Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 480
Страница 310 из 548-
Pediatric brain tumors as a developmental disease.
PURPOSE OF REVIEW: Brain tumors are the most frequent solid cancer in the pediatric population. Owing to the rarity of environmental clues about their origin, it is tempting to consider these neoplasms as developmental processes gone awry. Our review will explore the heuristic power of this hypothesis and the influence of these findings on the clinical management. RECENT FINDING: A more accurate description of cancer predisposition syndrome has shown their frequent association with developmental abnormalities. Several genes involved in pediatric brain tumor oncogenesis are involved in developmental processes. Modeling of several pediatric brain tumor in cerebral organoids, mimicking embryonal stage of brain development, indicates that early events during brain development create the conditions necessary for their oncogenesis. SUMMARY: The onset of multiple brain tumor types early in life suggests a functional relationship between brain development and oncogenesis. A growing body of evidence seems to support the hypothesis that some of the main developmental steps in the brain can be highjacked by the tumors during their initiation. Collaborations between neuroscientists and oncologists should provide room for improvement in the knowledge for these neoplasms.
-
Zika Virus Can Strongly Infect and Disrupt Secondary Organizers in the Ventricular Zone of the Embryonic Chicken Brain.
Zika virus (ZIKV) is associated with severe neurodevelopmental impairments in human fetuses, including microencephaly. Previous reports examining neural progenitor tropism of ZIKV in organoid and animal models did not address whether the virus infects all neural progenitors uniformly. To explore this, ZIKV was injected into the neural tube of 2-day-old chicken embryos, resulting in nonuniform periventricular infection 3 days later. Recurrent foci of intense infection were present at specific signaling centers that influence neuroepithelial patterning at a distance through secretion of morphogens. ZIKV infection reduced transcript levels for 3 morphogens, SHH, BMP7, and FGF8 expressed at the midbrain basal plate, hypothalamic floor plate, and isthmus, respectively. Levels of Patched1, a SHH-pathway downstream gene, were also reduced, and a SHH-dependent cell population in the ventral midbrain was shifted in position. Thus, the diminishment of signaling centers through ZIKV-mediated apoptosis may yield broader, non-cell-autonomous changes in brain patterning.
-
Xiaoyaosan reactivates the muscle-brain axis via FNDC5/Irisin to ameliorate LPS-induced depression.
BACKGROUND: The muscle-brain axis is critical in neuropsychiatric disorders. However, its role in the antidepressant mechanism of Xiaoyaosan (XYS) remains unclear. This study explored whether XYS exerts antidepressant effects by modulating the muscle FNDC5/Irisin-mediated muscle-brain axis to restore hippocampal synaptic plasticity. METHODS: LPS-induced mouse model was established for in vivo evaluation. In vitro, siRNA knockdown in C2C12-HT22 Transwell co-culture system was used to investigate the involvement of FNDC5/Irisin signaling in muscle-neuron communication. Neuromuscular organoids were established as a three-dimensional platform to model key features of muscle-neuron interactions. Untargeted metabolomics, immunohistochemistry, immunofluorescence, Western blotting, and ELISA were performed. RESULTS: XYS dose-dependently ameliorated LPS-induced depressive-like behaviors, restored muscle fiber integrity, and reversed hippocampal neuronal loss and synaptic deficits. Metabolomics analysis showed that XYS was associated with normalized metabolite profiles associated with β-alanine and taurine metabolism in the hippocampus and PPAR signaling pathway in the muscle. XYS was also associated with activation of the muscle PPARγ/PGC-1α/FNDC5/Irisin signaling pathway, accompanied by increased circulating Irisin levels and upregulation of hippocampal BDNF, PSD95, and synaptophysin. siRNA knockdown of FNDC5 attenuated the effects of XYS on Irisin secretion and synaptic marker restoration in co-cultured neurons. In organoids, XYS protected both myotube and neuronal compartments from LPS-induced injury. CONCLUSION: XYS exerts antidepressant effects, at least in part, through the activation of the muscle PPARγ/PGC-1α/FNDC5/Irisin axis and the restoration of hippocampal BDNF-mediated synaptic plasticity. The present findings support a potential role for FNDC5/Irisin in peripheral-to-central signaling associated with the antidepressant effects of XYS. These findings further suggest that the muscle-brain axis may represent a promising therapeutic target for depression and warrants further investigation.
-
MTOR pathway in focal cortical dysplasia type 2: What do we know?
