SiO2 Nanoparticles Modulate The Electrical Activity Of Neuroendocrine Cells Without Exerting Genomic Effects
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98032 | GEO | 2018/04/20
REPOSITORIES: GEO
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Project description:Background: Neuronal activity can be modeled as a nonlinear dynamical system to yield novel measures of neuronal state and dysfunction. We hypothesized that electrical activity during neuronal differentiation would be marked by a reduction in dynamical complexity in autism spectrum disorder (ASD). Methods: Electrical activity of induced pluripotent stem cell (iPSC)-derived neurons from ASD patients and controls were recorded using a multielectrode array (MEA). Minimum embedding dimension (MED) analysis was performed to characterize the complexity present in the electrical recordings of the neuronal cultures during differentiation. Gene expression changes with respect to the MED were analyzed, and gene ontology analysis and the BrainSpan Atlas were used to identify gene enrichments in specific biological pathways, brain regions, and developmental stages. Results: We found that the MED showed a statistically significant deficit in the ASD samples, suggesting that, compared to controls, network complexity is reduced in ASD during neuronal differentiation. MED was correlated to clinical endpoints such as nonverbal intelligence and was associated with 53 differentially expressed genes. These differentially expressed genes were overrepresented in ASD gene lists and pathways related to neurodevelopment, cell morphology, and cell migration. Spatiotemporal analysis also showed a prenatal temporal enrichment in cortical and deep brain structures. Conclusion: Reduced network complexity in ASD was observed by MED analysis during neuronal differentiation, indicating deficits in integrated and synchronized firing. The results present nonlinear dynamical analysis of iPSC-derived neuronal electrical recordings as a new paradigm for the investigation of aberrant brain activity in neurodevelopmental disorders.
2020-05-18 | GSE125020 | GEO
Project description:Silica nanoparticles (SiO2 NPs) are commonly used in medical and pharmaceutical fields. Research into the cytotoxicity and overall proteomic changes occurring during initial exposure to SiO2 NPs is limited. We investigated the mechanism of toxicity in human liver cells according to exposure time [0, 4, 10, and 16 hours (h)] to SiO2 NPs through proteomic analysis using mass spectrometry. SiO2 NP-induced cytotoxicity through various pathways in HepG2 cells. Interestingly, when cells were exposed to SiO2 NPs for 4 h, the morphology of the cells remained intact, while the expression of proteins involved in mRNA splicing, cell cycle, and mitochondrial function was significantly downregulated. These results show that the toxicity of the nanoparticles affects protein expression even if there is no change in cell morphology at the beginning of exposure to SiO2 NPs. The levels of reactive oxygen species changed significantly after 10 h of exposure to SiO2 NPs, and the expression of proteins associated with oxidative phosphorylation, and the immune system was upregulated. Eventually, these changes in protein expression induced HepG2 cell death. This study provides insights into cytotoxicity evaluation at early stages of exposure to SiO2 NPs through in vitro experiments.
2021-09-10 | PXD024206 | Pride
Project description:Objective: To assess the development of neuronal subtypes and the emergence of evoked electrical activity within the developing human ENS. Methods: Human foetal gut samples were obtaining via the MRC-Wellcome Trust Human Developmental Biology Resource (UK). Characterisation of the developing ENS was performed by immunohistochemistry, calcium imaging, RNAseq and qRT-PCR Results: Human foetal colon samples displayed robust Tuj1 immunohistochemistry by embryonic week (EW) 12 with a dense neuronal network at the level of the myenteric plexus. At EW12 expression of excitatory neurotransmitter markers (VAChT and Sub P) was observed. By contrast, inhibitory neurotransmitter markers (nNOS and VIP) were not observed until EW14. Co-labeling with synaptic markers (SYN1/SNAP-25) demonstrated the development of synaptic contacts by EW12. However, electrical train stimulation (40V,2s,20Hz of 300?s electrical pulses) did not evoke activity within the myenteric plexus of EW12 foetal gut (n=0/3). Similarly, the majority of EW14 gut tissues assessed (80%), demonstrated no response to electrical stimulation (n=4/5). Interestingly, at EW16 Tuj1+ expression, in the myenteric plexus, was observed within discrete ganglia and was combined with the emergence of calcium transients (F/F0=1.273±0.024;n=3), upon electrical stimulation (n=3/3), which were abolished after the addition of 1uM TTX (n=3/3). RNAseq and qRT-PCR analysis between EW12-16 revealed increases in expression in genes involved in neurotransmission and action potential generation including SCN9A and KCNQ3. Conclusion: Here we demonstrate the temporal development of human enteric neuronal subtypes from EW12-14 and the subsequent emergence of coordinated electrical activity within the human foetal ENS at approximately EW16.
