Publications by authors named "Stefan Günther"

138 Publications

Biosynthesis of the Tricyclic Aromatic Type II Polyketide Rishirilide: New Potential Third Ring Oxygenation after Three Cyclization Steps.

Mol Biotechnol 2021 Mar 24. Epub 2021 Mar 24.

Institute of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-Universität, Stefan-Meier-Straße 19, 79104, Freiburg, Germany.

Rishirilides are a group of PKS II secondary metabolites produced by Streptomyces bottropensis Gö C4/4. Biosynthetic studies in the past have elucidated early and late steps of rishirilide biosynthesis. This work is aiming to solve the remaining steps in the rishirilide biosynthesis. Inactivation of the cyclase gene rslC3 in Streptomyces bottropensis resulted in an interruption of rishirilide production. Instead, accumulation of the tricyclic aromatic galvaquinones was observed. Similar results were observed after deletion of rslO4. Closer inspection into RslO4 crystal structure in addition to site-directed mutagenesis and molecular dynamic simulations revealed that RslO4 might be responsible for quinone formation on the third ring. The RslO1 three-dimensional structure shows a high similarity to FMN-dependent luciferase-like monooxygenases such as the epoxy-forming MsnO8 which acts with the flavin reductase MsnO3 in mensacarcin biosynthesis in the same strain. The high sequence similarity between RslO2 and MsnO3 suggests that RslO2 provides RslO1 with reduced FMN to form an epoxide that serves as substrate for RslO5.
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http://dx.doi.org/10.1007/s12033-021-00314-xDOI Listing
March 2021

A hierarchical regulatory network analysis of the vitamin D induced transcriptome reveals novel regulators and complete VDR dependency in monocytes.

Sci Rep 2021 Mar 22;11(1):6518. Epub 2021 Mar 22.

Institute for Cardiovascular Physiology, Medical Faculty, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

The transcription factor vitamin D receptor (VDR) is the high affinity nuclear target of the biologically active form of vitamin D (1,25(OH)D). In order to identify pure genomic transcriptional effects of 1,25(OH)D, we used VDR cistrome, transcriptome and open chromatin data, obtained from the human monocytic cell line THP-1, for a novel hierarchical analysis applying three bioinformatics approaches. We predicted 75.6% of all early 1,25(OH)D-responding (2.5 or 4 h) and 57.4% of the late differentially expressed genes (24 h) to be primary VDR target genes. VDR knockout led to a complete loss of 1,25(OH)D-induced genome-wide gene regulation. Thus, there was no indication of any VDR-independent non-genomic actions of 1,25(OH)D modulating its transcriptional response. Among the predicted primary VDR target genes, 47 were coding for transcription factors and thus may mediate secondary 1,25(OH)D responses. CEBPA and ETS1 ChIP-seq data and RNA-seq following CEBPA knockdown were used to validate the predicted regulation of secondary vitamin D target genes by both transcription factors. In conclusion, a directional network containing 47 partly novel primary VDR target transcription factors describes secondary responses in a highly complex vitamin D signaling cascade. The central transcription factor VDR is indispensable for all transcriptome-wide effects of the nuclear hormone.
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http://dx.doi.org/10.1038/s41598-021-86032-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985518PMC
March 2021

Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation.

Nat Commun 2021 02 16;12(1):1072. Epub 2021 Feb 16.

Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE), Creteil, France.

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.
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http://dx.doi.org/10.1038/s41467-021-21227-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886895PMC
February 2021

Ethephon Activates the Transcription of Senescence-Associated Genes and Nitrogen Mobilization in Grapevine Leaves ( cv. Riesling).

Plants (Basel) 2021 Feb 9;10(2). Epub 2021 Feb 9.

Department of Soil Science and Plant Nutrition, Hochschule Geisenheim University, Von-Lade-Str. 1, D-65366 Geisenheim, Germany.

