and regeneration in the adult zebrafish spinal cord.


Assuntos
Locomoção , Neuroglia/metabolismo , Neurônios/metabolismo , Medula Espinal/crescimento & desenvolvimento , Animais , Interneurônios/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Condicionamento Físico Animal , Receptores Colinérgicos/metabolismo , Receptores de GABA-A/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/citologia , Medula Espinal/fisiologia , Transmissão Sináptica , Peixe-Zebra , Ácido gama-Aminobutírico/metabolismo
6.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360906

RESUMO

The most common cause of dementia, especially in elderly people, is Alzheimer's disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer's disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose/metabolismo , Terapia de Alvo Molecular/métodos , Idoso , Envelhecimento/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Insulina/metabolismo , Insulina/uso terapêutico , Neuroglia/metabolismo , Neurônios/metabolismo , Fatores de Risco
7.
Nature ; 596(7870): 97-102, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290404

RESUMO

Infection-induced aversion against enteropathogens is a conserved sickness behaviour that can promote host survival1,2. The aetiology of this behaviour remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviours against toxic microorganisms3-5. Whether and how enteric infections directly influence sensory perception to induce or modulate such behaviours remains unknown. Here we show that enteropathogen infection in Drosophila can modulate olfaction through metabolic reprogramming of ensheathing glia of the antennal lobe. Infection-induced unpaired cytokine expression in the intestine activates JAK-STAT signalling in ensheathing glia, inducing the expression of glial monocarboxylate transporters and the apolipoprotein glial lazarillo (GLaz), and affecting metabolic coupling of glia and neurons at the antennal lobe. This modulates olfactory discrimination, promotes the avoidance of bacteria-laced food and increases fly survival. Although transient in young flies, gut-induced metabolic reprogramming of ensheathing glia becomes constitutive in old flies owing to age-related intestinal inflammation, which contributes to an age-related decline in olfactory discrimination. Our findings identify adaptive glial metabolic reprogramming by gut-derived cytokines as a mechanism that causes lasting changes in a sensory system in ageing flies.


Assuntos
Envelhecimento/metabolismo , Citocinas/metabolismo , Drosophila melanogaster/metabolismo , Intestinos , Neuroglia/metabolismo , Olfato/fisiologia , Animais , Aprendizagem da Esquiva , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/microbiologia , Feminino , Inflamação/metabolismo , Inflamação/microbiologia , Intestinos/microbiologia , Janus Quinases/metabolismo , Ácido Láctico/metabolismo , Metabolismo dos Lipídeos , Neurônios/metabolismo , Pectobacterium carotovorum , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Fatores de Transcrição/metabolismo
8.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299185

RESUMO

Nervous system development involves proliferation and cell specification of progenitor cells into neurons and glial cells. Unveiling how this complex process is orchestrated under physiological conditions and deciphering the molecular and cellular changes leading to neurological diseases is mandatory. To date, great efforts have been aimed at identifying gene mutations associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the RNA/DNA binding protein Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) have been associated with motor neuron degeneration in rodents and humans. Furthermore, increased levels of the wild-type protein can promote neuronal cell death. Despite the well-established causal link between FUS mutations and ALS, its role in neural cells remains elusive. In order to shed new light on FUS functions we studied its role in the control of neural stem progenitor cell (NSPC) properties. Here, we report that human wild-type Fused in Sarcoma (WT FUS), exogenously expressed in mouse embryonic spinal cord-derived NSPCs, was localized in the nucleus, caused cell cycle arrest in G1 phase by affecting cell cycle regulator expression, and strongly reduced neuronal differentiation. Furthermore, the expression of the human mutant form of FUS (P525L-FUS), associated with early-onset ALS, drives the cells preferentially towards a glial lineage, strongly reducing the number of developing neurons. These results provide insight into the involvement of FUS in NSPC proliferation and differentiation into neurons and glia.


