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2.
J Neuroimmune Pharmacol ; 19(1): 8, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427092

RESUMO

Aberrant activation of complement cascades plays an important role in the progress of neurological disorders. Complement C3, the central complement component, has been implicated in synaptic loss and cognitive impairment. Recent study has shown that wound injury-induced systemic inflammation can trigger the increase of C3 in the brain. Our previous studies have demonstrated that laparotomy-triggered systemic inflammation could induce neuroinflammation and cognitive dysfunctions. Furthermore, sustained activation of microglia was observed even 14 days after laparotomy, while most of cytokines had returned to basal levels rapidly at the earlier time point. Although we have demonstrated that anti-inflammatory intervention successfully attenuated cognitive dysfunction by preventing increase of cytokines and activation of microglia, how sustained activation of microglia and cognitive dysfunction occur is still a mystery. In this study, we investigated the role of C3 in mediating activation of microglia and cognitive dysfunction by using laparotomy in adult male mouse only as the experimental model of systemic inflammation and AAV9-C3shRNA. Our data observed that laparotomy induced neurotoxic reactive astrocytes with an increase of C3 in the hippocampus. Furthermore, inhibition of C3 by AAV9-C3shRNA prevented synaptic engulfment by microglia and attenuated cognitive dysfunctions after laparotomy. Inhibition of C3 did not modulate activation of astrocytes and expression of various cytokines. Current findings demonstrated that C3 plays significant roles in sustained activation of microglia and cognitive dysfunctions, which suggests that C3 is the valuable molecule target to attenuate in neurological conditions characterised by neuroinflammation and cognitive dysfunction.


Assuntos
Disfunção Cognitiva , Complemento C3 , Animais , Masculino , Camundongos , Astrócitos/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Laparotomia/efeitos adversos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Doenças Neuroinflamatórias
3.
Methods Mol Biol ; 2761: 431-455, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427254

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease, which is also referred to as an autoimmune disorder with chronic inflammatory demyelination affecting the core system that is the central nervous system (CNS). Demyelination is a pathological manifestation of MS. It is the destruction of myelin sheath, which is wrapped around the axons, and it results in the loss of synaptic connections and conduction along the axon is also compromised. Various attempts are made to understand MS and demyelination using various experimental models out of them. The most popular model is experimental autoimmune encephalomyelitis (EAE), in which autoimmunity against CNS components is induced in experimental animals by immunization with self-antigens derived from basic myelin protein. Astrocytes serve as a dual-edged sword both in demyelination and remyelination. Various drug targets have also been discussed that can be further explored for the treatment of MS. An extensive literature research was done from various online scholarly and research articles available on PubMed, Google Scholar, and Elsevier. Keywords used for these articles were astrocyte, demyelination, astrogliosis, and reactive astrocytes. This includes articles being the most relevant information to the area compiled to compose a current review.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Doenças Neurodegenerativas , Animais , Camundongos , Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Doenças Neurodegenerativas/metabolismo , Humanos
4.
Nihon Yakurigaku Zasshi ; 159(2): 118-122, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38432920

RESUMO

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function, and an imbalance of brain PUFAs is linked to mental disorders like autism and schizophrenia. However, the cellular and molecular mechanisms underlying the effects of PUFAs on the brain remain largely unknown. Since they are insoluble in water, specific transporters like fatty acid binding proteins (FABPs), are required for transport and function of PUFAs within cells. We focused on the relationship between FABP-mediated homeostasis of brain PUFAs and neural plasticity. We found that FABP3, with a high affinity for n-6 PUFAs, is predominantly expressed in the GABAergic inhibitory interneurons of the anterior cingulate cortex (ACC) in the adult mouse brain. FABP3 knockout (KO) mice show increased GABA synthesis and inhibitory synaptic transmission in the ACC. We also found that FABP7 controls lipid raft function in astrocytes, and astrocytes lacking FABP7 exhibit changes in response to external stimuli. Furthermore, in FABP7 KO mice, dendritic protrusion formation in pyramidal neurons becomes abnormal, and we have reported a decrease in spine density and excitatory synaptic transmission. Here, we introduced recent advances in the understanding of the functions of PUFAs and FABPs in the brain, focusing especially on FABP3 and FABP7, in relation to human mental disorders.