Nitrogen (N) remobilization in the context of leaf senescence is of considerable importance for the viability of perennial plants. In late-ripening crops, such as , it may also affect berry ripening and fruit quality. Numerous studies on the model plant have confirmed an involvement of the plant hormone ethylene in the regulation of senescence. However, ethylene research on grapevine was mostly focused on its involvement in berry ripening and stress tolerance until now. To investigate the effect of ethylene on the initiation, regulation, and progress of senescence-dependent N mobilization in grapevine leaves, we treated field-grown cv. Riesling vines with 25 mM ethephon at the end of berry ripening. Ethephon induced premature chlorophyll degradation and caused a shift of the leaf transcriptome equivalent to developmental leaf senescence. The upregulated metabolic processes covered the entire N remobilization process chain, altered the amino acid composition in the leaves, and resulted in an average 60% decrease in leaf N. Our findings increase the fundamental knowledge about the initiation and manipulation of leaf N remobilization in perennial woody plants by ethephon. This offers a methodological approach to the targeted induction of senescence and thus to an improvement in the N supply of grapes.
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http://dx.doi.org/10.3390/plants10020333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916130PMC
February 2021

Bioprinting of Magnetically Deformable Scaffolds.

ACS Biomater Sci Eng 2021 02 28;7(2):648-662. Epub 2021 Jan 28.

Centre for Translational Bone, Joint and Soft Tissue Research, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.

Mechanical stimulation of cells embedded in scaffolds is known to increase the cellular performance toward osteogenic or chondrogenic differentiation and tissue development. Three-dimensional bioplotting of magnetically deformable scaffolds enables the spatially defined distribution of magnetically inducible scaffold regions. In this study, a magnetic bioink based on alginate (alg, 3%) and methylcellulose (MC, 9%) with incorporated magnetite microparticles (25% w/w) was developed and characterized. The size and shape of particles were monitored scanning electron microscopy and X-ray micro-computed tomography. Shear-thinning properties of the algMC ink were maintained after the addition of different concentrations of magnetite microparticles to the ink. Its viscosity proportionally increased with the added amount of magnetite, and so did the level of saturation magnetization as determined vibrating sample magnetometry. The printability and shape fidelity of various shapes were evaluated, so that the final composition of algMC + 25% w/w magnetite was chosen. With application of this ink, cytocompatibility was proven in indirect cell culture and bioplotting experiments using a human mesenchymal stem cell line. Toward the deformation of cell-laden scaffolds to support cell differentiation in the future, radiography allowed the real-time monitoring of magnetically induced deformation of scaffolds of different pore architectures and scaffold orientations inside the magnetic field. Varying the strand distance and scaffold design will allow fine-tuning the degree of deformation in stimulatory experiments.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01371DOI Listing
February 2021

Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican.

Cancers (Basel) 2021 Jan 8;13(2). Epub 2021 Jan 8.

Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.

Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown . Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican () as a novel downstream target of IRF9. Indeed, and expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
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http://dx.doi.org/10.3390/cancers13020208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827113PMC
January 2021

SeMPI 2.0-A Web Server for PKS and NRPS Predictions Combined with Metabolite Screening in Natural Product Databases.

Metabolites 2020 Dec 29;11(1). Epub 2020 Dec 29.

Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Straße 9, 79104 Freiburg, Germany.

Microorganisms produce secondary metabolites with a remarkable range of bioactive properties. The constantly increasing amount of published genomic data provides the opportunity for efficient identification of biosynthetic gene clusters by genome mining. On the other hand, for many natural products with resolved structures, the encoding biosynthetic gene clusters have not been identified yet. Of those secondary metabolites, the scaffolds of nonribosomal peptides and polyketides (type I modular) can be predicted due to their building block-like assembly. SeMPI v2 provides a comprehensive prediction pipeline, which includes the screening of the scaffold in publicly available natural compound databases. The screening algorithm was designed to detect homologous structures even for partial, incomplete clusters. The pipeline allows linking of gene clusters to known natural products and therefore also provides a metric to estimate the novelty of the cluster if a matching scaffold cannot be found. Whereas currently available tools attempt to provide comprehensive information about a wide range of gene clusters, SeMPI v2 aims to focus on precise predictions. Therefore, the cluster detection algorithm, including building block generation and domain substrate prediction, was thoroughly refined and benchmarked, to provide high-quality scaffold predictions. In a benchmark based on 559 gene clusters, SeMPI v2 achieved comparable or better results than antiSMASH v5. Additionally, the SeMPI v2 web server provides features that can help to further investigate a submitted gene cluster, such as the incorporation of a genome browser, and the possibility to modify a predicted scaffold in a workbench before the database screening.
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http://dx.doi.org/10.3390/metabo11010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823522PMC
December 2020

Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration.