Assuntos
Mutação , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neurônios/patologia , Proteína FUS de Ligação a RNA/metabolismo , Medula Espinal/citologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Camundongos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Proteína FUS de Ligação a RNA/genética , Medula Espinal/embriologia , Medula Espinal/metabolismo , Medula Espinal/patologia
9.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298872

RESUMO

Connexins can assemble into either gap junctions (between two cells) or hemichannels (from one cell to the extracellular space) and mediate cell-to-cell signalling. A subset of connexins (Cx26, Cx30, Cx32) are directly sensitive to CO2 and fluctuations in the level within a physiological range affect their open probability, and thus, change cell conductance. These connexins are primarily found on astrocytes or oligodendrocytes, where increased CO2 leads to ATP release, which acts on P2X and P2Y receptors of neighbouring neurons and changes excitability. CO2-sensitive hemichannels are also found on developing cortical neurons, where they play a role in producing spontaneous neuronal activity. It is plausible that the transient opening of hemichannels allows cation influx, leading to depolarisation. Recently, we have shown that dopaminergic neurons in the substantia nigra and GABAergic neurons in the VTA also express Cx26 hemichannels. An increase in the level of CO2 results in hemichannel opening, increasing whole-cell conductance, and decreasing neuronal excitability. We found that the expression of Cx26 in the dopaminergic neurons in the substantia nigra at P7-10 is transferred to glial cells by P17-21, displaying a shift from being inhibitory (to neuronal activity) in young mice, to potentially excitatory (via ATP release). Thus, Cx26 hemichannels could have three modes of signalling (release of ATP, excitatory flickering open and shut and inhibitory shunting) depending on where they are expressed (neurons or glia) and the stage of development.


Assuntos
Dióxido de Carbono/metabolismo , Conexinas/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Animais , Astrócitos/metabolismo , Comunicação Celular/fisiologia , Humanos
10.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203972

RESUMO

Opioid abuse has become a major public health crisis that affects millions of individuals across the globe. This widespread abuse of prescription opioids and dramatic increase in the availability of illicit opioids have created what is known as the opioid epidemic. Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Limited information exists regarding the effect of oxycodone (oxy) on synaptic alterations. To fill this knowledge gap, we employed an integrated system approach to identify proteomic signatures and pathways impacted on mixed neuroglial cultures treated with oxy for 24 h. Differentially expressed proteins were mapped onto global canonical pathways using ingenuity pathway analysis (IPA), identifying enriched pathways associated with ephrin signaling, semaphorin signaling, synaptic long-term depression, endocannabinoid signaling, and opioid signaling. Further analysis by ClueGO identified that the dominant category of differentially expressed protein functions was associated with GDP binding. Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function.


Assuntos
Neuroglia/metabolismo , Oxicodona/farmacologia , Proteoma/metabolismo , Análise de Sistemas , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Ontologia Genética , Neuroglia/efeitos dos fármacos , Proteômica , Ratos Sprague-Dawley
11.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208383

RESUMO

Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-ß regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-ß, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and Müller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-ß, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.


Assuntos
Perfilação da Expressão Gênica , Neuroproteção/genética , Retinite Pigmentosa/genética , Transcrição Genética , Regulação para Cima/genética , Animais , Quimiocina CCL2/metabolismo , Feminino , Proteínas de Ligação ao GTP/metabolismo , Redes Reguladoras de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neuroglia/metabolismo , Degeneração Retiniana/complicações , Degeneração Retiniana/patologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Rodopsina/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281158

RESUMO

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron-glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury.


Assuntos
Lesões por Esmagamento/metabolismo , Citocinas/metabolismo , Neurônios/metabolismo , Animais , Constrição Patológica/metabolismo , Lesões por Esmagamento/genética , Citocinas/genética , Gânglios Espinais/metabolismo , Expressão Gênica/genética , Hiperalgesia/metabolismo , Masculino , Tecido Nervoso/metabolismo , Neuralgia/metabolismo , Neuroglia/metabolismo , Limiar da Dor , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Células Receptoras Sensoriais/metabolismo
13.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199982

RESUMO

Lysine succinylation is a post-translational modification which alters protein function in both physiological and pathological processes. Mindful that it requires succinyl-CoA, a metabolite formed within the mitochondrial matrix that cannot permeate the inner mitochondrial membrane, the question arises as to how there can be succinylation of proteins outside mitochondria. The present mini-review examines pathways participating in peroxisomal fatty acid oxidation that lead to succinyl-CoA production, potentially supporting succinylation of extramitochondrial proteins. Furthermore, the influence of the mitochondrial status on cytosolic NAD+ availability affecting the activity of cytosolic SIRT5 iso1 and iso4-in turn regulating cytosolic protein lysine succinylations-is presented. Finally, the discovery that glia in the adult human brain lack subunits of both alpha-ketoglutarate dehydrogenase complex and succinate-CoA ligase-thus being unable to produce succinyl-CoA in the matrix-and yet exhibit robust pancellular lysine succinylation, is highlighted.


