27 results on '"Grossklaus S"'
Search Results
2. Developmental endothelial locus-1 (Del-1) is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination: FT08 – Talk Lim
- Author
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Lim, J., Choi, E., Lee, S., Samus, M., Kim, H., Grossklaus, S., and Chavakis, T.
- Published
- 2013
3. LFA-1 regulates trafficking of regulatory T cells into adipose tisse (AT) and maintains insulin sensitivity in diet induced obesity (DIO): FT01 – Talk Chung
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Chung, K., Gebler, J., Klotzsche - von Ameln, A., Prucnal, M., Grossklaus, S., Bornstein, S., Alexaki, V., and Chavakis, T.
- Published
- 2013
4. Dehydroepiandrosterone: a modulator of microglial cell polarization: 1.27
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Alexaki, V. I., Helms, M., Boehm, S., Bdeir, M., Soehnnichsen, B., Echeverri, C., Mund, C., Grossklaus, S., Charalampopoulos, I., Chavakis, T., Gravanis, A., and Tsatsanis, C.
- Published
- 2013
5. DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway
- Author
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Alexaki, V I, primary, Fodelianaki, G, additional, Neuwirth, A, additional, Mund, C, additional, Kourgiantaki, A, additional, Ieronimaki, E, additional, Lyroni, K, additional, Troullinaki, M, additional, Fujii, C, additional, Kanczkowski, W, additional, Ziogas, A, additional, Peitzsch, M, additional, Grossklaus, S, additional, Sönnichsen, B, additional, Gravanis, A, additional, Bornstein, S R, additional, Charalampopoulos, I, additional, Tsatsanis, C, additional, and Chavakis, T, additional
- Published
- 2017
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6. The role of hematopoietic TLR-signaling in sepsis-associated adrenal inflammation and the HPA axis activation
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Kanczkowski, W, primary, Neuwirth, A, additional, Grossklaus, S, additional, Zacharowski, K, additional, Chavakis, T, additional, and Bornstein, SR, additional
- Published
- 2015
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7. Dehydroepiandrosterone and a synthetic analogue regulate microglial cell polarization
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Alexaki, VI, primary, Charalampopoulos, I, additional, Neuwirth, A, additional, Soehnnichsen, B, additional, Echeverri, C, additional, Bornstein, SR, additional, Mund, C, additional, Grossklaus, S, additional, Tsatsanis, C, additional, Gravanis, A, additional, and Chavakis, T, additional
- Published
- 2014
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8. The role of IL17 in systemic inflammation mediated downregulation of the endothelial anti-inflammatory factor Del-1 in the adrenal gland and related HPA axis dysregulation
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Kanczkowski, W, primary, Chatzigeorgiou, A, additional, Lehnert, U, additional, Großklaus, S, additional, Bornstein, SR, additional, and Chavakis, T, additional
- Published
- 2014
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9. DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway
- Author
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Alexaki, V I, Fodelianaki, G, Neuwirth, A, Mund, C, Kourgiantaki, A, Ieronimaki, E, Lyroni, K, Troullinaki, M, Fujii, C, Kanczkowski, W, Ziogas, A, Peitzsch, M, Grossklaus, S, Sönnichsen, B, Gravanis, A, Bornstein, S R, Charalampopoulos, I, Tsatsanis, C, and Chavakis, T
- Abstract
Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.
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- 2018
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10. Charakterisierung eines Mikroemulsionsgebietes; Teil 1 / Characterization of a Single-Phase Microemulsion; Part 1
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Großklaus, S., primary, Pfestorf, R., additional, Quitzsch, K., additional, Möhle, L., additional, and Hauthal, H.-G., additional
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- 1989
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11. Formyl peptide receptor 2 regulates dendritic cell metabolism and Th17 cell differentiation during neuroinflammation.