2019-02-20 | GSE111307 | GEO
Project description:Dravet syndrome is a developmental and epileptic encephalopathy characterized by seizures, behavioral abnormalities, developmental deficits, and elevated risk of sudden unexpected death in epilepsy (SUDEP). Most patient cases are caused by de novo loss-of-function mutations in the gene SCN1A, causing a haploinsufficiency of the alpha subunit of the voltage-gated sodium channel NaV1.1. Within the brain, NaV1.1 is primarily localized to the axons of inhibitory neurons, and decreased NaV1.1 function is hypothesized to reduce GABAergic inhibitory neurotransmission within the brain, driving neuronal network hyperexcitability and subsequent pathology. We have developed a human in vitro model of Dravet syndrome using differentiated neurons derived from patient iPSC and enriched for GABA expressing neurons. Neurons were plated on high definition multielectrode arrays (HD-MEAs), permitting recordings from the same cultures over the 7-weeks duration of study at the network, single cell, and subcellular resolution. Using this capability, we characterized the features of axonal morphology and physiology. Neurons developed increased spiking activity and synchronous network bursting. Recordings were processed through a spike sorting pipeline for curation of single unit activity and to assess the effects of pharmacological treatments. At 7-weeks, the application of the GABAAR receptor agonist muscimol eliminated network bursting, indicating the presence of GABAergic neurotransmission. To identify the role of NaV1.1 on neuronal and network activity, cultures were treated with a dose-response of the NaV1.1 potentiator δ-theraphotoxin-Hm1a. This resulted in a strong increase in firing rates of putative GABAergic neurons, an increase in the intraburst firing rate, and eliminated network bursting. These results validate that potentiation of NaV1.1 in Dravet patient iPSC-derived neurons results in decreased firing synchrony in neuronal networks through increased GABAergic neuron activity and support the use of human neurons and HD-MEAs as viable high-throughput electrophysiological platform to enable therapeutic discovery.
2023-11-10 | GSE245113 | GEO
Project description:Elevated or ectopic expression of neuronal receptors and ion channels promotes tumor progression in many cancer types; neuroendocrine (NE) transformation of various adenocarcinomas has also been associated with increased aggressiveness. Whether the defining neuronal feature, namely electrical excitability, exists in cancer cells and whether this impacts cancer progression remains mostly unexplored. Small cell lung cancer (SCLC) is an archetypical example of highly aggressive NE cancers and is comprised of two major distinct subtypes of cancer cells: NE cells and non-NE cells. Here, we show that the NE cells are excitable, like neurons, while non-NE cells cannot fire action potentials, like astrocytes and other non-excitable cells. Action potential firing in NE cells directly promotes SCLC malignancy; however, the high ATP demand of electrical activity also leads to an unusual dependency on oxidative phosphorylation (OXPHOS) in NE cells. This finding contrasts with most cancer cells reported in the literature, which are non-excitable and heavily rely on aerobic glycolysis. Additionally, we find that non-NE cells metabolically support NE cells to supply their high ATP demand, promoting their excitability and malignancy, a process akin to the astrocyte-neuron metabolite shuttle. Lastly, we observe drastic changes in the innervation landscape during SCLC progression, which coincide with increased intratumoral heterogeneity (ITH) and elevated neuronal protein expression in SCLC cells, suggesting an induction of a tumor autonomous vicious cycle driven by cancer cell-intrinsic electrical activity, which confers long-term tumorigenic capability and metastatic potential.
2024-11-07 | GSE270281 | GEO
Project description:Secretomics analysis of conditioned media from first trimester/term human placental explant cultures after exposure to SiO2, TiO2 nanoparticles (NPs) (25 μg/mL) or diesel exhaust particles (DEPs, 0.45 μg/mL)using LC-MS/MS based label-free quantification (LFQ) analysis.