Assuntos
Lisina/química , Lisina/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/química , Proteínas/metabolismo , Humanos , Complexo Cetoglutarato Desidrogenase/metabolismo , Neuroglia/metabolismo , Sirtuínas/metabolismo , Succinato Desidrogenase/metabolismo
14.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201807

RESUMO

MicroRNAs (miRNAs) are small, non-coding RNAs that function as endogenous gene silencers. Soon after the discovery of miRNAs, a subset of brain-enriched and brain-specific miRNAs were identified and significant advancements were made in delineating miRNA function in brain development. However, understanding the molecular mechanisms that regulate miRNA biogenesis in normal and diseased brains has become a prevailing challenge. Besides transcriptional regulation of miRNA host genes, miRNA processing intermediates are subjected to multifaceted regulation by canonical miRNA processing enzymes, RNA binding proteins (RBPs) and epitranscriptomic modifications. Further still, miRNA activity can be regulated by the sponging activity of other non-coding RNA classes, namely circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Differential abundance of these factors in neuronal and glial lineages partly underlies the spatiotemporal expression and function of lineage-specific miRNAs. Here, we review the continuously evolving understanding of the regulation of neuronal and glial miRNA biogenesis at the transcriptional and posttranscriptional levels and the cooperativity of miRNA species in targeting key mRNAs to drive lineage-specific development. In addition, we review dysregulation of neuronal and glial miRNAs and the detrimental impacts which contribute to developmental brain disorders.


Assuntos
Encefalopatias/patologia , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Neuroglia/patologia , Neurônios/patologia , RNA Mensageiro/metabolismo , Animais , Encefalopatias/genética , Encefalopatias/metabolismo , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética
15.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298977

RESUMO

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.


Assuntos
Sistema Nervoso Central/fisiopatologia , Inflamação/fisiopatologia , Lipídeos de Membrana/fisiologia , Modelos Biológicos , Degeneração Neural/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Esfingolipídeos/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Ceramidas/fisiologia , Eicosanoides/fisiologia , Previsões , Homeostase , Humanos , Inflamação/patologia , Lipoxigenase/fisiologia , Lisofosfolipídeos/fisiologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia
16.
Methods Mol Biol ; 2352: 13-29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324177

RESUMO

Spontaneous neuronal replacement is almost absent in the postnatal mammalian nervous system. However, several studies have shown that both early postnatal and adult astroglia can be reprogrammed in vitro or in vivo by forced expression of proneural transcription factors, such as Neurogenin-2 or Achaete-scute homolog 1 (Ascl1), to acquire a neuronal fate. The reprogramming process stably induces properties such as distinctly neuronal morphology, expression of neuron-specific proteins, and the gain of mature neuronal functional features. Direct conversion of astroglia into neurons thus possesses potential as a basis for cell-based strategies against neurological diseases. In this chapter, we describe a well-established protocol used for direct reprogramming of postnatal cortical astrocytes into functional neurons in vitro and discuss available tools and approaches to dissect molecular and cell biological mechanisms underlying the reprogramming process.


Assuntos
Astrócitos/citologia , Astrócitos/metabolismo , Reprogramação Celular , Neurônios/citologia , Neurônios/metabolismo , Animais , Diferenciação Celular/genética , Separação Celular/métodos , Células Cultivadas , Reprogramação Celular/genética , Camundongos , Neocórtex/citologia , Neuroglia/citologia , Neuroglia/metabolismo , Cultura Primária de Células , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Methods Mol Biol ; 2352: 117-126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324183

RESUMO

Somatic cell nuclear transfer and in vitro induction of pluripotency in somatic cells by defined factors provided unambiguous evidence that the epigenetic state of terminally differentiated somatic cells is not static and can be reversed to a more primitive one. Inspired by these results, stem cell biologists have identified approaches to directly convert fibroblasts into induced neuronal (iN) cells, indicating that direct lineage conversions are possible between distantly related cell types. More recently, we took advantages of pro-neurogenic capacity of iN factors and developed methods to rapidly derive functionally mature neurons directly from human pluripotent stem cells (hPSCs) through a brief induction of defined transcription factors. In this chapter, we describe the detailed methods used to attain the direct conversion from hPSCs to glutamatergic and GABAergic iN cells.