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Lim JH, Neuwirth A, Chung KJ, Grossklaus S, Soehnlein O, Hajishengallis G, and Chavakis T
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- Animals, Mice, Mice, Inbred C57BL, Cytokines metabolism, Neuroinflammatory Diseases immunology, Neuroinflammatory Diseases metabolism, Female, Spinal Cord immunology, Spinal Cord metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Receptors, Formyl Peptide genetics, Receptors, Formyl Peptide metabolism, Th17 Cells immunology, Th17 Cells metabolism, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Cell Differentiation, Mice, Knockout
- Abstract
Formyl peptide receptor 2 (FPR2) is a receptor for formylated peptides and specific pro-resolving mediators, and is involved in various inflammatory processes. Here, we aimed to elucidate the role of FPR2 in dendritic cell (DC) function and autoimmunity-related central nervous system (CNS) inflammation by using the experimental autoimmune encephalomyelitis (EAE) model. EAE induction was accompanied by increased Fpr2 mRNA expression in the spinal cord. FPR2-deficient ( Fpr2
KO ) mice displayed delayed onset of EAE compared to wild-type (WT) mice, associated with reduced frequencies of Th17 cells in the inflamed spinal cord at the early stage of the disease. However, FPR2 deficiency did not affect EAE severity after the disease reached its peak. FPR2 deficiency in mature DCs resulted in decreased expression of Th17 polarizing cytokines IL6, IL23p19, IL1β, and thereby diminished the DC-mediated activation of Th17 cell differentiation. LPS-activated FPR2-deficient DCs showed upregulated Nos2 expression and nitric oxide (NO) production, as well as reduced oxygen consumption rate and impaired mitochondrial function, including decreased mitochondrial superoxide levels, lower mitochondrial membrane potential and diminished expression of genes related to the tricarboxylic acid cycle and genes related to the electron transport chain, as compared to WT DCs. Treatment with a NO inhibitor reversed the reduced Th17 cell differentiation in the presence of FPR2-deficient DCs. Together, by regulating DC metabolism, FPR2 enhances the production of DC-derived Th17-polarizing cytokines and hence Th17 cell differentiation in the context of neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lim, Neuwirth, Chung, Grossklaus, Soehnlein, Hajishengallis and Chavakis.)- Published
- 2024
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12. Stromal cell-derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis.
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Wang H, Li X, Kajikawa T, Shin J, Lim JH, Kourtzelis I, Nagai K, Korostoff JM, Grossklaus S, Naumann R, Chavakis T, and Hajishengallis G
- Subjects
- Animals, Cell Differentiation, Female, Germinal Center immunology, Lymphocyte Function-Associated Antigen-1 physiology, Male, Mice, Mice, Inbred C57BL, Stromal Cells chemistry, T Follicular Helper Cells cytology, Arthritis, Experimental prevention & control, Calcium-Binding Proteins physiology, Cell Adhesion Molecules physiology, Lymphocyte Activation, T Follicular Helper Cells immunology
- Abstract
The secreted protein developmental endothelial locus 1 (DEL-1) regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab-induced arthritis (CAIA) models. In both models, mice with endothelium-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, whereas arthritis was exacerbated in DEL-1-deficient mice. Compared with WT controls, mice with collagen VI promoter-driven overexpression of DEL-1 in mesenchymal cells were protected against CIA but not CAIA, suggesting a role for DEL-1 in the induction of the arthritogenic Ab response. Indeed, DEL-1 was expressed in perivascular stromal cells of the lymph nodes and inhibited Tfh and germinal center B cell responses. Mechanistically, DEL-1 inhibited DC-dependent induction of Tfh cells by targeting the LFA-1 integrin on T cells. Overall, DEL-1 restrained arthritis through a dual mechanism, one acting locally in the joints and associated with the anti-recruitment function of endothelial cell-derived DEL-1; the other mechanism acting systemically in the lymph nodes and associated with the ability of stromal cell-derived DEL-1 to restrain Tfh responses. DEL-1 may therefore be a promising therapeutic for the treatment of inflammatory arthritis.
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- 2021
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13. Glycolysis is integral to histamine-induced endothelial hyperpermeability.