Cell Rep 2020 Dec;33(12):108549

Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392 Giessen, Germany; Institute for Lung Health (ILH), 35392 Giessen, Germany. Electronic address:

Tissue regeneration requires coordinated and dynamic remodeling of stem and progenitor cells and the surrounding niche. Although the plasticity of epithelial cells has been well explored in many tissues, the dynamic changes occurring in niche cells remain elusive. Here, we show that, during lung repair after naphthalene injury, a population of PDGFRα cells emerges in the non-cartilaginous conducting airway niche, which is normally populated by airway smooth muscle cells (ASMCs). This cell population, which we term "repair-supportive mesenchymal cells" (RSMCs), is distinct from conventional ASMCs, which have previously been shown to contribute to epithelial repair. Gene expression analysis on sorted lineage-labeled cells shows that RSMCs express low levels of ASMC markers, but high levels of the pro-regenerative marker Fgf10. Organoid co-cultures demonstrate an enhanced ability for RSMCs in supporting club-cell growth. Our study highlights the dynamics of mesenchymal cells in the airway niche and has implications for chronic airway-injury-associated diseases.
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http://dx.doi.org/10.1016/j.celrep.2020.108549DOI Listing
December 2020

YAP/TAZ Are Required to Suppress Osteogenic Differentiation of Vascular Smooth Muscle Cells.

iScience 2020 Dec 26;23(12):101860. Epub 2020 Nov 26.

Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim 61231, Germany.

Vascular smooth muscle cells (VSMCs) represent the prevailing cell type of arterial vessels and are essential for blood vessel structure and homeostasis. They have substantial potential for phenotypic plasticity when exposed to various stimuli in their local microenvironment. How VSMCs maintain their differentiated contractile phenotype is still poorly understood. Here we demonstrate that the Hippo pathway effectors YAP and TAZ play a critical role in maintaining the differentiated contractile phenotype of VSMCs. In the absence of YAP/TAZ, VSMCs lose their differentiated phenotype and undergo osteogenic differentiation, which results in vascular calcification. Osteogenic transdifferentiation was accompanied by the upregulation of Wnt target genes. The absence of YAP/TAZ in VSMCs led to Disheveled 3 (DVL3) nuclear translocation and upregulation of osteogenesis-associated genes independent of canonical Wnt/β-catenin signaling activation. Our data indicate that cytoplasmic YAP/TAZ interact with DVL3 to avoid its nuclear translocation and osteogenic differentiation, thereby maintaining the differentiated phenotype of VSMCs.
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http://dx.doi.org/10.1016/j.isci.2020.101860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726335PMC
December 2020

4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.

J Med Chem 2020 12 4;63(24):15603-15620. Epub 2020 Dec 4.

Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 8, D-79104 Freiburg, Germany.

Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00478DOI Listing
December 2020

Ccn2a is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish.

Development 2021 Jan 18;148(2). Epub 2021 Jan 18.

Department of Developmental Biology, Agharkar Research Institute, Pune 411004, India

The ability of zebrafish to heal their heart after injury makes them an attractive model for investigating the mechanisms governing the regenerative process. In this study, we show that the gene (), previously known as , is induced in endocardial cells in the injured tissue and regulates CM proliferation and repopulation of the damaged tissue. We find that, whereas in wild-type animals, CMs track along the newly formed blood vessels that revascularize the injured tissue, in mutants CM proliferation and repopulation are disrupted, despite apparently unaffected revascularization. In addition, we find that overexpression enhances CM proliferation and improves the resolution of transient collagen deposition. Through loss- and gain-of-function as well as pharmacological approaches, we provide evidence that Ccn2a is necessary for and promotes heart regeneration by enhancing the expression of pro-regenerative extracellular matrix genes, and by inhibiting the chemokine receptor gene through a mechanism involving Tgfβ/pSmad3 signaling. Thus, Ccn2a positively modulates the innate regenerative response of the adult zebrafish heart.
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http://dx.doi.org/10.1242/dev.193219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847265PMC
January 2021

Limited predictive value of admission time in clinical psychiatry.

BMC Health Serv Res 2020 Nov 13;20(1):1041. Epub 2020 Nov 13.

Department of Psychiatry and Psychotherapy, University of Regensburg, Universitätsstrasse 84, 93053, Regensburg, Germany.

