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Article ; Online: P2 Purinergic Signaling in the Distal Lung in Health and Disease.

Wirsching, Eva / Fauler, Michael / Fois, Giorgio / Frick, Manfred

International journal of molecular sciences

2020 Volume 21, Issue 14

Abstract: The distal lung provides an intricate structure for gas exchange in mammalian lungs. Efficient gas exchange depends on the functional integrity of lung alveoli. The cells in the alveolar tissue serve various functions to maintain alveolar structure, ... ...

Abstract	The distal lung provides an intricate structure for gas exchange in mammalian lungs. Efficient gas exchange depends on the functional integrity of lung alveoli. The cells in the alveolar tissue serve various functions to maintain alveolar structure, integrity and homeostasis. Alveolar epithelial cells secrete pulmonary surfactant, regulate the alveolar surface liquid (ASL) volume and, together with resident and infiltrating immune cells, provide a powerful host-defense system against a multitude of particles, microbes and toxicants. It is well established that all of these cells express purinergic P2 receptors and that purinergic signaling plays important roles in maintaining alveolar homeostasis. Therefore, it is not surprising that purinergic signaling also contributes to development and progression of severe pathological conditions like pulmonary inflammation, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pulmonary fibrosis. Within this review we focus on the role of P2 purinergic signaling in the distal lung in health and disease. We recapitulate the expression of P2 receptors within the cells in the alveoli, the possible sources of ATP (adenosine triphosphate) within alveoli and the contribution of purinergic signaling to regulation of surfactant secretion, ASL volume and composition, as well as immune homeostasis. Finally, we summarize current knowledge of the role for P2 signaling in infectious pneumonia, ALI/ARDS and idiopathic pulmonary fibrosis (IPF).
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Humans ; Lung/metabolism ; Lung/pathology ; Lung Injury/metabolism ; Lung Injury/pathology ; Pneumonia/metabolism ; Pneumonia/pathology ; Pulmonary Alveoli/metabolism ; Pulmonary Alveoli/pathology ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Pulmonary Surfactants/metabolism ; Receptors, Purinergic P2/metabolism ; Signal Transduction/physiology
Chemical Substances	Pulmonary Surfactants ; Receptors, Purinergic P2 ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2020-07-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21144973
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Article ; Online: Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner.

Föhr, Karl Josef / Rapp, Michael / Fauler, Michael / Zimmer, Thomas / Jungwirth, Bettina / Messerer, David Alexander Christian

International journal of molecular sciences

2022 Volume 23, Issue 21

Abstract: Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an ... ...

Abstract	Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion channels has been classified as weak. Meanwhile, we identified aripiprazole in a preliminary test as a potent blocker of voltage-gated sodium channels. Here, we present a detailed analysis about the interaction of aripiprazole with the dominant voltage-gated sodium channel of heart muscle (hNa
MeSH term(s)	Humans ; Aripiprazole/pharmacology ; Kinetics ; Patch-Clamp Techniques ; Voltage-Gated Sodium Channels ; Myocardium ; Sodium Channel Blockers/pharmacology
Chemical Substances	Aripiprazole (82VFR53I78) ; Voltage-Gated Sodium Channels ; Sodium Channel Blockers
Language	English
Publishing date	2022-10-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232112890
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Article: Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner.

Föhr, Karl Josef / Nastos, Ariadni / Fauler, Michael / Zimmer, Thomas / Jungwirth, Bettina / Messerer, David Alexander Christian

Frontiers in pharmacology

2021 Volume 12, Page(s) 622489

Abstract: Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of ... ...

Abstract	Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2-3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties.
Language	English
Publishing date	2021-02-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.622489
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Article: Multi-Electrode Array Analysis Identifies Complex Dopamine Responses and Glucose Sensing Properties of Substantia Nigra Neurons in Mouse Brain Slices.

Mannal, Nadja / Kleiner, Katharina / Fauler, Michael / Dougalis, Antonios / Poetschke, Christina / Liss, Birgit

Frontiers in synaptic neuroscience

2021 Volume 13, Page(s) 635050

Abstract: Dopaminergic (DA) midbrain neurons within the substantia nigra (SN) display an autonomous pacemaker activity that is crucial for dopamine release and voluntary movement control. Their progressive degeneration is a hallmark of Parkinson's disease. Their ... ...

