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CRISPR/Cas9-mediated knockout of p22phox leads to loss of Nox1 and Nox4, but not Nox5 activity
(2016)
The NADPH oxidases are important transmembrane proteins producing reactive oxygen species (ROS). Within the Nox family, different modes of activation can be discriminated. Nox1-3 are dependent on different cytosolic subunits, Nox4 seems to be constitutively active and Nox5 is directly activated by calcium. With the exception of Nox5, all Nox family members are thought to depend on the small transmembrane protein p22phox. With the discovery of the CRISPR/Cas9-system, a tool to alter genomic DNA sequences has become available. So far, this method has not been widely used in the redox community. On such basis, we decided to study the requirement of p22phox in the Nox complex using CRISPR/Cas9-mediated knockout. Knockout of the gene of p22phox, CYBA, led to an ablation of activity of Nox4 and Nox1 but not of Nox5. Production of hydrogen peroxide or superoxide after knockout could be rescued with either human or rat p22phox, but not with the DUOX-maturation factors DUOXA1/A2. Furthermore, different mutations of p22phox were studied regarding the influence on Nox4-dependent H2O2 production. P22phox Q130* and Y121H affected maturation and activity of Nox4. Hence, Nox5-dependent O2•- production is independent of p22phox, but native p22phox is needed for maturation of Nox4 and production of H2O2.
Das Sehen steht am Anfang jeglicher Deutung und Analyse filmischer Werke. Die Lektüre eines Films bedarf der visuellen Erfahrung. So trivial dieser Sachverhalt, so grundlegend ist doch die damit verbundene Frage nach der Bedeutung des Sehens für das filmische Bild. Wie wäre also eine filmische Lektüre von einer Lektüre im klassischen Sinn zu unterscheiden? Den Film als Text im weiten Sinn aufzufassen und zu lesen ist in den Medienwissenschaften durchaus geläufig. Knut Hickethier zufolge haben Film und Fernsehen das „Erzählen visualisiert". Doch wird eine solche durchaus legitime, ja für die Analyse produktive Annahme dem Filmbild gerecht? Sind Filmbilder per se narrativ oder zeigt sich in ihnen auch ein spezifisches ikonisches Moment, das nicht in einer Erzählstruktur aufgeht? In der anhaltenden Diskussion um den Iconic Turn wird stets auf die Differenz des Bildlichen als Erkenntnismodell und Wissenskategorie hingewiesen. Ein wesentlicher Bestandteil der ikonischen Differenz betrifft dabei die Darstellungsweise narrativer Episteme. Die Gleichzeitigkeit des Ungleichzeitigen in der Bilderzählung demonstriert etwa das simultane Erscheinen zeitlich-sukzessiver Ereignisse. Der Film wird zwar in der Regel auch den Bildkünsten zugeschlagen, doch eine solche Simultanität von Handlungsabläufen ist in diesem Medium eher selten zu beobachten. Der Mythos des Kinofilms installiert sich vielmehr gerade über die allgemeine Vorstellung, dass der Film Geschichten erzähle. Gleichwohl artikuliert sich - und nicht nur im experimentellen oder im Essay-Film - in der filmischen Darstellungsform eine Differenz des Bildlichen. Sie wird dann besonders relevant und anschaulich, wenn das Bildliche selbst in den Fokus der Narration gerät, wenn mithin die Erzählung in Bildern von Bildern erzählt. Dies geschieht insbesondere im autothematischen, selbstreferentiellen Film. Im deutschen Film findet sich dieser Gestus vor allem im Werk von Wim Wenders. Wenders gehört zweifelsohne zu den bedeutendsten Geschichten-Erzählern des Neuen Deutschen Films. Doch gleichzeitig dokumentieren seine Filme eine deutliche Sympathie für eine nicht-narrative Bildlichkeit.