Assuntos
Proteínas de Ligação a Ácido Graxo , Transtornos Mentais , Adulto , Animais , Camundongos , Humanos , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos Insaturados , Encéfalo , Astrócitos , Camundongos Knockout
5.
Dev Cell ; 59(5): 559-560, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38471436

RESUMO

Developing therapeutics to improve metastatic brain cancer prognosis is hampered by limited experimental systems that recapitulate the brain tumor microenvironment. In this issue of Developmental Cell, Ishibashi et al. describe a glial-cancer cell co-culture system that enabled the identification of a targetable, astrocyte-driven mechanism of brain metastasis.


Assuntos
Astrócitos , Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/patologia , Encéfalo/patologia , Neuroglia , Microambiente Tumoral
6.
Cell Mol Life Sci ; 81(1): 139, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38480559

RESUMO

Neurotoxic amyloid-ß (Aß) peptides cause neurodegeneration in Alzheimer's disease (AD) patients' brains. They are released upon proteolytic processing of the amyloid precursor protein (APP) extracellularly at the ß-secretase site and intramembranously at the γ-secretase site. Several AD mouse models were developed to conduct respective research in vivo. Most of these classical models overexpress human APP with mutations driving AD-associated pathogenic APP processing. However, the resulting pattern of Aß species in the mouse brains differs from those observed in AD patients' brains. Particularly mutations proximal to the ß-secretase cleavage site (e.g., the so-called Swedish APP (APPswe) fostering Aß1-x formation) lead to artificial Aß production, as N-terminally truncated Aß peptides are hardly present in these mouse brains. Meprin ß is an alternative ß-secretase upregulated in brains of AD patients and capable of generating N-terminally truncated Aß2-x peptides. Therefore, we aimed to generate a mouse model for the production of so far underestimated Aß2-x peptides by conditionally overexpressing meprin ß in astrocytes. We chose astrocytes as meprin ß was detected in this cell type in close proximity to Aß plaques in AD patients' brains. The meprin ß-overexpressing mice showed elevated amyloidogenic APP processing detected with a newly generated neo-epitope-specific antibody. Furthermore, we observed elevated Aß production from endogenous APP as well as AD-related behavior changes (hyperlocomotion and deficits in spatial memory). The novel mouse model as well as the established tools and methods will be helpful to further characterize APP cleavage and the impact of different Aß species in future studies.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Humanos , Camundongos , Animais , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Astrócitos/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Proteólise , Encéfalo/metabolismo
7.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38473758

RESUMO

Alzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of ß-amyloid plaques, tau tangles, neuroinflammation, and synaptic/neuronal loss, the latter being the strongest correlating factor with memory and cognitive impairment. Through an in vitro study on a neurons-astrocytes-microglia (NAM) co-culture system, we analyzed the effects of cerebrospinal fluid (CSF) samples from AD and non-AD patients (other neurodegenerative pathologies). Treatment with CSF from AD patients showed a loss of neurofilaments and spheroids, suggesting the presence of elements including CX3CL1 (soluble form), destabilizing the neurofilaments, cellular adhesion processes, and intercellular contacts. The NAM co-cultures were analyzed in immunofluorescence assays for several markers related to AD, such as through zymography, where the expression of proteolytic enzymes was quantified both in cell extracts and the co-cultures' conditioned medium (CM). Through qRT-PCR assays, several genes involved in the formation of ß-amyloid plaque, in phosphorylation of tau, and in inflammation pathways and MMP expression were investigated.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Microglia/metabolismo , Técnicas de Cocultura , Astrócitos/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo
8.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473812