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Ziogas A, Sajib MS, Lim JH, Alves TC, Das A, Witt A, Hagag E, Androulaki N, Grossklaus S, Gerlach M, Noll T, Grinenko T, Mirtschink P, Hajishengallis G, Chavakis T, Mikelis CM, and Sprott D
- Subjects
- Adherens Junctions drug effects, Adherens Junctions metabolism, Anaphylaxis metabolism, Anaphylaxis pathology, Animals, Capillary Permeability drug effects, Endothelial Cells metabolism, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Mice, Phospholipase C beta metabolism, Signal Transduction drug effects, Capillary Permeability physiology, Endothelial Cells drug effects, Glycolysis physiology, Histamine pharmacology
- Abstract
Histamine-induced vascular leakage is a core process of allergic pathologies, including anaphylaxis. Here, we show that glycolysis is integral to histamine-induced endothelial barrier disruption and hyperpermeability. Histamine rapidly enhanced glycolysis in endothelial cells via a pathway that involved histamine receptor 1 and phospholipase C beta signaling. Consistently, partial inhibition of glycolysis with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) prevented histamine-induced hyperpermeability in human microvascular endothelial cells, by abolishing the histamine-induced actomyosin contraction, focal adherens junction formation, and endothelial barrier disruption. Pharmacologic blockade of glycolysis with 3PO in mice reduced histamine-induced vascular hyperpermeability, prevented vascular leakage in passive cutaneous anaphylaxis and protected from systemic anaphylaxis. In conclusion, we elucidated the role of glycolysis in histamine-induced disruption of endothelial barrier integrity. Our data thereby point to endothelial glycolysis as a novel therapeutic target for human pathologies related to excessive vascular leakage, such as systemic anaphylaxis., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2021
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14. DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1.
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Ziogas A, Maekawa T, Wiessner JR, Le TT, Sprott D, Troullinaki M, Neuwirth A, Anastasopoulou V, Grossklaus S, Chung KJ, Sperandio M, Chavakis T, Hajishengallis G, and Alexaki VI
- Subjects
- Animals, CCAAT-Enhancer-Binding Protein-beta immunology, CD18 Antigens immunology, Cell Adhesion immunology, Endothelium, Vascular immunology, Female, Gene Expression Regulation immunology, Leukocytes cytology, Mice, Phosphatidylinositol 3-Kinases immunology, Promoter Regions, Genetic immunology, Proto-Oncogene Proteins c-akt immunology, Receptor, trkA immunology, Calcium-Binding Proteins immunology, Cell Adhesion Molecules immunology, Dehydroepiandrosterone pharmacology, Leukocytes immunology, Signal Transduction immunology
- Abstract
Leukocytes are rapidly recruited to sites of inflammation via interactions with the vascular endothelium. The steroid hormone dehydroepiandrosterone (DHEA) exerts anti-inflammatory properties; however, the underlying mechanisms are poorly understood. In this study, we show that an anti-inflammatory mechanism of DHEA involves the regulation of developmental endothelial locus 1 (DEL-1) expression. DEL-1 is a secreted homeostatic factor that inhibits β2-integrin-dependent leukocyte adhesion, and the subsequent leukocyte recruitment and its expression is downregulated upon inflammation. Similarly, DHEA inhibited leukocyte adhesion to the endothelium in venules of the inflamed mouse cremaster muscle. Importantly, in a model of lung inflammation, DHEA limited neutrophil recruitment in a DEL-1-dependent manner. Mechanistically, DHEA counteracted the inhibitory effect of inflammation on DEL-1 expression. Indeed, whereas TNF reduced DEL-1 expression and secretion in endothelial cells by diminishing C/EBPβ binding to the DEL-1 gene promoter, DHEA counteracted the inhibitory effect of TNF via activation of tropomyosin receptor kinase A (TRKA) and downstream PI3K/AKT signaling that restored C/EBPβ binding to the DEL-1 promoter. In conclusion, DHEA restrains neutrophil recruitment by reversing inflammation-induced downregulation of DEL-1 expression. Therefore, the anti-inflammatory DHEA/DEL-1 axis could be harnessed therapeutically in the context of inflammatory diseases., (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Published
- 2020
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15. 53BP1 Deficiency Promotes Pathological Neovascularization in Proliferative Retinopathy.
