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  • 1
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    Online Resource
    A human stem cell-derived test system for agents modifying neuronal N-methyl-d-aspartate-type glutamate receptor Ca2+-signalling
    Springer Science and Business Media LLC ; 2021
    In:  Archives of Toxicology Vol. 95, No. 5 ( 2021-05), p. 1703-1722
    Details
    In: Archives of Toxicology, Springer Science and Business Media LLC, Vol. 95, No. 5 ( 2021-05), p. 1703-1722
    Abstract: Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neuroepithelial stem cell (NESC) population, we generate “mixed cortical cultures” (MCC) within 24 days. Characterization by immunocytochemistry, gene expression profiling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the N -methyl- d -aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell-derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca 2+ signalling. Changes of the intracellular free calcium ion concentration ([Ca 2+ ] i ) were measured by fluorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low µM range. MCC responded to kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and a subpopulation of 50% had functional NMDA-R. The receptor was modulated by Mg 2+ , Zn 2+ and Pb 2+ in the expected ways, and various toxicologically relevant agonists (quinolinic acid, ibotenic acid, domoic acid) triggered [Ca 2+ ] i responses in MCC. Antagonists, such as phencyclidine, ketamine and dextromethorphan, were also readily identified. Thus, the MCC developed here may fill an important gap in the panel of test systems available to characterize the effects of chemicals on neurotransmitter receptors.
    Type of Medium: Online Resource
    ISSN: 0340-5761 , 1432-0738
    URL: Article
    DOI: 10.1007/s00204-021-03024-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 2
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    G × E interactions as a basis for toxicological uncertainty
    Springer Science and Business Media LLC ; 2023
    In:  Archives of Toxicology Vol. 97, No. 7 ( 2023-07), p. 2035-2049
    Details
    In: Archives of Toxicology, Springer Science and Business Media LLC, Vol. 97, No. 7 ( 2023-07), p. 2035-2049
    Abstract: To transfer toxicological findings from model systems, e.g. animals, to humans, standardized safety factors are applied to account for intra-species and inter-species variabilities. An alternative approach would be to measure and model the actual compound-specific uncertainties. This biological concept assumes that all observed toxicities depend not only on the exposure situation (environment = E), but also on the genetic (G) background of the model (G  ×  E). As a quantitative discipline, toxicology needs to move beyond merely qualitative G  ×  E concepts. Research programs are required that determine the major biological variabilities affecting toxicity and categorize their relative weights and contributions. In a complementary approach, detailed case studies need to explore the role of genetic backgrounds in the adverse effects of defined chemicals. In addition, current understanding of the selection and propagation of adverse outcome pathways (AOP) in different biological environments is very limited. To improve understanding, a particular focus is required on modulatory and counter-regulatory steps. For quantitative approaches to address uncertainties, the concept of “genetic” influence needs a more precise definition. What is usually meant by this term in the context of G  ×  E are the protein functions encoded by the genes. Besides the g ene sequence, the regulation of the gene expression and function should also be accounted for. The widened concept of past and present “ g ene expression” influences is summarized here as G e . Also, the concept of “environment” needs some re-consideration in situations where exposure timing (E t ) is pivotal: prolonged or repeated exposure to the insult (chemical, physical, life style) affects G e . This implies that it changes the model system. The interaction of G e with E t might be denoted as G e  ×  E t . We provide here general explanations and specific examples for this concept and show how it could be applied in the context of New Approach Methodologies (NAM).