RESUMO

Gliomas are diffusely infiltrating brain tumors whose prognosis is strongly influenced by their extent of invasion into the surrounding brain tissue. While lower-grade gliomas present more circumscribed borders, high-grade gliomas are aggressive tumors with widespread brain infiltration and dissemination. Glioblastoma (GBM) is known for its high invasiveness and association with poor prognosis. Its low survival rate is due to the certainty of its recurrence, caused by microscopic brain infiltration which makes surgical eradication unattainable. New insights into GBM biology at the single-cell level have enabled the identification of mechanisms exploited by glioma cells for brain invasion. In this review, we explore the current understanding of several molecular pathways and mechanisms used by tumor cells to invade normal brain tissue. We address the intrinsic biological drivers of tumor cell invasion, by tackling how tumor cells interact with each other and with the tumor microenvironment (TME). We focus on the recently discovered neuronal niche in the TME, including local as well as distant neurons, contributing to glioma growth and invasion. We then address the mechanisms of invasion promoted by astrocytes and immune cells. Finally, we review the current literature on the therapeutic targeting of the molecular mechanisms of invasion.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/metabolismo , Invasividade Neoplásica/patologia , Glioma/metabolismo , Neoplasias Encefálicas/metabolismo , Astrócitos/metabolismo , Microambiente Tumoral
9.
Int J Mol Sci ; 25(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474060

RESUMO

The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.


Assuntos
Hiperglicinemia não Cetótica , Células-Tronco Pluripotentes Induzidas , Humanos , Hiperglicinemia não Cetótica/genética , Hiperglicinemia não Cetótica/patologia , Glicina Desidrogenase (Descarboxilante)/genética , Astrócitos/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Glicina , Serina
10.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474295

RESUMO

Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood-brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate-glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders.


Assuntos
Astrócitos , Ácido Glutâmico , Glutamina , Doenças Neurodegenerativas , Neurônios , Humanos , Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Comunicação Celular
11.
J Mol Neurosci ; 74(1): 28, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38441703

RESUMO

Mounting evidence suggests a significant correlation between depressive disorders and neurodegenerative conditions, encompassing Alzheimer's disease and Parkinson's disease (PD). Depression represents a substantial non-motor manifestation frequently identified in individuals with PD, posing a significant threat to patients' overall well-being and necessitating the implementation of effective management strategies. Despite its high prevalence, impacting over 40% of PD patients, the precise cellular and molecular mechanisms underlying depression and its relationship to dopaminergic system degeneration remain largely ambiguous. In this study, we presented our findings demonstrating distinct characteristics of cortical astrocytes in PD patients compared to reactivated glial cells in the substantia nigra. We identified a subset of differentially expressed genes associated with depressive disorders from PD-associated cortical astrocytes. Furthermore, we uncovered the potential involvement of the hypoxia signaling in driving cortical astrocytic dysfunctions. Through a comprehensive investigation utilizing transcriptome and chromatin accessibility analyses on cultured human astrocytes, we revealed that hypoxic treatment could induce similar expression changes observed in cortex from PD patients. Additionally, we provided evidence that activation of the HIF-1 signaling pathway suppressed the expression of key components of mitochondrial ribosomes and electron transport chain proteins COX2 and CYTB, resulting in abnormal mitochondrial membrane potential. Our results underscore the potential impact of glial metabolic abnormalities on the development of depressive disorders associated with Parkinson's disease.


Assuntos
Astrócitos , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Depressão/etiologia , Neuroglia , Hipóxia
12.
Chem Biol Drug Des ; 103(3): e14481, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38458969