Abstract	Dopaminergic (DA) midbrain neurons within the substantia nigra (SN) display an autonomous pacemaker activity that is crucial for dopamine release and voluntary movement control. Their progressive degeneration is a hallmark of Parkinson's disease. Their metabolically demanding activity-mode affects Ca
Language	English
Publishing date	2021-02-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592086-8
ISSN	1663-3563
ISSN	1663-3563
DOI	10.3389/fnsyn.2021.635050
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Article ; Online: Cell-Specific RNA Quantification in Human SN DA Neurons from Heterogeneous Post-mortem Midbrain Samples by UV-Laser Microdissection and RT-qPCR.

Duda, Johanna / Fauler, Michael / Gründemann, Jan / Liss, Birgit

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1723, Page(s) 335–360

Abstract: Cell specificity of gene expression analysis is from particular relevance when the abundance of target cells is not homogeneous in the compared tissue samples, like it is the case, e.g., when comparing brain tissues from controls and in neurodegenerative ...

Abstract	Cell specificity of gene expression analysis is from particular relevance when the abundance of target cells is not homogeneous in the compared tissue samples, like it is the case, e.g., when comparing brain tissues from controls and in neurodegenerative disease states. While single-cell gene expression profiling is already a methodological challenge per se, it becomes even more prone to artifacts when analyzing individual cells from human post-mortem samples. Not only because human samples can never be matched as precisely as those from animal models, but also, because the RNA-quality that can be obtained from human samples usually displays a high range of variability. Here, we detail our most actual method for combining contact-free UV-laser microdissection (UV-LMD) with reverse transcription and quantitative PCR (RT-qPCR) that addresses all these issues. We specifically optimized our protocols to quantify and compare mRNA as well as miRNA levels in human neurons from post-mortem brain tissue. As human post-mortem tissue samples are never perfectly matched (e.g., in respect to distinct donor ages and RNA integrity numbers RIN), we refined data analysis by applying a linear mixed effects model to RT-qPCR data, which allows dissecting and subtracting linear contributions of distinct confounders on detected gene expression levels (i.e., RIN, age). All these issues were considered for comparative gene expression analysis in dopamine (DA) midbrain neurons of the Substantia nigra (SN) from controls and Parkinson's disease (PD) specimens, as the preferential degeneration of SN DA neurons in the pathological hallmark of PD. By utilizing the here-described protocol we identified that a variety of genes-encoding for ion channels, dopamine metabolism proteins, and PARK gene products-display a transcriptional dysregulation in remaining human SN DA neurons from PD brains compared to those of controls. We show that the linear mixed effects model allows further stratification of RT-qPCR data, as it indicated that differential gene expression of some genes was rather correlated with different ages of the analyzed human brain samples than with the disease state.
MeSH term(s)	Autopsy ; Brain/metabolism ; Case-Control Studies ; Dopaminergic Neurons/metabolism ; Humans ; Laser Capture Microdissection/methods ; Parkinson Disease/genetics ; RNA/analysis ; RNA/genetics ; Real-Time Polymerase Chain Reaction/methods ; Substantia Nigra/metabolism ; Ultraviolet Rays
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2018-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7558-7_19
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Article ; Online: Acute effects of cell stretch on keratin filaments in A549 lung cells.

Lutz, Anngrit / Jung, Dominik / Diem, Kathrin / Fauler, Michael / Port, Fabian / Gottschalk, Kay / Felder, Edward

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2020 Volume 34, Issue 8, Page(s) 11227–11242

Abstract: Keratin filaments (KFs) comprise the intermediate filaments of epithelial cells and are well known for their cytoprotective properties and their mechanical resilience. Although, several studies have demonstrated KFs' remarkable tensile properties ... ...