    Type of Medium: Online Resource
    ISSN: 0340-5761 , 1432-0738
    URL: Article
    DOI: 10.1007/s00204-023-03500-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 3
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    Distinct and Dynamic Transcriptome Adaptations of iPSC-Generated Astrocytes after Cytokine Stimulation
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 17 ( 2022-08-25), p. 2644-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 17 ( 2022-08-25), p. 2644-
    Abstract: Astrocytes (ACs) do not only play a role in normal neurogenesis and brain homeostasis, but also in inflammatory and neurodevelopmental disorders. We studied here the different patterns of inflammatory activation triggered by cytokines in human induced pluripotent stem cell (iPSC)-derived ACs. An optimized differentiation protocol provided non-inflamed ACs. These cells reacted to TNFα with a rapid translocation of NFκB, while AC precursors showed little response. Transcriptome changes were quantified at seven time points (2–72 h) after stimulation with TNFα, IFNγ or TNFα plus IFNγ. TNFα triggered a strong response within 2 h. It peaked from 12–24 h and reverted towards the ground state after 72 h. Activation by IFNγ was also rapid, but the response pattern differed from that of TNFα. For instance, several chemokines up-regulated by TNFα were not affected by IFNγ. Instead, MHC-II-related antigen presentation was drastically enhanced. The combination of the two cytokines led to a stronger and more persistent response. For instance, TRIB3 up-regulation by the combination of TNFα plus IFNγ may have slowed NFκB inactivation. Additionally, highly synergistic regulation was observed for inflammation modifiers, such as CASP4, and for STAT1-controlled genes. The combination of the cytokines also increased oxidative stress markers (e.g., CHAC1), led to phenotypic changes in ACs and triggered markers related to cell death. In summary, these data demonstrate that there is a large bandwidth of pro-inflammatory AC states, and that single markers are not suitable to describe AC activation or their modulation in disease, development and therapy.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11172644
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 4
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    Modeling ferroptosis in human dopaminergic neurons: Pitfalls and opportunities for neurodegeneration research
    Elsevier BV ; 2024
    In:  Redox Biology Vol. 73 ( 2024-07), p. 103165-
    Details
    In: Redox Biology, Elsevier BV, Vol. 73 ( 2024-07), p. 103165-
    Type of Medium: Online Resource
    ISSN: 2213-2317
    URL: Article
    DOI: 10.1016/j.redox.2024.103165
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
    detail.hit.zdb_id: 2701011-9
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  • 5
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    Establishment of an a priori protocol for the implementation and interpretation of an in‐vitro testing battery for the assessment of developmental neurotoxicity
    Wiley ; 2020
    In:  EFSA Supporting Publications Vol. 17, No. 10 ( 2020-10)
    Details
    In: EFSA Supporting Publications, Wiley, Vol. 17, No. 10 ( 2020-10)
    Type of Medium: Online Resource
    ISSN: 2397-8325 , 2397-8325
    URL: Article
    DOI: 10.2903/sp.efsa.2020.EN-1938
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 6
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    Definition of the Neurotoxicity-Associated Metabolic Signature Triggered by Berberine and Other Respiratory Chain Inhibitors
    MDPI AG ; 2023
    In:  Antioxidants Vol. 13, No. 1 ( 2023-12-28), p. 49-
    Details
    In: Antioxidants, MDPI AG, Vol. 13, No. 1 ( 2023-12-28), p. 49-
    Abstract: To characterize the hits from a phenotypic neurotoxicity screen, we obtained transcriptomics data for valinomycin, diethylstilbestrol, colchicine, rotenone, 1-methyl-4-phenylpyridinium (MPP), carbaryl and berberine (Ber). For all compounds, the concentration triggering neurite degeneration correlated with the onset of gene expression changes. The mechanistically diverse toxicants caused similar patterns of gene regulation: the responses were dominated by cell de-differentiation and a triggering of canonical stress response pathways driven by ATF4 and NRF2. To obtain more detailed and specific information on the modes-of-action, the effects on energy metabolism (respiration and glycolysis) were measured. Ber, rotenone and MPP inhibited the mitochondrial respiratory chain and they shared complex I as the target. This group of toxicants was further evaluated by metabolomics under experimental conditions that did not deplete ATP. Ber (204 changed metabolites) showed similar effects as MPP and rotenone. The overall metabolic situation was characterized by oxidative stress, an over-abundance of NADH ( 〉 1000% increase) and a re-routing of metabolism in order to dispose of the nitrogen resulting from increased amino acid turnover. This unique overall pattern led to the accumulation of metabolites known as biomarkers of neurodegeneration (saccharopine, aminoadipate and branched-chain ketoacids). These findings suggest that neurotoxicity of mitochondrial inhibitors may result from an ensemble of metabolic changes rather than from a simple ATP depletion. The combi-omics approach used here provided richer and more specific MoA data than the more common transcriptomics analysis alone. As Ber, a human drug and food supplement, mimicked closely the mode-of-action of known neurotoxicants, its potential hazard requires further investigation.
    Type of Medium: Online Resource
    ISSN: 2076-3921
    URL: Article
    DOI: 10.3390/antiox13010049
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2704216-9
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  • 7
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    Investigation of histone H4 hyperacetylation dynamics in the 5S rRNA genes family by chromatin immunoprecipitation assay
    Cambridge University Press (CUP) ; 2015
    In:  Zygote Vol. 23, No. 6 ( 2015-12), p. 951-954
    Details
    In: Zygote, Cambridge University Press (CUP), Vol. 23, No. 6 ( 2015-12), p. 951-954
    Abstract: Oogenesis is a critical event in the formation of female gamete, whose role in development is to transfer genomic information to the next generation. During this process, the gene expression pattern changes dramatically concomitant with genome remodelling, while genomic information is stably maintained. The aim of the present study was to investigate the presence of H4 acetylation of the oocyte and somatic 5S rRNA genes in Triturus cristatus , using chromatin immunoprecipitation assay (ChIP). Our findings suggest that some epigenetic mechanisms such as histone acetylation could be involved in the transcriptional regulation of 5S rRNA gene families.