Focal cortical dysplasia (FCD) is the most commonly encountered developmental malformation that causes refractory epilepsy. Focal cortical dysplasia type 2 is one of the most usual neuropathological findings in tissues resected therapeutically from patients with drug-resistant epilepsy. Unlike other types of FCD, it is characterized by laminar disorganization and dysplastic neurons, which compromise the organization of the six histologically known layers in the cortex; the morphology and/or cell location can also be altered. A comprehensive review about the pathogenesis of this disease is important because of the necessity to update the results reported over the past years. Here, we present an updated review through Pubmed about the mammalian target of rapamycin (MTOR) pathway in FCD type 2. A wide variety of aspects was covered in 44 articles related to molecular and cellular biology, including experiments in animal and human models. The first publications appeared in 2004, but there is still a lack of studies specifically for one type of FCD. With the advancement of techniques and greater access to molecular and cellular experiments, such as induced pluripotent stem cells (iPSCs) and organoids, it is believed that the trend is increasing the number of publications contributing to the achievement of new discoveries.
-
Identification and mechanism analysis of biomarkers related to butyrate metabolism in COVID-19 patients.
BACKGROUND: Butyrate may inhibit SARS-CoV-2 replication and affect the development of COVID-19. However, there have been no systematic comprehensive analyses of the role of butyrate metabolism-related genes (BMRGs) in COVID-19. METHODS: We performed differential expression analysis of BMRGs in the brain, liver and pancreas of COVID-19 patients and controls in GSE157852 and GSE151803. The differentially expressed genes (DEGs) and module genes between COVID-19 patients and healthy controls in GSE171110 were screened through 'limma' and 'WGANA' R package, respectively, followed by an intersection with BMRGs via 'ggvenn' R package. Six machine learning algorithms were employed to determine the best model for identifying biomarkers, and receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic value of the biomarkers in COVID-19. Moreover, the differences in immune-infiltrating cells between the COVID-19 and control groups were compared using CIBERSORT. The differences in immune cells and expression levels of biomarkers in immune cells among different tissues were analysed using GSE171668. RESULTS: The BMRGs were the most different in the brain between the COVID-19 and control groups, including 21 upregulated and 16 downregulated genes. Five important common BMRGs were screened as biomarkers for COVID-19 using XGBoost, namely CCNB1, CCNA2, BRCA1, HBB and HSPA5, with increased diagnostic performance. Enrichment analysis revealed that these five genes were related to the cell cycle, cell proliferation and cell senescence. The infiltrating abundance of 12 immune cells was different between the COVID-19 and control groups. Finally, the expression levels of HSPA5, BRCA1 and HBB were higher in annotated cells than in CCNB1 and CCNA2, and there were four different types of immune cells in the liver, heart, lungs and kidneys. CONCLUSIONS: These five genes may be potential biomarkers of butyrate metabolism in COVID-19 patients. These findings provide a direction for further studies on the molecular mechanisms underlying COVID-19.
-
Tensor-cell2cell v2 unravels coordinated dynamics of protein- and metabolite-mediated cell-cell communication.
SUMMARY: Cell-cell communication dynamically changes across time while involving diverse cell populations and ligand types such as proteins and metabolites. Single-cell transcriptomics enables its inference, but existing tools typically analyze ligand types separately and overlook their coordinated activity. Here, we present Tensor-cell2cell v2, a computational tool that can jointly analyze protein- and metabolite-mediated communication over time using coupled tensor component analysis, while preserving each modality of inferred communication scores independently, as well as their data structures and distributions. Applied to brain organoid development, Tensor-cell2cell v2 uncovers dynamic, coordinated communication programs involving key proteins and metabolites across relevant cell types and specific time points. AVAILABILITY AND IMPLEMENTATION: Tensor-cell2cell v2 and its new coupled tensor component analysis are implemented in Python and available as part of the cell2cell framework at https://github.com/earmingol/cell2cell. This python library is available on PyPI. Code for the analyses of this manuscript can be found in a Code Ocean capsule at https://doi.org/10.24433/CO.0061424.v3, where analyses can be also run and reproduced online. Tutorials can be found at https://cell2cell.readthedocs.io.
-
Advances in construction and modeling of functional neural circuits in vitro.