Das [im Marmorbild] in Aussicht gestellte Leben ist […] das Band, das die Erzählung der Künste und der Liebe zusammenhält. In dieser Fügung von Kunst und Leben ist der Pygmalion-Mythos als Intertext der Eichendorffschen Novelle eingeschrieben. Die folgenden Überlegungen unternehmen den Versuch diese Textkonstellation unter dem Fokus der bildlichen Lebendigkeit zu lesen.
In Carl Barks' 1963 comic strip "The Invisible Intruder", the bed becomes the main theme of the story. We get to know how Uncle Scrooge became a creative and successful entrepreneur. Since his parents were too poor to provide a proper sleeping place for their son, Scrooge had to sleep in a cabinet drawer. Therefore, Scrooge's only aim was to buy himself a bed. His capitalist creativity is, as he himself admits, driven by the "desire for a better bed." With the economic growth of his company, his bed becomes bigger too. But in the end, he throws out his enormous mattress because it is too sensitive to the vibrations caused by the money rammer in the money bin; and moreover, the investigation into the cause of the vibrations became far too expensive. Eventually, Scrooge is returning to his childhood bed: the cabinet drawer. What is striking about this story is not the idea that objects of everyday culture play a leading role within a narrative; it is the fact that the usual cultural function of furniture is altered in a significant way. The misapplication of the drawer draws attention to the object of everyday culture as signifier of the everyday experience in capitalist societies. The function of the bed is no longer defined by criteria of good sleep but of economic calculation. The bed thereby becomes an agency within the narrative that questions the stability of the cultural and linguistic semantics of the everyday. In the following, I will press the point that the representation of the bed in literary texts from Homer to Kafka can be read as an implicit linguistic theory of cultural signification.
Propranolol as a potentially novel treatment of arteriovenous malformations: from bench to bedside
(2022)
Background: Propranolol is a non-selective blocker of the β-adrenergic receptor and has been used for treatment of proliferative infantile hemangiomas. The vasoconstrictive and antiangiogenic effects of propranolol led us to explore its potential application for the treatment of AVMs.
Methods: AVM tissue was cultured after surgical resection in the presence of 100μM propranolol or solvent DMSO. After incubation for 72 hours, tissue was harvested for testing. The expression levels of SDF1α, CXCR4, VEGF and HIF-1 was measured by rt-PCR. Furthermore, data of patients in 2 vascular centres harboring AVM was retrospectively interrogated for a time period of 20 years. The database included information about hemorrhage, AVM size and antihypertensive medication. Descriptive analyses were performed, focusing on the risk of hemorrhage, size of the lesion at presentation and clinical follow-up in patients on β-blocker medication versus those who were not.
Results: Among 483 patients, 73 (15%) were under β-blocker-treatment. 48% AVMs presented with hemorrhage at diagnosis. Patients under β-blocker-treatment had a lower risk of hemorrhage at the time of diagnosis in a univariate analysis (p<0,0001;OR13). Patients under β-blocker-treatment showed a significant higher chance for a lower Spetzler-Martin-grade ≤III (p<0,0001;OR6,5) and a lower risk for the presence of an associated aneurysm (p<0,0001;OR3,6).
Multivariate analysis including Spetzler-Martin-Grading, young age ≤50, presence of associated aneurysm and β-blocker-treatment showed reduced risk for hemorrhage under β-blocker-treatment (p<0,01,OR0,2).
The expression of CXCR4 was suppressed by propranolol most likely through the HIF-1-pathways. The gene-expression of vasculogenesis factors was decreased in with propranolol incubated AVMs.
Conclusion: β-Blocker medication seems to be associated with a decreased risk of AVM-related hemorrhage and AVM-size at presentation or during follow-up. Propranolol inhibits SDF1α-induced vasculogenesis by suppressing the expression of CXCR4 most likely through the HIF-1-pathways. Therefore, SDF1α/CXCR4 axis plays an important role in the vasculogenesis and migration of inflammatory cells in AVM lesions.