Abstract	Keratin filaments (KFs) comprise the intermediate filaments of epithelial cells and are well known for their cytoprotective properties and their mechanical resilience. Although, several studies have demonstrated KFs' remarkable tensile properties relatively little is known about acute implications of mechanical stretch on KFs in living cells. This includes structural effects on the KFs and their higher level assembly structures as well as posttranslational response mechanisms to possibly modify KF's properties. We subjected simple epithelial A549 lung cells to 30% unidirectional stretch and already after 10 seconds we observed morphological changes of the KF-network as well as structural effects on their desmosomal anchor sites-both apparently caused by the tensile strain. Interestingly, the effect on the desmosomes was attenuated after 30 seconds of cell stretch with a concomitant increase in phosphorylation of keratin8-S432, keratin18-S53, and keratin18-S34 without an apparent increase in keratin solubility. When mimicking the phosphorylation of keratin18-S34 the stretch-induced effect on the desmosomes could be diminished and probing the cell surface with atomic force microscopy showed a lowered elastic modulus. We conclude that the stretch-induced KF phosphorylation affects KF's tensile properties, probably to lower the mechanical load on strained desmosomal cell-cell contacts, and hence, preserve epithelial integrity.
MeSH term(s)	A549 Cells ; Cell Line, Tumor ; Cytoskeletal Proteins/metabolism ; Cytoskeleton/metabolism ; Epithelial Cells/metabolism ; Humans ; Intermediate Filaments/metabolism ; Keratins/metabolism ; Lung/metabolism ; Phosphorylation/physiology
Chemical Substances	Cytoskeletal Proteins ; Keratins (68238-35-7)
Language	English
Publishing date	2020-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201903160RR
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Article ; Online: Do medical students recognise the deteriorating patient by analysing their vital signs? A monocentric observational study based on the National Early Warning Score 2.

Messerer, David Alexander Christian / Fauler, Michael / Horneffer, Astrid / Schneider, Achim / Keis, Oliver / Mauder, Lea-Marie / Radermacher, Peter

BMJ open

2021 Volume 11, Issue 2, Page(s) e044354

Abstract: Objective: Assessment of the expertise of medical students in evaluating vital signs and their implications for the current risk of a patient, an appropriate monitoring frequency, and a proper clinical response.: Methods: 251 second-year and 267 ... ...

Abstract	Objective: Assessment of the expertise of medical students in evaluating vital signs and their implications for the current risk of a patient, an appropriate monitoring frequency, and a proper clinical response. Methods: 251 second-year and 267 fifth-year medical students in a curriculum consisting of 6 years of medical school at Ulm University, Germany, were interviewed in a paper-based questionnaire. The students were asked to rate their proficiency in interpreting vital signs and to give pathological thresholds of vital signs. Based on the National Early Warning Score 2 (NEWS2), nine vital signs of fictional patients were created and students were asked to comment on their clinical risk, to set an appropriate monitoring frequency as well as a clinical response. Results: Interviewing medical students regarding each vital sign individually, the students indicated a pathological threshold in accordance with the NEWS2 for respiratory rate, temperature, and heart rate. By contrast, inappropriate pathological limits were given regarding oxygen saturation and systolic blood pressure. Translating the vital signs into nine fictional patients, fifth-year medical students overall chose an appropriate response in 78% (67%-78%, median±IQR). In detail, fifth-year students successfully identified patients at very high or low risk and allocated them accordingly. However, cases on the edge were often stratified inappropriately. For example, a fictional case with vital signs indicating a surging sepsis was frequently underappreciated (48.5%) and allocated to an insufficient clinical response by fifth-year students. Conclusions: Recognising the healthy as well as the deteriorating patient is a key ability for future physicians. NEWS2-based education might be a valuable tool to assess and give feedback on student's knowledge in this vital professional activity.
MeSH term(s)	Early Warning Score ; Germany ; Humans ; Respiratory Rate ; Students, Medical ; Vital Signs
Language	English
Publishing date	2021-02-23
Publishing country	England
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2020-044354
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Article: Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10.

Fuchs, Eva / Messerer, David Alexander Christian / Karpel-Massler, Georg / Fauler, Michael / Zimmer, Thomas / Jungwirth, Bettina / Föhr, Karl Josef

Frontiers in pharmacology

2021 Volume 12, Page(s) 737637

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2021-10-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.737637
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Article ; Online: Measuring the Action of Oligonucleotide Therapeutics in the Lung at the Cell Type-Specific Level by Tissue Disruption and Cell Sorting (TDCS).

Graves, Helen / Evans, Steven / Fauler, Michael / Frick, Manfred / Moschos, Sterghios A

Methods in molecular biology (Clifton, N.J.)