RESUMO

Studies have shown that saikosaponin D (SSD) has favorable neurotherapeutic effects. Therefore, the objective of this study was to explore the efficacy and possible molecular mechanisms of SSD on pilocarpine (PP)-induced astrocyte injury. Primary astrocytes were isolated from juvenile rats and identified using immunofluorescence. The cells were treated with PP and/or SSD for 6 h and 12 h, respectively, followed by measurement of their viability through 3-(4,5-dimethylthiazol)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Next, quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of Glial fibrillary acidic protein (GFAP), C3, S100 calcium binding protein A10 (S100a10), pentraxin 3 (Ptx3), toll-like receptor 4 (TLR4), and RAG in astrocytes after different treatments. Enzyme-linked immunosorbent assay and biochemical tests were utilized to evaluate the level of inflammatory factors [interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α)] secreted by cells and the content of oxidative stress-related factors (malondialdehyde [MDA] and glutathione [GSH]) or enzyme activity (catalase [CAT] and glutathione peroxidase [GPX]) in cells. The JC-1 mitochondrial membrane potential (MMP) fluorescence probe was used to measure the MMP in astrocytes. Additionally, western blot was applied to test the expression of proteins related to the nod-like receptor protein 3 (NLRP3)/caspase-1 signaling pathway. PP treatment (1 mM) induced cell injury by significantly reducing the viability of astrocytes and expression of cellular markers. SSD treatment (4 µM) had no toxicity to astrocytes. Besides, SSD (4 µM) treatment could significantly up-regulate the cell viability and marker expression of PP-induced astrocytes. Furthermore, SSD could be employed to inhibit inflammation (reduce IL-1ß, IL-6, and TNF-α levels) and oxidative stress (decrease MDA level, elevate GSH level, the activity of CAT and GPX), and ameliorate mitochondrial dysfunction (upregulate JC-1 ratio) in PP-induced astrocytes. Moreover, further mechanism exploration revealed that SSD treatment significantly reduced the activity of the NLRP3/caspase-1 signaling pathway activated by PP induction. SSD increased cell viability, inhibited inflammation and oxidative stress response, and ameliorated mitochondrial dysfunction in PP-induced astrocyte injury model, thus playing a neuroprotective role. The mechanism of SSD may be related to the inhibition of the NLRP3/caspase-1 inflammasome.


Assuntos
Benzimidazóis , Carbocianinas , Doenças Mitocondriais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ácido Oleanólico/análogos & derivados , Saponinas , Ratos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Pilocarpina/toxicidade , Fator de Necrose Tumoral alfa/genética , Caspases/metabolismo , Interleucina-6 , Transdução de Sinais , Inflamação/metabolismo
13.
Sci Rep ; 14(1): 5272, 2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438491

RESUMO

We sought to identify alterations in the quantity of plasma brain-derived extracellular vesicles (EV) over the first month post-stroke to shed light on related injury and repair mechanisms. We assessed plasma levels of presumed neuron-derived EVs (NDEs), astrocyte-derived EVs (ADEs), and oligodendrocyte-derived EVs (ODEs) in 58 patients 5, 15, and 30 days post-ischemic stroke and 46 controls matched for cardiovascular risk factors using sandwich immunoassays. Subsets of brain-derived EVs were identified by co-expression of the general EV marker CD9 and markers for neurons (L1CAM, CD171), astrocytes (EAAT1), and oligodendrocytes (MOG) respectively. Clinical MRIs assessed lesion volume and presence of hemorrhagic transformation. ADE levels were elevated 5, 15, and 30 days post-stroke compared to controls (p = 0.002, p = 0.002, and p = 0.005 respectively) with no significant change for NDE or ODE. ADEs were increased 15 days post-stroke in patients with hemorrhagic transformation (p = 0.04) compared to patients with no hemorrhage. We conclude that ADE levels are preferentially increased over the first month post-stroke in humans, possibly to provide trophic support to injured neurons following ischemia. ADEs hold potential as biomarkers of blood-brain barrier breakdown and hemorrhagic transformation, but this requires further study at earlier time points post-stroke.


Assuntos
Vesículas Extracelulares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Astrócitos , Encéfalo
14.
Nat Commun ; 15(1): 2102, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453901

RESUMO

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.