- Author
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Troullinaki M, Garcia-Martin R, Sprott D, Klotzsche-von Ameln A, Grossklaus S, Mitroulis I, Chavakis T, and Economopoulou M
- Subjects
- Animals, Apoptosis, Cell Hypoxia, Cells, Cultured, Disease Models, Animal, Endothelial Cells drug effects, Endothelial Cells pathology, Genetic Predisposition to Disease, Humans, Mice, Knockout, Morpholines pharmacology, Phenotype, Pyrroles pharmacology, Retinal Neovascularization genetics, Retinal Neovascularization pathology, Retinal Neovascularization prevention & control, Retinal Vessels drug effects, Retinal Vessels pathology, Retinopathy of Prematurity genetics, Retinopathy of Prematurity pathology, Retinopathy of Prematurity prevention & control, Signal Transduction, Tumor Suppressor p53-Binding Protein 1 genetics, Cell Proliferation drug effects, Endothelial Cells metabolism, Homologous Recombination drug effects, Retinal Neovascularization metabolism, Retinal Vessels metabolism, Retinopathy of Prematurity metabolism, Tumor Suppressor p53-Binding Protein 1 deficiency, Tumor Suppressor p53-Binding Protein 1 metabolism
- Abstract
The replication stress inflicted on retinal endothelial cells (ECs) in the context of hypoxia-induced pathological neovascularization during proliferative retinopathy is linked with activation of the deoxyribonucleic acid (DNA) repair response. Here, we studied the effect of deficiency of the DNA damage response adaptor 53BP1, which is an antagonist of homologous recombination (HR), in the context of proliferative retinopathy. In the model of retinopathy of prematurity (ROP), 53BP1-deficient mice displayed increased hypoxia-driven pathological neovascularization and tuft formation, accompanied by increased EC proliferation and reduced EC apoptosis, as compared with 53BP1-sufficient mice. In contrast, physiological retina angiogenesis was not affected by 53BP1 deficiency. Knockdown of 53BP1 in ECs in vitro also resulted in enhanced proliferation and reduced apoptosis of the cells under hypoxic conditions. Additionally, upon 53BP1 knockdown, ECs displayed increased HR rate in hypoxia. Consistently, treatment with an HR inhibitor reversed the hyper-proliferative angiogenic phenotype associated with 53BP1 deficiency in ROP. Thus, by unleashing HR, 53BP1 deletion increases pathological EC proliferation and neovascularization in the context of ROP. Our data shed light to a previously unknown interaction between the DNA repair response and pathological neovascularization in the retina., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2019
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16. DEL-1 promotes macrophage efferocytosis and clearance of inflammation.
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Kourtzelis I, Li X, Mitroulis I, Grosser D, Kajikawa T, Wang B, Grzybek M, von Renesse J, Czogalla A, Troullinaki M, Ferreira A, Doreth C, Ruppova K, Chen LS, Hosur K, Lim JH, Chung KJ, Grossklaus S, Tausche AK, Joosten LAB, Moutsopoulos NM, Wielockx B, Castrillo A, Korostoff JM, Coskun Ü, Hajishengallis G, and Chavakis T
- Subjects
- Adult, Animals, Calcium-Binding Proteins, Carrier Proteins genetics, Cell Adhesion Molecules, Cellular Reprogramming, Cytokines metabolism, Gene Expression Regulation, Humans, Inflammation chemically induced, Intercellular Signaling Peptides and Proteins, K562 Cells, Liver X Receptors metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis, Carrier Proteins metabolism, Inflammation immunology, Macrophages physiology, Neutrophils immunology, Periodontitis immunology
- Abstract
Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.
- Published
- 2019
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17. Endothelial Cell-Specific Overexpression of Del-1 Drives Expansion of Haematopoietic Progenitor Cells in the Bone Marrow.
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Chen LS, Kourtzelis I, Singh RP, Grossklaus S, Wielockx B, Hajishengallis G, Chavakis T, and Mitroulis I
- Abstract
Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
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18. Hes3 expression in the adult mouse brain is regulated during demyelination and remyelination.