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
Im Folgenden sollen zwei literarische Freundschaftsgeschichten fokussiert werden, deren Kern in einer gewissen Zufälligkeit des Freundschaftsbundes besteht. Freundschaft erwächst bei so unterschiedlichen Autoren wie Baudelaire und Kafka aus einer Ethik der Täuschung, die im Zeichen des Bösen zu stehen scheint. Dem allgemeinen Verständnis nach beruht Freundschaft auf Gemeinsamkeit, auf Geschichte, auf Erinnerung. Die Protagonisten bei Baudelaire und Kafka kennen nichts von dem: Der Freund, von dem sie je erzählen, erscheint als zufälliger Einbruch in die Welt des literarischen Subjekts.
Rezension zu Barbara Naumann u. Edgar Pankow (Hg.): Bilder-Denken. Bildlichkeit und Argumentation. München (Wilhelm Fink) 2004. 307 S.
Das Denk-Bild ist mittlerweile ein geradezu klassischer Topos der Kulturwissenschaften. Dem vorliegenden Band geht es aber nicht vorrangig um die Benjamin'sche Figur eines dialektischen Bildes. Vielmehr wird der Frage nach einer eigenständigen Denkweise der Bilder und des Bildlichen in philosophischer, kultur-, kunst-, literatur- und medienwissenschaftlicher Perspektive nachgegangen.
Wenn im Folgenden von Masken des Erzählens die Rede sein wird, dann geschieht dies durchaus absichtsvoll mit Blick auf das Verständnis von Maske als Verstellung und als einer Form des Verbergens. Hinter der (Gesichts-)Maske liegt das wahre Gesicht. Die Rhetorik der Maske ist mithin immer schon ein Spiel mit der Figur des wahren Antlitzes und des wahren Blickes, eine Szene des Sehens und des Gesehenwerdens. Als Spielform des literarischen Diskurses ist die Maske ein genuin theatrales Moment. Das lateinische 'persona' meint in diesem Kontext die Maske im Sinne der durch die Schauspieler dargestellten Figuren, die 'dramatis personae'. Im Drama wird die gegenständliche, leblose Maske zur personalen Identität, die durch den Schauspieler buchstäblich Stimme und Leben erhält. Aus dieser Perspektive mag es widersinnig erscheinen, von Masken des Erzählens zu sprechen, zeichnet sich doch gerade das narrative Moment durch die Diegese aus. Die Erzählung als solche bedarf gerade nicht der theatralen Maske als Vermittlungsinstanz. Der Erzähler übernimmt hier die Funktion, die im Drama die Maske einnimmt. Die 'persona' kommt dabei allenfalls in einer uneigentlichen Bedeutung zur Geltung, in der Figuren- oder Personenrede. In der narratologischen Textanalyse ist es üblich, die Form der Rede als dramatischen Modus zu bezeichnen. Insofern schreibt sich dann doch das theatrale Moment der Maske in den narrativen Text ein. Doch nur selten wird die Person als 'persona', die Maske als Maske gelesen. Der folgende Versuch, das Erzählen als ein Modell der Maske zu lesen, ist nicht einer spezifisch narratologischen Perspektive geschuldet, sondern einigen Textbeobachtungen anhand einer Lektüre von John von Düffels Roman 'Houwelandt'. Vergleichend wird außerdem die Schlusssequenz aus Thomas Manns 'Buddenbrooks' in den Blick genommen, in der von Düffels narratives Masken-Spiel schon vorgezeichnet ist.
Dysfunction of the NO/sGC/cGMP signaling pathway has been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, agents stimulating cGMP synthesis via sGC are important therapeutic options for treatment of PH patients. An unwanted effect of this novel class of drugs is their systemic hypotensive effect. We tested the hypothesis that aerosolized intra-tracheal delivery of the sGC stimulator BAY41-8543 could diminish its systemic vasodilating effect.