Background: A large proportion of admissions to psychiatric hospitals happen as emergency admissions and many of them occur out of core working hours (during the weekends, on public holidays and during night time). However, very little is known about what determines admission times and whether the information of admission time bears any relevance for the clinical course of the patients. In other words, do admission times correlate with diagnostic groups? Can accumulations of crises be detected regarding circadian or weekly rhythms? Can any differences between workdays and weekends/public holidays be detected? May it even be possible to use information on admission times as a predictor for clinical relevance and severity of the presented condition measured by the length of stay?

Methods: In the present manuscript we analyzed data derived from 37'705 admissions to the Psychiatric District Hospital of Regensburg located in the Southern part of Germany covering the years 2013 to 2018 with regard to ICD-10 diagnostic groups and admission times. The hospital provides 475 beds for in-patient treatment in all fields of clinical psychiatry including geriatrics and addiction medicine.

Results: Several core questions could be answered based on our analysis: 1st Our analysis confirms that there is a high percentage of unheralded admissions out of core time showing broad variation. 2nd In contrary to many psychiatrists' misconceptions the time of admission has no relevant impact on the length of stay in the hospital. 3rd The predictive value of admission time regarding the allocation to ICD-10 diagnostic groups is low explaining only 1% of variability.

Conclusions: Taken together, our data reveal the enormous variation of admission times of psychiatric patients accounting for the need of adequate and consistent provision of personnel and spatial resources.
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http://dx.doi.org/10.1186/s12913-020-05806-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663873PMC
November 2020

Particulate Matter (PM) from Biomass Combustion Induces an Anti-Oxidative Response and Cancer Drug Resistance in Human Bronchial Epithelial BEAS-2B Cells.

Int J Environ Res Public Health 2020 11 6;17(21). Epub 2020 Nov 6.

Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, 79104 Freiburg, Germany.

Nearly half of the world's population relies on combustion of solid biofuels to cover fundamental energy demands. Epidemiologic data demonstrate that particularly long-term emissions adversely affect human health. However, pathological molecular mechanisms are insufficiently characterized. Here we demonstrate that long-term exposure to fine particulate matter (PM) from biomass combustion had no impact on cellular viability and proliferation but increased intracellular reactive oxygen species (ROS) levels in bronchial epithelial BEAS-2B cells. Exposure to PM induced the nuclear factor erythroid 2-related factor 2 (Nrf2) and mediated an anti-oxidative response, including enhanced levels of intracellular glutathione (GSH) and nuclear accumulation of heme oxygenase-1 (HO-1). Activation of Nrf2 was promoted by the c-Jun N-terminal kinase JNK1/2, but not p38 or Akt, which were also induced by PM. Furthermore, cells exposed to PM acquired chemoresistance to doxorubicin, which was associated with inhibition of apoptosis and elevated levels of GSH in these cells. Our findings propose that exposure to PM induces molecular defense mechanisms, which prevent cellular damage and may thus explain the initially relative rare complications associated with PM. However, consistent induction of pro-survival pathways may also promote the progression of diseases. Environmental conditions inducing anti-oxidative responses may have the potential to promote a chemoresistant cellular phenotype.
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http://dx.doi.org/10.3390/ijerph17218193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664250PMC
November 2020

ZNF354C is a transcriptional repressor that inhibits endothelial angiogenic sprouting.

Sci Rep 2020 11 5;10(1):19079. Epub 2020 Nov 5.

Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Zinc finger proteins (ZNF) are a large group of transcription factors with diverse functions. We recently discovered that endothelial cells harbour a specific mechanism to limit the action of ZNF354C, whose function in endothelial cells is unknown. Given that ZNF354C has so far only been studied in bone and tumour, its function was determined in endothelial cells. ZNF354C is expressed in vascular cells and localises to the nucleus and cytoplasm. Overexpression of ZNF354C in human endothelial cells results in a marked inhibition of endothelial sprouting. RNA-sequencing of human microvascular endothelial cells with and without overexpression of ZNF354C revealed that the protein is a potent transcriptional repressor. ZNF354C contains an active KRAB domain which mediates this suppression as shown by mutagenesis analysis. ZNF354C interacts with dsDNA, TRIM28 and histones, as observed by proximity ligation and immunoprecipitation. Moreover, chromatin immunoprecipitation revealed that the ZNF binds to specific endothelial-relevant target-gene promoters. ZNF354C suppresses these genes as shown by CRISPR/Cas knockout and RNAi. Inhibition of endothelial sprouting by ZNF354C is dependent on the amino acids DV and MLE of the KRAB domain. These results demonstrate that ZNF354C is a repressive transcription factor which acts through a KRAB domain to inhibit endothelial angiogenic sprouting.
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http://dx.doi.org/10.1038/s41598-020-76193-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645770PMC
November 2020

YAP and TAZ protect against white adipocyte cell death during obesity.