    Type of Medium: Online Resource
    ISSN: 0967-1994 , 1469-8730
    URL: Article
    DOI: 10.1017/S0967199414000562
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2015
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  • 8
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    Generation of Human Nociceptor-Enriched Sensory Neurons for the Study of Pain-Related Dysfunctions
    Oxford University Press (OUP) ; 2022
    In:  Stem Cells Translational Medicine Vol. 11, No. 7 ( 2022-07-20), p. 727-741
    Details
    In: Stem Cells Translational Medicine, Oxford University Press (OUP), Vol. 11, No. 7 ( 2022-07-20), p. 727-741
    Abstract: In vitro models of the peripheral nervous system would benefit from further refinements to better support studies on neuropathies. In particular, the assessment of pain-related signals is still difficult in human cell cultures. Here, we harnessed induced pluripotent stem cells (iPSCs) to generate peripheral sensory neurons enriched in nociceptors. The objective was to generate a culture system with signaling endpoints suitable for pharmacological and toxicological studies. Neurons generated by conventional differentiation protocols expressed moderate levels of P2X3 purinergic receptors and only low levels of TRPV1 capsaicin receptors, when maturation time was kept to the upper practically useful limit of 6 weeks. As alternative approach, we generated cells with an inducible NGN1 transgene. Ectopic expression of this transcription factor during a defined time window of differentiation resulted in highly enriched nociceptor cultures, as determined by functional (P2X3 and TRPV1 receptors) and immunocytochemical phenotyping, complemented by extensive transcriptome profiling. Single cell recordings of Ca2+-indicator fluorescence from & gt;9000 cells were used to establish the “fraction of reactive cells” in a stimulated population as experimental endpoint, that appeared robust, transparent and quantifiable. To provide an example of application to biomedical studies, functional consequences of prolonged exposure to the chemotherapeutic drug oxaliplatin were examined at non-cytotoxic concentrations. We found (i) neuronal (allodynia-like) hypersensitivity to otherwise non-activating mechanical stimulation that could be blocked by modulators of voltage-gated sodium channels; (ii) hyper-responsiveness to TRPV1 receptor stimulation. These findings and several other measured functional alterations indicate that the model is suitable for pharmacological and toxicological studies related to peripheral neuropathies.
    Type of Medium: Online Resource
    ISSN: 2157-6564 , 2157-6580
    URL: Article
    DOI: 10.1093/stcltm/szac031
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    Correlations Between Deaf-Muteness and Cephalometric Characteristics in Adults
    European Scientific Institute, ESI ; 2017
    In:  European Scientific Journal, ESJ Vol. 13, No. 30 ( 2017-10-31), p. 1-
    Details
    In: European Scientific Journal, ESJ, European Scientific Institute, ESI, Vol. 13, No. 30 ( 2017-10-31), p. 1-
    Abstract: Objective: The purpose of this study was to assess any existing correlations between the phonatory function obviously affected in deaf-mute patients and dento-maxillary and/or facial anomalies. Material and Methods: The study comprised 55 deaf-mute patients (28 males and 27 females) aged between 23 and 76 from 2 cities of Romania, belonging to the Hearing Deficiency Persons’ Association. 13 were edentulous. Each patient was clinically and radiographically assessed. We applied computer assisted interpretetation of the profile teleradiographies using AudaxCeph and Scanora Lite 3.2.6 software for the following parameters: SNA, SNB, ANB, SN/ML, FH/ML, NL/ML, NL/+1 and ML/-1 angles, Ls-ELine, Li-ELine, UP and LP distances.The data was compared to normal values as referred to in the mentioned computer programs by using Student’s t-tests and the Bland Altman plot. Results: The following characteristics were identified as being statistically different from the normal values: SN/ML with a mean of -5,5°, FH/ML by 6,2°, NL/ML with -5,2°, Ls-ELine by -4,2 mm and Li-ELine with a mean of -3,7 mm. Conclusions: Deaf-mute patients tend to present hypodivergent vertical skeletal patterns, anterior mandibular growth/rotation and skeletal deep bite and also protruded lips, aspects which must be taken into consideration when commencing an orthodontic treatment.
    Type of Medium: Online Resource
    ISSN: 1857-7431 , 1857-7881
    URL: Issue
    URL: Article
    DOI: 10.19044/esj.2017.v13n30
    DOI: 10.19044/esj.2017.v13n30p1
    Language: Unknown
    Publisher: European Scientific Institute, ESI
    Publication Date: 2017
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    detail.hit.zdb_id: 2648284-8
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  • 10
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    Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors
    Springer Science and Business Media LLC ; 2021
    In:  Archives of Toxicology Vol. 95, No. 2 ( 2021-02), p. 591-615
    Details
    In: Archives of Toxicology, Springer Science and Business Media LLC, Vol. 95, No. 2 ( 2021-02), p. 591-615
    Abstract: Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at  〉  1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency.
    Type of Medium: Online Resource
    ISSN: 0340-5761 , 1432-0738
    URL: Article
    DOI: 10.1007/s00204-020-02970-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 124992-7
    detail.hit.zdb_id: 1458459-1
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