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Toutouna L, Nikolakopoulou P, Poser SW, Masjkur J, Arps-Forker C, Troullinaki M, Grossklaus S, Bosak V, Friedrich U, Ziemssen T, Bornstein SR, Chavakis T, and Androutsellis-Theotokis A
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Culture Techniques, Culture Media, Conditioned, Cuprizone, Demyelinating Diseases chemically induced, Demyelinating Diseases metabolism, Male, Mice, Mice, Inbred C57BL, Myelin Basic Protein metabolism, Myelin Sheath drug effects, Myelin Sheath metabolism, Nerve Tissue Proteins metabolism, RNA, Messenger metabolism, Repressor Proteins, Basic Helix-Loop-Helix Transcription Factors genetics, Demyelinating Diseases genetics, Gene Expression Regulation, Motor Cortex metabolism, Myelin Sheath genetics, Nerve Tissue Proteins genetics
- Abstract
Hes3 is a component of the STAT3-Ser/Hes3 Signaling Axis controlling the growth and survival of neural stem cells and other plastic cells. Pharmacological activation of this pathway promotes neuronal rescue and behavioral recovery in models of ischemic stroke and Parkinson's disease. Here we provide initial observations implicating Hes3 in the cuprizone model of demyelination and remyelination. We focus on the subpial motor cortex of mice because we detected high Hes3 expression. This area is of interest as it is impacted both in human demyelinating diseases and in the cuprizone model. We report that Hes3 expression is reduced at peak demyelination and is partially restored within 1 week after cuprizone withdrawal. This raises the possibility of Hes3 involvement in demyelination/remyelination that may warrant additional research. Supporting a possible role of Hes3 in the maintenance of oligodendrocyte markers, a Hes3 null mouse strain shows lower levels of myelin basic protein in undamaged adult mice, compared to wild-type controls. We also present a novel method for culturing the established oligodendrocyte progenitor cell line oli-neu in a manner that maintains Hes3 expression as well as its self-renewal and differentiation potential, offering an experimental tool to study Hes3. Based upon this approach, we identify a Janus kinase inhibitor and dbcAMP as powerful inducers of Hes3 gene expression. We provide a new biomarker and cell culture method that may be of interest in demyelination/remyelination research., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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19. Milk Fat Globule-Epidermal Growth Factor 8 (MFG-E8) Is a Novel Anti-inflammatory Factor in Rheumatoid Arthritis in Mice and Humans.
- Author
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Albus E, Sinningen K, Winzer M, Thiele S, Baschant U, Hannemann A, Fantana J, Tausche AK, Wallaschofski H, Nauck M, Völzke H, Grossklaus S, Chavakis T, Udey MC, Hofbauer LC, and Rauner M
- Subjects
- Aged, Animals, Antigens, Surface blood, Arthritis, Rheumatoid blood, Arthritis, Rheumatoid pathology, Bone Resorption pathology, Cytokines metabolism, Disease Progression, Down-Regulation, Female, Humans, Inflammation pathology, Inflammation Mediators metabolism, Joints pathology, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Milk Proteins blood, Neutrophil Infiltration, Tumor Necrosis Factor-alpha, Anti-Inflammatory Agents metabolism, Antigens, Surface metabolism, Arthritis, Rheumatoid metabolism, Milk Proteins metabolism
- Abstract
Milk fat globule-epidermal growth factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG-E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG-E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG-E8 knock-out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α downregulated the expression of MFG-E8 by 30% to 35%. MFG-E8-deficient osteoblasts responded to LPS with a stronger production of pro-inflammatory cytokines. In vivo, MFG-E8 mRNA levels were 52% lower in the paws of collagen-induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA (n = 93) had lower serum concentrations of MFG-E8 (-17%) compared with healthy controls (n = 140). In a subgroup of patients who had a moderate to high disease activity (n = 21), serum concentrations of MFG-E8 rose after complete or partial remission had been achieved (+67%). Finally, MFG-E8-deficient mice subjected to STA exhibited a stronger disease burden, an increased number of neutrophils in the joints, and a more extensive local and systemic bone loss. This was accompanied by an increased activation of osteoclasts and a suppression of osteoblast function in MFG-E8-deficient mice. Thus, MFG-E8 is a protective factor in the pathogenesis of RA and subsequent bone loss. Whether MFG-E8 qualifies as a novel biomarker or therapeutic target for the treatment of RA is worth addressing in further studies., (© 2015 American Society for Bone and Mineral Research.)
- Published
- 2016
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20. Brief Report: Endothelial-Specific X-Box Binding Protein 1 Deficiency Limits Tumor Necrosis Factor-Induced Leukocyte Recruitment and Vasculitis.