Nat Commun 2020 10 28;11(1):5455. Epub 2020 Oct 28.

Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.

The expansion of the white adipose tissue (WAT) in obesity goes along with increased mechanical, metabolic and inflammatory stress. How adipocytes resist this stress is still poorly understood. Both in human and mouse adipocytes, the transcriptional co-activators YAP/TAZ and YAP/TAZ target genes become activated during obesity. When fed a high-fat diet (HFD), mice lacking YAP/TAZ in white adipocytes develop severe lipodystrophy with adipocyte cell death. The pro-apoptotic factor BIM, which is downregulated in adipocytes of obese mice and humans, is strongly upregulated in YAP/TAZ-deficient adipocytes under HFD, and suppression of BIM expression reduces adipocyte apoptosis. In differentiated adipocytes, TNFα and IL-1β promote YAP/TAZ nuclear translocation via activation of RhoA-mediated actomyosin contractility and increase YAP/TAZ-mediated transcriptional regulation by activation of c-Jun N-terminal kinase (JNK) and AP-1. Our data indicate that the YAP/TAZ signaling pathway may be a target to control adipocyte cell death and compensatory adipogenesis during obesity.
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http://dx.doi.org/10.1038/s41467-020-19229-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595161PMC
October 2020

StreptomeDB 3.0: an updated compendium of streptomycetes natural products.

Nucleic Acids Res 2021 01;49(D1):D600-D604

Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Straße 9, D-79104 Freiburg, Germany.

Antimicrobial resistance is an emerging global health threat necessitating the rapid development of novel antimicrobials. Remarkably, the vast majority of currently available antibiotics are natural products (NPs) isolated from streptomycetes, soil-dwelling bacteria of the genus Streptomyces. However, there is still a huge reservoir of streptomycetes NPs which remains pharmaceutically untapped and a compendium thereof could serve as a source of inspiration for the rational design of novel antibiotics. Initially released in 2012, StreptomeDB (http://www.pharmbioinf.uni-freiburg.de/streptomedb) is the first and only public online database that enables the interactive phylogenetic exploration of streptomycetes and their isolated or mutasynthesized NPs. In this third release, there are substantial improvements over its forerunners, especially in terms of data content. For instance, about 2500 unique NPs were newly annotated through manual curation of about 1300 PubMed-indexed articles, published in the last five years since the second release. To increase interoperability, StreptomeDB entries were hyperlinked to several spectral, (bio)chemical and chemical vendor databases, and also to a genome-based NP prediction server. Moreover, predicted pharmacokinetic and toxicity profiles were added. Lastly, some recent real-world use cases of StreptomeDB are highlighted, to illustrate its applicability in life sciences.
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http://dx.doi.org/10.1093/nar/gkaa868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779017PMC
January 2021

Tie1 regulates zebrafish cardiac morphogenesis through Tolloid-like 1 expression.

Dev Biol 2021 01 21;469:54-67. Epub 2020 Sep 21.

Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany. Electronic address:

Tie1 is a receptor tyrosine kinase expressed in endothelial cells, where it modulates Angiopoietin/Tie2 signaling. Previous studies have shown that mouse Tie1 mutants exhibit severe cardiovascular defects; however, much remains to be learned about the role of Tie1, especially during cardiac development. To further understand Tie1 function, we generated a zebrafish tie1 mutant line. Homozygous mutant embryos display reduced endothelial and endocardial cell numbers and reduced heart size. Live imaging and ultrastructural analyses at embryonic stages revealed increased cardiac jelly thickness as well as cardiomyocyte defects, including a loss of sarcomere organization and altered cell shape. Transcriptomic profiling of embryonic hearts uncovered the downregulation of tll1, which encodes a Tolloid-like protease, in tie1 compared with wild-type siblings. Using mRNA injections into one-cell stage embryos, we found that tll1 overexpression could partially rescue the tie1 mutant cardiac phenotypes including the endocardial and myocardial cell numbers as well as the cardiac jelly thickness. Altogether, our results indicate the importance of a Tie1-Tolloid-like 1 axis in paracrine signaling during cardiac development.
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http://dx.doi.org/10.1016/j.ydbio.2020.09.008DOI Listing
January 2021

SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes.