Assuntos
Gorduras na Dieta , NAD , Masculino , Camundongos , Animais , NAD/metabolismo , Gorduras na Dieta/metabolismo , Astrócitos/metabolismo , Obesidade/metabolismo , Hipotálamo/metabolismo , Citocinas/metabolismo
15.
J Pharmacol Sci ; 154(4): 312-315, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38485349

RESUMO

We previously identified a spinal astrocyte population that expresses hairy and enhancer of split 5 (Hes5) and is selectively present in superficial laminae in mice. However, it was unclear whether such astrocyte heterogeneity is commonly observed across species. Using adeno-associated viral (AAV) vectors incorporating a rat Hes5 promotor (AAV-Hes5P), we found that AAV-Hes5P-captured astrocytes were selectively located in the superficial laminae in rats. Furthermore, activation of AAV-Hes5P+ astrocytes elicited allodynia-like behavior and increased c-FOS+ cells in the superficial laminae. Thus, laminar-selective Hes5+ astrocytes are conserved beyond species and have the capability to convert tactile information to nociceptive.


Assuntos
Astrócitos , Medula Espinal , Ratos , Camundongos , Animais , Nociceptividade , Proteínas Proto-Oncogênicas c-fos/genética , Hiperalgesia
16.
Alzheimers Res Ther ; 16(1): 63, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38521950

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia, and its underlying mechanisms have been a subject of great interest. The mainstream theory of AD pathology suggests that the disease is primarily associated with tau protein and amyloid-beta (Aß). However, an increasing body of research has revealed that abnormalities in lipid metabolism may be an important event throughout the pathophysiology of AD. Astrocytes, as important members of the lipid metabolism network in the brain, play a significant role in this event. The study of abnormal lipid metabolism in astrocytes provides a new perspective for understanding the pathogenesis of AD. This review focuses on the abnormal metabolism of fatty acids (FAs) and cholesterol in astrocytes in AD, and discusses it from three perspectives: lipid uptake, intracellular breakdown or synthesis metabolism, and efflux transport. We found that, despite the accumulation of their own fatty acids, astrocytes cannot efficiently uptake fatty acids from neurons, leading to fatty acid accumulation within neurons and resulting in lipotoxicity. In terms of cholesterol metabolism, astrocytes exhibit a decrease in endogenous synthesis due to the accumulation of exogenous cholesterol. Through a thorough investigation of these metabolic abnormalities, we can provide new insights for future therapeutic strategies by literature review to navigate this complex metabolic maze and bring hope to patients with Alzheimer's disease.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Ácidos Graxos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Colesterol
17.
J Cell Biol ; 223(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38477830

RESUMO

Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow adaptation to such complex environments are poorly understood. N-cadherin is highly expressed in pediatric gliomas and associated with shorter survival. We found that intercellular homotypic N-cadherin interactions differentially regulate glioma migration according to the microenvironment, stimulating migration on cultured neurons or astrocytes but inhibiting invasion into reconstituted or astrocyte-deposited extracellular matrix. N-cadherin localizes to filamentous connections between migrating leader cells but to epithelial-like junctions between followers. Leader cells have more surface and recycling N-cadherin, increased YAP1/TAZ signaling, and increased proliferation relative to followers. YAP1/TAZ signaling is dynamically regulated as leaders and followers change position, leading to altered N-cadherin levels and organization. Together, the results suggest that pediatric glioma cells adapt to different microenvironments by regulating N-cadherin dynamics and cell-cell contacts.


Assuntos
Caderinas , Glioma , Criança , Humanos , Astrócitos , Axônios , Caderinas/metabolismo , Movimento Celular , Glioma/metabolismo , Glioma/patologia , Microambiente Tumoral
18.
Ann Clin Lab Sci ; 54(1): 47-55, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38514065