Pharmacodynamics and -kinetics of BAY41-8543 after single intra-tracheal delivery was tested in healthy rats. Four weeks after a single injection of monocrotaline (MCT, 60 mg/kg s.c.), rats were randomized to a two-week treatment with either placebo, BAY 41-8543 (10 mg/kg per os (PO)) or intra-tracheal (IT) instillation (3 mg/kg or 1 mg/kg).
Circulating concentrations of the drug 10 mg/kg PO and 3 mg/kg IT were comparable. BAY 41-8543 was detected in the lung tissue and broncho-alveolar fluid after IT delivery at higher concentrations than after PO administration. Systemic arterial pressure transiently decreased after oral BAY 41-8543 and was unaffected by intratracheal instillation of the drug. PO 10 mg/kg and IT 3 mg/kg regimens partially reversed pulmonary hypertension and improved heart function in MCT-injected rats. Minor efficacy was noted in rats treated IT with 1 mg/kg. The degree of pulmonary vascular remodeling was largely reversed in all treatment groups.
Intratracheal administration of BAY 41-8543 reverses PAH and vascular structural remodeling in MCT-treated rats. Local lung delivery is not associated with systemic blood pressure lowering and represents thus a further development of PH treatment with sGC stimulators.
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.
Background
Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.
Results
In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH-/- mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH-/- mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.
Conclusion
Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.
Aim: NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.
Results: In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.
Innovation and conclusion: ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
Background: Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness.
Methods and Results: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ~506 ms with notched T waves). Parents were I° cousins – both heterozygous for the mutation and clinically unremarkable (QTc ~447 ms, father and ~396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q.
Conclusion: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.
Die Meridian-Rede ist als die zentrale poetologische Schrift Celans anzusehen, in der er sich mit unterschiedlichen poetologischen und philosophischen Konzepten auseinandersetzt. Im Folgenden werden die vielen für die Rede bedeutsamen Intertexte jedoch nicht nochmals thematisiert; es soll vielmehr das Augenmerk auf die Rhetorik des Raums gerichtet werden. [...] Aufbauend auf Celans Poetik des globalen Raums soll der Versuch unternommen werden, dessen Konzeption einer dichterischen Toposforschung anhand eines Gedichts aus dem im Jahr 1967 erschienenen Band "Atemwende" plausibel zu machen. Es handelt sich um das letzte Gedicht des zweiten Zyklus und trägt den Titel "Hafen".
Die globalen Waren, mit denen die Literatur handelt, sind oftmals Gegenstände, die sich der Wertform des Kapitals entziehen: Sie sind Gaben, die - etwa im Sinne Greenblatts - eine Zirkulation sozialer Energien bewirken oder - im Sinne Derridas - ein die Ökonomie des Tauschprinzips unterbrechendes Ereignis stiften können. Das globale Moment der Literatur bestünde demnach darin, dass, wie es Goethe in "Dichtung und Wahrheit" formuliert hat, "die Dichtkunst überhaupt eine Welt- und Völkergabe sei". Diesem Verständnis von Literatur als "Welt- und Völkergabe" ist auch Paul Celans Werk verpflichtet. In der Gabenstruktur seiner Gedichte, die sich in der bewussten Hinwendung zum Anderen anzeigt, kommt auch der Weltbezug dieser Dichtung zum Ausdruck. Diesen vielfältigen Facetten von Celans literarischem Weltbezug sind die in diesem Themenschwerpunkt versammelten Beiträge gewidmet. Dem Werk Celans muss die Struktur der Globalisierung nicht erst künstlich zugeschrieben werden: Sie ist ihm inhärent. Denn zum einen hat die Erfahrung von Migration und Mehrsprachigkeit Celans Schreiben in hohem Maß geprägt; zum anderen ist aber auch die globale Dimension der Literatur, nämlich der weltliterarische Gestus seines Schreibens, in den Texten stets präsent.