- Author
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Ziogas A, Muders MH, Economopoulou M, Sprott D, Grossklaus S, Siegert G, Baretton GB, Mitroulis I, and Chavakis T
- Subjects
- Animals, Cell Adhesion drug effects, Cell Adhesion immunology, DNA-Binding Proteins immunology, Disease Models, Animal, Endothelial Cells drug effects, Endothelial Cells immunology, Leukocytes drug effects, Leukocytes immunology, Leukocytes metabolism, Mice, Mice, Knockout, NF-kappa B drug effects, NF-kappa B immunology, Neutrophil Infiltration drug effects, Neutrophil Infiltration immunology, Regulatory Factor X Transcription Factors, Shwartzman Phenomenon immunology, Transcription Factors immunology, Tumor Necrosis Factor-alpha pharmacology, Vasculitis immunology, X-Box Binding Protein 1, Cell Adhesion genetics, DNA-Binding Proteins genetics, Endothelial Cells metabolism, NF-kappa B metabolism, Neutrophil Infiltration genetics, Shwartzman Phenomenon genetics, Transcription Factors genetics, Vasculitis genetics
- Abstract
Objective: Endothelial cell activation by tumor necrosis factor (TNF) and associated leukocyte infiltration are hallmarks of vasculitis. The aim of this study was to investigate the potential role of the cellular stress-associated endothelial X-box binding protein 1 (XBP-1) transcription factor in TNF-induced endothelial cell inflammation and vasculitis., Methods: Mice with an endothelial cell-specific XBP-1 deficiency were used in a modified local Shwartzman reaction (LSR) model of TNF-induced small vessel vasculitis. To address the contribution of XBP-1 to the TNF-mediated inflammatory response in endothelial cells, we examined the activation of XBP-1 expression by TNF as well as the effect of XBP-1 knockdown in endothelial cells on TNF-induced signaling, proinflammatory gene expression, and leukocyte-endothelial cell adhesion., Results: The active spliced form of XBP-1 in endothelial cells was triggered by TNF. In addition, endothelial XBP-1 contributed to the sustained TNF-triggered NF-κB-dependent transcriptional activation of proinflammatory molecules, which was associated with leukocyte-endothelial cell adhesion. In the LSR model, endothelial cell-specific XBP-1-deficient mice displayed significantly less vascular damage, accompanied by reduced perivascular neutrophil infiltration, as compared with wild-type mice., Conclusion: Endothelial XBP-1 is activated by TNF and regulates leukocyte-endothelial cell adhesion in vitro as well as neutrophil infiltration and vascular damage in murine vasculitis., (© 2015, American College of Rheumatology.)
- Published
- 2015
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21. Endothelial-specific deficiency of Junctional Adhesion Molecule-C promotes vessel normalisation in proliferative retinopathy.
- Author
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Economopoulou M, Avramovic N, Klotzsche-von Ameln A, Korovina I, Sprott D, Samus M, Gercken B, Troullinaki M, Grossklaus S, Funk RH, Li X, Imhof BA, Orlova VV, and Chavakis T
- Subjects
- Animals, Cell Adhesion, Cell Hypoxia, Cell Line, Cell Size, Cell Surface Extensions, Disease Models, Animal, Endothelial Cells, Endothelium, Vascular pathology, Fibronectins, Human Umbilical Vein Endothelial Cells, Humans, Integrin beta1 physiology, Ischemia physiopathology, Junctional Adhesion Molecule C physiology, Mice, Mice, Knockout, Neovascularization, Pathologic etiology, Organ Specificity, Platelet Endothelial Cell Adhesion Molecule-1 analysis, RNA Interference, RNA, Small Interfering genetics, Retinal Vessels ultrastructure, rap1 GTP-Binding Proteins physiology, Endothelium, Vascular physiopathology, Junctional Adhesion Molecule C deficiency, Neovascularization, Pathologic physiopathology, Retinal Vessels physiopathology, Retinopathy of Prematurity physiopathology, Vitreoretinopathy, Proliferative physiopathology
- Abstract
In proliferative retinopathies, like proliferative diabetic retinopathy and retinopathy of prematurity (ROP), the hypoxia response is sustained by the failure of the retina to revascularise its ischaemic areas. Non-resolving retina ischaemia/hypoxia results in upregulation of pro-angiogenic factors and pathologic neovascularisation with ectopic, fragile neovessels. Promoting revascularisation of the retinal avascular area could interfere with this vicious cycle and lead to vessel normalisation. Here, we examined the function of endothelial junctional adhesion molecule-C (JAM-C) in the context of ROP. Endothelial-specific JAM-C-deficient (EC-JAM-C KO) mice and littermate JAM-C-proficient (EC-JAM-C WT) mice were subjected to the ROP model. An increase in total retinal vascularisation was found at p17 owing to endothelial JAM-C deficiency, which was the result of enhanced revascularisation and vessel normalisation, thereby leading to significantly reduced avascular area in EC-JAM-C KO mice. In contrast, pathologic neovessel formation was not affected by endothelial JAM-C deficiency. Consistent with improved vessel normalisation, tip cell formation at the interface between vascular and avascular area was higher in EC-JAM-C KO mice, as compared to their littermate controls. Consistently, JAM-C inactivation in endothelial cells resulted in increased spreading on fibronectin and enhanced sprouting in vitro in a manner dependent on β1-integrin and on the activation of the small GTPase RAP1. Together, endothelial deletion of JAM-C promoted endothelial cell sprouting, and consequently vessel normalisation and revascularisation of the hypoxic retina without altering pathologic neovascularisation. Thus, targeting endothelial JAM-C may provide a novel therapeutic strategy for promoting revascularisation and vessel normalisation in the treatment of proliferative retinopathies.