2019 Volume 2036, Page(s) 187–203

Abstract: The clinical potential of DNA and RNA-targeting therapeutics for airways disease has been hampered by the poor translation of promising drug candidates from cell culture to in vivo models and the clinic. For example, classical preclinical approaches ... ...

Abstract	The clinical potential of DNA and RNA-targeting therapeutics for airways disease has been hampered by the poor translation of promising drug candidates from cell culture to in vivo models and the clinic. For example, classical preclinical approaches routinely report 20-60% target knockdown effects in the lung, where 1 or 2 log effects are observed in isolated cell cultures in vitro. Preparation of monocellular suspensions of tissues by mechanoenzymatic disruption followed by cell sorting (TDCS) after in vivo drug dosing, however, can offer pharmacokinetic and pharmacodynamic insights on the effects of drugs to precise cell subpopulations. Moreover, this can be reliably achieved with up to 66% fewer animals than standard in vivo pharmacology approaches due to lower data variance afforded through analytics on defined, viable cell numbers. Here we describe the TDCS methodology for the isolation of total lung epithelia, lung macrophages, and epithelium/macrophage-depleted cell fractions from mouse lungs using a two-stage sorting process of immunomagnetic bead separation followed by flow cytometric sorting using fluorescent antibodies against well-established surface markers such as F4/80, CD11b, and CD326. Validated antibodies for additional cell types and markers are also provided.
MeSH term(s)	Alveolar Epithelial Cells/metabolism ; Animals ; Biomarkers ; Flow Cytometry ; Immunomagnetic Separation/methods ; Lung/cytology ; Lung/drug effects ; Lung/metabolism ; Macrophages, Alveolar/drug effects ; Macrophages, Alveolar/metabolism ; Mice ; Oligonucleotides/pharmacology ; Oligonucleotides/therapeutic use ; Organ Specificity
Chemical Substances	Biomarkers ; Oligonucleotides
Language	English
Publishing date	2019-08-13
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9670-4_11
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Article ; Online: Deep learning-based image analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra.

Burkert, Nicole / Roy, Shoumik / Häusler, Max / Wuttke, Dominik / Müller, Sonja / Wiemer, Johanna / Hollmann, Helene / Oldrati, Marvin / Ramirez-Franco, Jorge / Benkert, Julia / Fauler, Michael / Duda, Johanna / Goaillard, Jean-Marc / Pötschke, Christina / Münchmeyer, Moritz / Parlato, Rosanna / Liss, Birgit

Communications biology

2023 Volume 6, Issue 1, Page(s) 1146

Abstract: Here we present a deep learning-based image analysis platform (DLAP), tailored to autonomously quantify cell numbers, and fluorescence signals within cellular compartments, derived from RNAscope or immunohistochemistry. We utilised DLAP to analyse ... ...

Abstract	Here we present a deep learning-based image analysis platform (DLAP), tailored to autonomously quantify cell numbers, and fluorescence signals within cellular compartments, derived from RNAscope or immunohistochemistry. We utilised DLAP to analyse subtypes of tyrosine hydroxylase (TH)-positive dopaminergic midbrain neurons in mouse and human brain-sections. These neurons modulate complex behaviour, and are differentially affected in Parkinson's and other diseases. DLAP allows the analysis of large cell numbers, and facilitates the identification of small cellular subpopulations. Using DLAP, we identified a small subpopulation of TH-positive neurons (~5%), mainly located in the very lateral Substantia nigra (SN), that was immunofluorescence-negative for the plasmalemmal dopamine transporter (DAT), with ~40% smaller cell bodies. These neurons were negative for aldehyde dehydrogenase 1A1, with a lower co-expression rate for dopamine-D2-autoreceptors, but a ~7-fold higher likelihood of calbindin-d28k co-expression (~70%). These results have important implications, as DAT is crucial for dopamine signalling, and is commonly used as a marker for dopaminergic SN neurons.
MeSH term(s)	Animals ; Humans ; Mice ; Deep Learning ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Dopaminergic Neurons ; Substantia Nigra
Chemical Substances	Dopamine (VTD58H1Z2X) ; Dopamine Plasma Membrane Transport Proteins
Language	English
Publishing date	2023-11-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05441-6
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