Assuntos
Diferenciação Celular , Neurônios/citologia , Neurônios/metabolismo , Células-Tronco Pluripotentes/citologia , Linhagem Celular , Separação Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Imunofluorescência , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/metabolismo , Vetores Genéticos/administração & dosagem , Vetores Genéticos/biossíntese , Vetores Genéticos/genética , Humanos , Lentivirus/genética , Neurogênese , Neuroglia/citologia , Neuroglia/metabolismo , Células-Tronco Pluripotentes/metabolismo , Fatores de Transcrição , Transdução Genética
18.
Commun Biol ; 4(1): 656, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079050

RESUMO

Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by systemic glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer's disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.


Assuntos
Encéfalo/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Neuroglia/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Doença de Alzheimer/genética , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Exenatida/farmacologia , Estudos de Viabilidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Neuroglia/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
19.
Nutrients ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063417

RESUMO

Severe and long-term vitamin C deficiency can lead to fatal scurvy, which is fortunately considered rare today. However, a moderate state of vitamin C (vitC) deficiency (hypovitaminosis C)-defined as a plasma concentration below 23 µM-is estimated to affect up to 10% of the population in the Western world, albeit clinical hallmarks in addition to scurvy have not been linked to vitC deficiency. The brain maintains a high vitC content and uniquely high levels during deficiency, supporting vitC's importance in the brain. Actions include both antioxidant and co-factor functions, rendering vitamin C deficiency likely to affect several targets in the brain, and it could be particularly significant during development where a high cellular metabolism and an immature antioxidant system might increase sensitivity. However, investigations of a non-scorbutic state of vitC deficiency and effects on the developing young brain are scarce. This narrative review provides a comprehensive overview of the complex mechanisms that regulate vitC homeostasis in vivo and in the brain in particular. Functions of vitC in the brain and the potential consequences of deficiency during brain development are highlighted, based primarily on findings from experimental animal models. Perspectives for future investigations of vitC are outlined.


Assuntos
Deficiência de Ácido Ascórbico/sangue , Ácido Ascórbico/metabolismo , Encéfalo/metabolismo , Escorbuto/metabolismo , Animais , Antioxidantes/metabolismo , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacocinética , Deficiência de Ácido Ascórbico/genética , Encéfalo/crescimento & desenvolvimento , Carnitina , Ácidos Graxos Insaturados/metabolismo , Homeostase , Humanos , Camundongos Knockout , Modelos Animais , Neuroglia/metabolismo , Neurônios/metabolismo , Transportadores de Sódio Acoplados à Vitamina C/genética
20.
Wiad Lek ; 74(6): 1409-1413, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159929

RESUMO

OBJECTIVE: The aim: To define the degree for glial acidic fibrillary protein expression on the structural components of cerebellum of the rats in health and when rats influenced by the food additives complex. PATIENTS AND METHODS: Materials and methods: In order to determine the degree of expression of the immunohistochemical marker GFAP on the structural components of the cerebellum of rats we applied immunohistochemical, morphometric and statistical methods in our study. RESULTS: Results: In histological specimens at the end of 1st week of observation in the gray matter of the cerebellum there occurred a gradual increase in 1.16 times of the average number of GFAP-positive cells. At the end of 4th week of the experimental study, the average number of GFAP-positive cells increased accurately (at p<0.05 compared to the control group) in 1.27 times, at the end of 8th week it has increased in 1.99 times, at the end of 12th week in 2.25, and at the end of 16th week in 2.39 times. CONCLUSION: Conclusions: The outcomes of our study are as follows the increase in the average number of GFAP-positive cells is directly related to the decrease in the average number of major neurons of the gray matter of the brain, while the fluctuations in the average number of astrocytic glia cells represent a compensatory mechanism in the recovery of gray matter neurons of the brain from neural stem cells with the subsequent development of reactive astrogliosis and, thereafter the possible development of neuropathology.


Assuntos
Aditivos Alimentares , Neuroglia , Astrócitos/metabolismo , Cerebelo/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Neuroglia/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...