2024-05-21 | PXD047037 | Pride
Project description:Analysis of the effect of electrical field stimulation frequency at the gene expression level. Electrical stimulation has been shown to mature nascent cardiomyocytes and alter their beating properties. The purpose of the array was to identify potential mediators of these effects. Total RNA was isolated from cardiomyocytes subjected to 0.5 Hz, 1 Hz, or 2 Hz continuous electrical stimulation for 7 days, compared to an unstimulated control. Three samples from each group were analyzed
2015-11-05 | E-GEOD-74669 | biostudies-arrayexpress
Project description:Central nervous system (CNS) injuries and neurodegenerative diseases have markedly poor prognoses and can result in permanent dysfunction due to the general inability of CNS neurons to regenerate. Differentiation of transplanted stem cells has emerged as a therapeutic avenue to regenerate tissue architecture in damaged areas. Electrical stimulation is a promising approach for directing the differentiation outcomes and pattern of outgrowth of transplanted stem cells, however traditional inorganic bio-electrodes can induce adverse effects such as inflammation. Here, we demonstrate the implementation of two organic thin films, a polymer/reduced graphene oxide nanocomposite (P(rGO)) and PEDOT:PSS, that have favorable properties for implementation as conductive materials for electrical stimulation, as well as an inorganic indium tin oxide (ITO) conductive film. Transcriptomic analysis revealed that electrical stimulation improved neuronal differentiation of SH-SY5Y cells on all three films, with the greatest effect for P(rGO). Unique material- and electrical stimuli-mediated effects were observed, associated with differentiation, cell-substrate adhesion, and translation. Our work demonstrates that P(rGO) and PEDOT:PSS are highly promising organic materials for the development of biocompatible, conductive scaffolds that will enhance electrically-aided stem cell therapeutics for CNS injuries and neurodegenerative diseases.
2024-09-05 | GSE261580 | GEO
Project description:Rationale: Monitoring and controlling cardiomyocyte activity with optogenetic tools offers exciting possibilities for fundamental and translational cardiovascular research. Genetically encoded voltage indicators may be particularly attractive for minimal invasive and repeated assessments of cardiac excitation from the cellular to the whole heart level. Objective: To test the hypothesis that cardiomyocyte-targeted voltage-sensitive fluorescence protein 2.3 (VSFP2.3) can be exploited as optogenetic tool for the monitoring of electrical activity in isolated cardiomyocytes and the whole heart as well as function and maturity in induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Methods and Results: We first generated mice with cardiomyocyte-restricted expression of VSFP2.3 and demonstrated distinct sarcolemmal localization of VSFP2.3 without any signs for associated pathologies (assessed by echocardiography). Optically recorded VSFP2.3 signals correlated well with membrane voltage measured simultaneously by patch-clamping. The utility of VSFP2.3 for human action potential recordings was confirmed by simulation of immature and mature action potentials in murine VSFP2.3 cardiomyocytes. Optical cardiograms (OCGs) could be monitored in whole hearts ex vivo and minimally invasively in vivo via fiber optics at physiological heart rate (10 Hz) and under pacing-induced arrhythmia. Finally, we reprogrammed tail-tip fibroblasts from transgenic mice and used the VSFP2.3 sensor for benchmarking functional and structural maturation in iPSC-derived cardiomyocytes. Conclusions: We introduce a novel transgenic voltage-sensor model as a new method in cardiovascular research and provide proof-of-concept for its utility in optogenetic sensing of physiological and pathological excitation in mature and immature cardiomyocytes in vitro and in vivo. Determination of transgene (VSFP2.3) cardiotoxicity
2015-09-02 | E-GEOD-69190 | biostudies-arrayexpress
Project description:Purpose: To investigate the effect of transcorneal electrical stimulation (TES) on the retina of wildtype Brown Norway (BN) rats by gene expression profiling. Methods: TES was applied to BN adult wildtype rat retina in vivo for 1h (1ms biphasic pulses at 20Hz; current: 200 µA). RNA was isolated, processed and used for microarray-based expression profiling 4hrs after initial TES. An expression profile was generated for genes differentially expressed at 4hrs after TES vs. sham stimulated animals using a fold change cutoff of 1.2. We validated the profile by real-time quantitative reverse transcription-polymerase chain reaction (qPCR). In addition, the application of TES was verified at the structural and functional level. Results: Transcriptome changes associated with TES vs. sham stimulated BN wildtype retina were identified. 490 genes were differentially expressed in TES and included well-known genes as well as a large number of novel genes. Electrophysiological recordings showed physiological retinal function after TES and structural in vivo and ex vivo studies revealed intact retinal layers. Conclusion: Our results demonstrate that TES applied to the retina of wildtype BN rats induce a variety of transcriptome level changes and may help to understand the mechanisms underlying TES. In addition TES has no negative effect on structure and function of wildtype BN retina 24hrs after application.
2011-11-21 | GSE26174 | GEO