Cardiovasc Res 2020 12;116(14):2207-2215

Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany.

Aims: Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection.

Methods And Results: Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir.

Conclusion: This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir.
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http://dx.doi.org/10.1093/cvr/cvaa267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543363PMC
December 2020

Pharmacoinformatic Investigation of Medicinal Plants from East Africa.

Mol Inform 2020 11 8;39(11):e2000163. Epub 2020 Oct 8.

Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle/Saale, Germany.

Medicinal plants have widely been used in the traditional treatment of ailments and have been proven effective. Their contribution still holds an important place in modern drug discovery due to their chemical, and biological diversities. However, the poor documentation of traditional medicine, in developing African countries for instance, can lead to the loss of knowledge related to such practices. In this study, we present the Eastern Africa Natural Products Database (EANPDB) containing the structural and bioactivity information of 1870 unique molecules isolated from about 300 source species from the Eastern African region. This represents the largest collection of natural products (NPs) from this geographical region, covering literature data of the period from 1962 to 2019. The computed physicochemical properties and toxicity profiles of each compound have been included. A comparative analysis of some physico-chemical properties like molecular weight, H-bond donor/acceptor, logP , etc. as well scaffold diversity analysis has been carried out with other published NP databases. EANPDB was combined with the previously published Northern African Natural Products Database (NANPDB), to form a merger African Natural Products Database (ANPDB), containing ∼6500 unique molecules isolated from about 1000 source species (freely available at http://african-compounds.org). As a case study, latrunculins A and B isolated from the sponge Negombata magnifica (Podospongiidae) with previously reported antitumour activities, were identified via substructure searching as molecules to be explored as putative binders of histone deacetylases (HDACs).
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http://dx.doi.org/10.1002/minf.202000163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685152PMC
November 2020

Exploring Cocrystallized Aromatic Cage Binders to Target Histone Methylation Reader Proteins.

J Chem Inf Model 2020 10 19;60(10):5225-5233. Epub 2020 Aug 19.

Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Straße 9, D-79104 Freiburg, Germany.

Histone methylation reader proteins (HMRPs) regulate gene transcription by recognizing, at their "aromatic cage" domains, various Lys/Arg methylation states on histone tails. Because epigenetic dysregulation underlies a wide range of diseases, HMRPs have become attractive drug targets. However, structure-based efforts in targeting them are still in their infancy. Structural information from functionally unrelated aromatic-cage-containing proteins (ACCPs) and their cocrystallized ligands could be a good starting point. In this light, we mined the Protein Data Bank to retrieve the structures of ACCPs in complex with cationic peptidic/small-molecule ligands. Our analysis revealed that the vast majority of retrieved ACCPs belong to three classes: transcription regulators (chiefly HMRPs), signaling proteins, and hydrolases. Although acyclic (and monocyclic) amines and quats are the typical cation-binding functional groups found in HMRP small-molecule inhibitors, numerous atypical cationic groups were identified in non-HMRP inhibitors, which could serve as potential bioisosteres to methylated Lys/Arg on histone tails. Also, as HMRPs are involved in protein-protein interactions, they possess large binding sites, and thus, their selective inhibition might only be achieved by large and more flexible (beyond rule of five) ligands. Hence, the ligands of the collected dataset represent suitable versatile templates for further elaboration into potent and selective HMRP inhibitors.
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http://dx.doi.org/10.1021/acs.jcim.0c00765DOI Listing
October 2020

Fibroblast Growth Factor-14 Acts as Tumor Suppressor in Lung Adenocarcinomas.

Cells 2020 07 22;9(8). Epub 2020 Jul 22.

Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.