Over the years, techniques have been developed to culture and assemble neurons, which brought us closer to creating neuronal circuits that functionally and structurally mimic parts of the brain. Starting with primary culture of neurons, preparations of neuronal culture have advanced substantially. Development of stem cell research and brain organoids has opened a new path for generating three-dimensional human neural circuits. Along with the progress in biology, engineering technologies advanced and paved the way for construction of neural circuit structures. In this article, we overview research progress and discuss perspective of in vitro neural circuits and their ability and potential to acquire functions. Construction of in vitro neural circuits with complex higher-order functions would be achieved by converging development in diverse major disciplines including neuroscience, stem cell biology, tissue engineering, electrical engineering and computer science.
-
Consequences of Viral Infection and Cytokine Production During Pregnancy on Brain Development in Offspring.
Infections during pregnancy can seriously damage fetal neurodevelopment by aberrantly activating the maternal immune system, directly impacting fetal neural cells. Increasing evidence suggests that these adverse impacts involve alterations in neural stem cell biology with long-term consequences for offspring, including neurodevelopmental disorders such as autism spectrum disorder, schizophrenia, and cognitive impairment. Here we review how maternal infection with viruses such as Influenza A, Cytomegalovirus, and Zika during pregnancy can affect the brain development of offspring by promoting the release of maternal pro-inflammatory cytokines, triggering neuroinflammation of the fetal brain, and/or directly infecting fetal neural cells. In addition, we review insights into how these infections impact human brain development from studies with animal models and brain organoids. Finally, we discuss how maternal infection with SARS-CoV-2 may have consequences for neurodevelopment of the offspring.
-
RNA Sequencing Reveals a Strong Predominance of THRA Splicing Isoform 2 in the Developing and Adult Human Brain.
Thyroid hormone receptor alpha (THRα) is a nuclear hormone receptor that binds triiodothyronine (T3) and acts as an important transcription factor in development, metabolism, and reproduction. In mammals, THRα has two major splicing isoforms, THRα1 and THRα2. The better-characterized isoform, THRα1, is a transcriptional stimulator of genes involved in cell metabolism and growth. The less-well-characterized isoform, THRα2, lacks the ligand-binding domain (LBD) and is thought to act as an inhibitor of THRα1 activity. The ratio of THRα1 to THRα2 splicing isoforms is therefore critical for transcriptional regulation in different tissues and during development. However, the expression patterns of both isoforms have not been studied in healthy human tissues or in the developing brain. Given the lack of commercially available isoform-specific antibodies, we addressed this question by analyzing four bulk RNA-sequencing datasets and two scRNA-sequencing datasets to determine the RNA expression levels of human THRA1 and THRA2 transcripts in healthy adult tissues and in the developing brain. We demonstrate how 10X Chromium scRNA-seq datasets can be used to perform splicing-sensitive analyses of isoforms that differ at the 3'-end. In all datasets, we found a strong predominance of THRA2 transcripts at all examined stages of human brain development and in the central nervous system of healthy human adults.
-
The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model.
The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity. Untargeted mass spectrometry-based proteomics revealed that MLN4924 and CSN5i-3 substantially alter the microglial proteome, including inflammation-related proteins. Applying these drugs and mimicking microglial and endothelial inflammation as well as ischemic neuronal stress by TNF and oxygen-glucose-deprivation/reoxygenation (OGD/RO) treatment, respectively, we could link CSN5/CSN-mediated cullin deNEDDylation to reduction of microglial inflammation, attenuated cerebral endothelial inflammation, improved barrier integrity, as well as protection from ischemic stress-induced neuronal cell death. Specifically, MLN4924 reduced phagocytic activity, motility, and inflammatory cytokine expression of microglial cells, and this was linked to inhibition of inflammation-induced NF-κB and Akt signaling. Inversely, Csn5 knockdown and CSN5i-3 increased NF-κB signaling. Moreover, MLN4924 abrogated TNF-induced NF-κB signaling in cerebral microvascular endothelial cells (hCMECs) and rescued hCMEC monolayers from OGD/RO-triggered barrier leakage, while CSN5i-3 exacerbated permeability. In an ex vivo organotypic brain slice model of ischemia/reperfusion stress, MLN4924 protected from neuronal death, while CSN5i-3 impaired neuronal survival. Neuronal damage was attributable to microglial activation and inflammatory cytokines, as indicated by microglial shape tracking and TNF-blocking experiments. Our results indicate a protective role of the CSN in neuroinflammation via brain-resident cell types involved in ischemic brain disease and implicate CSN activity-mimicking deNEDDylating drugs as potential therapeutics.