RESUMO

OBJECTIVE: To investigate the clinical significance of miR-499a expression in the serum of ischemic stroke patients and its potential mechanism in regulating astrocytes to promote ischemic stroke. METHODS: Serum samples from 99 ischemic stroke patients and 99 healthy individuals were collected and analyzed for miR-499a expression through RT-PCR. Statistical analysis was performed to compare the expression differences between the two groups, and correlation between miR-499a expression and clinical pathological indices in stroke patients was analyzed. MiR-499a mimic, inhibitor, and negative control vectors were constructed and transfected into astrocyte SVGp12 cells. Afterward, miR-499a expression was validated by RT-PCR, cell viability was assessed by CCK8 assay, and apoptosis was detected using flow cytometry. The binding sites of miR-499a and Beclin1 were predicted by the Target-scan database and confirmed by dual luciferase assay. After overexpressing Beclin1, co-transfection with miR-499a mimic or negative control was conducted to observe the reverse effect of miR-499a mimic on Beclin1 overexpression. RESULTS: MiR-499a was significantly upregulated in the stroke group (p<0.001), it was positively correlated with TC (Total Cholesterol), LDL-C (Low-density lipoprotein cholesterol), and APO-A1 (Apolipoprotein A1) (R2>0.3, p<0.001). MiR-499a mimics promoted cell viability while inhibiting apoptosis of astrocytes. MiR-499a targeted Beclin 1 and inhibited its mRNA and protein expression, as well as the expression of autophagy-related proteins LC-3 and p62. MiR-499a could reverse the impact of Beclin1 overexpression on SVGp12 astrocyte proliferation and apoptosis. CONCLUSION: Serum miR-499a in stroke patients may serve as a potential diagnostic indicator. MiR-499a-mediated inhibition of Beclin 1, subsequently leading to suppression of astrocytic autophagy and viability, may represent a pivotal mechanism underlying its promotion of IS.


Assuntos
AVC Isquêmico , MicroRNAs , Acidente Vascular Cerebral , Humanos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Regulação para Cima/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Astrócitos , AVC Isquêmico/genética , Apoptose/genética , Acidente Vascular Cerebral/genética , Autofagia/genética , Colesterol
19.
Brain Res Bull ; 209: 110918, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38432497

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of high mortality and disability worldwide. Overactivation of astrocytes and overexpression of inflammatory responses in the injured brain are characteristic pathological features of TBI. Rosiglitazone (ROS) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist known for its anti-inflammatory activity. However, the relationship between the inflammatory response involved in ROS treatment and astrocyte A1 polarization remains unclear. OBJECTIVE: This study aimed to investigate whether ROS treatment improves dysfunction and astrocyte A1 polarization induced after TBI and to elucidate the underlying mechanisms of these functions. METHODS: SD rats were randomly divided into sham operation group, TBI group, TBI+ROS group, and TBI+ PPAR-γ antagonist group (GW9662 + TBI). The rat TBI injury model was prepared by the CCI method; brain water content test and wire grip test scores suggested the prognosis; FJB staining showed the changes of ROS on the morphology and number of neurons in the peripheral area of cortical injury; ELISA, immunofluorescence staining, and western blotting analysis revealed the effects of ROS on inflammatory response and astrocyte activation with the degree of A1 polarization after TBI. RESULTS: Brain water content, inflammatory factor expression, and astrocyte activation in the TBI group were higher than those in the sham-operated group (P < 0.05); compared with the TBI group, the expression of the above indexes in the ROS group was significantly lower (P < 0.05). Compared with the TBI group, PPAR-γ content was significantly higher and C3 content was considerably lower in the ROS group (P < 0.05); compared with the TBI group, PPAR-γ content was significantly lower and C3 content was substantially higher in the inhibitor group (P < 0.05). CONCLUSION: ROS can exert neuroprotective effects by inhibiting astrocyte A1 polarization through the PPAR-γ pathway based on the reduction of inflammatory factors and astrocyte activation in the brain after TBI.


Assuntos
Astrócitos , Lesões Encefálicas Traumáticas , Ratos , Animais , Rosiglitazona/farmacologia , Rosiglitazona/metabolismo , Astrócitos/metabolismo , Doenças Neuroinflamatórias , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ratos Sprague-Dawley , Lesões Encefálicas Traumáticas/metabolismo , Água/metabolismo
20.
Nature ; 627(8004): 604-611, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38448582

RESUMO

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.


Assuntos
Astrócitos , Esquizofrenia , Humanos , Astrócitos/metabolismo , Esquizofrenia/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal , Núcleo Solitário
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