Investigation of the molecular dynamics in lung cancer is crucial for the development of new treatment strategies. Fibroblast growth factor (FGF) 14 belongs to the FGF family, which might play a crucial role in cancer progression. We analyzed lung adenocarcinoma (LUAC) patients samples and found that FGF14 was downregulated, correlating with reduced survival and oncogenic mutation status. FGF14 overexpression in lung cancer cell lines resulted in decreased proliferation, colony formation, and migration, as well as increased expression of epithelial markers and a decreased expression of mesenchymal markers, indicating a mesenchymal to epithelial transition in vitro. We verified these findings using small interfering RNA against FGF14 and further confirmed the suppressive effect of FGF14 in a .- Il2rg/ immunodeficient xenograft tumor model. Moreover, FGF14 overexpressing tumor cell RNA sequencing data suggests that genes affected by FGF14 were related to the extracellular matrix, playing a role in proliferation and migration. Notably, newly identified FGF14 target genes, adenosine deaminase RNA specific B1 (), collagen and calcium-binding epidermal growth factor domain-containing protein 1 (), α1 chain of collagen XI (), and mucin 16 () expression was negatively correlated with overall survival when was downregulated in LUAC. These findings led us to suggest that FGF14 regulates proliferation and migration in LUAC.
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http://dx.doi.org/10.3390/cells9081755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466013PMC
July 2020

Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function.

Nat Immunol 2020 08 20;21(8):902-913. Epub 2020 Jul 20.

Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.

Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the receptor kinase (RK) motif. The RK motif is accessible only upon TCR ligation, demonstrating how ligand binding leads to Lck recruitment. Binding of the Lck SH3 domain to the exposed RK motif resulted in local augmentation of Lck activity, CD3 phosphorylation, T cell activation and thymocyte development. Introducing the RK motif into a well-characterized 41BB-based chimeric antigen receptor enhanced its antitumor function in vitro and in vivo. Our findings underscore how a better understanding of the functioning of the TCR might promote rational improvement of chimeric antigen receptor design for the treatment of cancer.
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http://dx.doi.org/10.1038/s41590-020-0732-3DOI Listing
August 2020

Proteomics of Galápagos Marine Iguanas Links Function of Femoral Gland Proteins to the Immune System.

Mol Cell Proteomics 2020 09 24;19(9):1523-1532. Epub 2020 Jun 24.

CECAD Research Center Institute for Genetics, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. Electronic address:

Communication between individuals via molecules, termed chemosignaling, is widespread among animal and plant species. However, we lack knowledge on the specific functions of the substances involved for most systems. The femoral gland is an organ that secretes a waxy substance involved in chemical communication in lizards. Although the lipids and volatile substances secreted by the femoral glands have been investigated in several biochemical studies, the protein composition and functions of secretions remain completely unknown. Applying a proteomic approach, we provide the first attempt to comprehensively characterize the protein composition of femoral gland secretions from the Galápagos marine iguana. Using samples from several organs, the marine iguana proteome was assembled by next-generation sequencing and MS, resulting in 7513 proteins. Of these, 4305 proteins were present in the femoral gland, including keratins, small serum proteins, and fatty acid-binding proteins. Surprisingly, no proteins with discernible roles in partner recognition or inter-species communication could be identified. However, we did find several proteins with direct associations to the innate immune system, including lysozyme C, antileukoproteinase (ALP), pulmonary surfactant protein (SFTPD), and galectin (LGALS1) suggesting that the femoral glands function as an important barrier to infection. Furthermore, we report several novel anti-microbial peptides from the femoral glands that show similar action against and such as oncocin, a peptide known for its effectiveness against Gram-negative pathogens. This proteomics data set is a valuable resource for future functional protein analysis and demonstrates that femoral gland secretions also perform functions of the innate immune system.
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http://dx.doi.org/10.1074/mcp.RA120.001947DOI Listing
September 2020

Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer.

Sci Adv 2020 Jun 5;6(23):eaaz6105. Epub 2020 Jun 5.

Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim 61231, Germany.

Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/β-catenin pathway. These findings were reproduced in a newly developed in vitro "trained" TAM model. Pharmacological and macrophage-specific genetic ablation of β-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that β-catenin-mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of β-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, β-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.
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http://dx.doi.org/10.1126/sciadv.aaz6105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274802PMC
June 2020

HIF-1α is involved in blood-brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis.

Acta Neuropathol 2020 08 11;140(2):183-208. Epub 2020 Jun 11.

Institute for Medical Microbiology and Infection Control, Goethe University, Frankfurt am Main, Germany.

Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from blood to the brain across the blood-cerebrospinal fluid barrier or the blood-brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1α activation was observed by immunohistochemistry. S. pneumoniae infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell-cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy, live-cell imaging). Hematogenously infected mice showed increased permeability, S. pneumoniae deposition in the brain, along with upregulation of genes in the HIF-1α/VEGF pathway (RNA sequencing of brain microvessels). Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells or using primary brain ECs from HIF-1α knock-out mice revealed reduced endothelial permeability and transmigration of S. pneumoniae. Therapeutic rescue using the HIF-1α inhibitor echinomycin resulted in increased survival and improvement of BBB function in S. pneumoniae-infected mice. We thus demonstrate paracellular migration of bacteria across BBB and a critical role for HIF-1α/VEGF therein and hence propose targeting this pathway to prevent BBB dysfunction and ensuing brain damage in infections.
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http://dx.doi.org/10.1007/s00401-020-02174-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360668PMC
August 2020

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1.

Eur J Med Chem 2020 Aug 18;200:112338. Epub 2020 May 18.

Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120, Halle/Saale, Germany. Electronic address:

Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.
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http://dx.doi.org/10.1016/j.ejmech.2020.112338DOI Listing
August 2020

Attenuated Epigenetic Suppression of Muscle Stem Cell Necroptosis Is Required for Efficient Regeneration of Dystrophic Muscles.

Cell Rep 2020 05;31(7):107652

Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; German Center for Cardiovascular Research (DZHK); German Center for Lung Research (DZL). Electronic address:

Somatic stem cells expand massively during tissue regeneration, which might require control of cell fitness, allowing elimination of non-competitive, potentially harmful cells. How or if such cells are removed to restore organ function is not fully understood. Here, we show that a substantial fraction of muscle stem cells (MuSCs) undergo necroptosis because of epigenetic rewiring during chronic skeletal muscle regeneration, which is required for efficient regeneration of dystrophic muscles. Inhibition of necroptosis strongly enhances suppression of MuSC expansion in a non-cell-autonomous manner. Prevention of necroptosis in MuSCs of healthy muscles is mediated by the chromatin remodeler CHD4, which directly represses the necroptotic effector Ripk3, while CHD4-dependent Ripk3 repression is dramatically attenuated in dystrophic muscles. Loss of Ripk3 repression by inactivation of Chd4 causes massive necroptosis of MuSCs, abolishing regeneration. Our study demonstrates how programmed cell death in MuSCs is tightly controlled to achieve optimal tissue regeneration.
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http://dx.doi.org/10.1016/j.celrep.2020.107652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242912PMC
May 2020

The endocannabinoid anandamide has an anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells.

Basic Res Cardiol 2020 04 22;115(3):34. Epub 2020 Apr 22.

Fachbereich Medizin, Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.

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.
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http://dx.doi.org/10.1007/s00395-020-0793-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176595PMC
April 2020

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice.

Front Neurosci 2020 2;14:280. Epub 2020 Apr 2.

Department of Neurology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.

With increasing distribution of endovascular stroke therapies, transient middle cerebral artery occlusion (tMCAO) in mice now more than ever depicts a relevant patient population with recanalized M1 occlusion. In this case, the desired therapeutic effect of blood flow restauration is accompanied by breakdown of the blood-brain barrier (BBB) and secondary reperfusion injury. The aim of this study was to elucidate short and intermediate-term transcriptional patterns and the involved pathways covering the different cellular players at the neurovascular unit after transient large vessel occlusion. To achieve this, male C57Bl/6J mice were treated according to an intensive post-stroke care protocol after 60 min occlusion of the middle cerebral artery or sham surgery to allow a high survival rate. After 24 h or 7 days, RNA from microvessel fragments from the ipsilateral and the contralateral hemispheres was isolated and used for mRNA sequencing. Bioinformatic analyses allowed us to depict gene expression changes at two timepoints of neurovascular post-stroke injury and regeneration. We validated our dataset by quantitative real time PCR of BBB-associated targets with well-characterized post-stroke dynamics. Hence, this study provides a well-controlled transcriptome dataset of a translationally relevant mouse model 24 h and 7 days after stroke which might help to discover future therapeutic targets in cerebral ischemia/reperfusion injury.
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http://dx.doi.org/10.3389/fnins.2020.00280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142359PMC
April 2020