- Published
- 2015
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22. Loss of milk fat globule-epidermal growth factor 8 (MFG-E8) in mice leads to low bone mass and accelerates ovariectomy-associated bone loss by increasing osteoclastogenesis.
- Author
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Sinningen K, Albus E, Thiele S, Grossklaus S, Kurth T, Udey MC, Chavakis T, Hofbauer LC, and Rauner M
- Subjects
- Animals, Antigens, Surface genetics, Bone Density, Cells, Cultured, Female, Gene Deletion, Mice, Mice, Knockout, Milk Proteins genetics, Osteoporosis etiology, Antigens, Surface physiology, Osteoclasts cytology, Osteoporosis physiopathology, Ovariectomy
- Abstract
Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that controls the engulfment of apoptotic cells and exerts inflammation-modulatory effects. Recently, it has been implicated in osteoclastogenesis and the pathogenesis of inflammatory periodontal bone loss, but its role in physiological bone homeostasis is still not well defined. Here, we evaluated the influence of MFG-E8 on osteoblasts and osteoclasts and its impact on bone remodeling in healthy and ovariectomized mice as a model for post-menopausal osteoporosis. Total and trabecular bone mineral densities at the lumbar spine in 6-week-old MFG-E8 KO mice were reduced by 11% (p < 0.05) and 17% (p < 0.01), respectively, as compared to wild-type (WT) mice. Accordingly, serum levels of the bone formation marker P1NP were decreased by 37% (p < 0.01) in MFG-E8 KO mice as were the ex vivo mineralization capacity and expression of osteoblast genes (Runx2, alkaline phosphatase, osteocalcin) in MFG-E8 KO osteoblasts. In contrast, serum bone resorption markers CTX1 and TRAP5b were increased by 30% and 60% (p < 0.05), respectively, in MFG-E8 KO mice. Furthermore, bone marrow macrophages from MFG-E8-KO mice differentiated more effectively into osteoclasts, as compared to WT cells. MFG-E8-deficient osteoclasts displayed increased bone resorption ex vivo, which could be reversed by the presence of recombinant MFG-E8. To determine the significance of the enhanced osteoclastogenesis in MFG-E8 KO mice, we performed an ovariectomy, which is associated with bone loss due to increased osteoclast activity. Indeed, MFG-E8 KO mice lost 12% more trabecular bone density than WT mice after ovariectomy. Together, these data indicate that MFG-E8 controls steady-state and pathological bone turnover and may therefore represent a new target gene in the treatment of bone diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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23. Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation.
- Author
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Kanczkowski W, Alexaki VI, Tran N, Großklaus S, Zacharowski K, Martinez A, Popovics P, Block NL, Chavakis T, Schally AV, and Bornstein SR
- Subjects
- Adrenal Cortex cytology, Adrenal Cortex drug effects, Adrenal Cortex metabolism, Aldehyde Reductase genetics, Aldehyde Reductase metabolism, Animals, Blotting, Western, Carrier Proteins genetics, Carrier Proteins metabolism, Chemokine CXCL2 genetics, Chemokine CXCL2 metabolism, Female, Gene Expression, Glucocorticoids metabolism, Hypothalamo-Hypophyseal System drug effects, Inflammation genetics, Inflammation metabolism, Lipopolysaccharides pharmacology, Male, Mice, Mice, Knockout, Mice, Transgenic, Myeloid Differentiation Factor 88 genetics, Myxovirus Resistance Proteins genetics, Myxovirus Resistance Proteins metabolism, Pituitary-Adrenal System drug effects, Pituitary-Adrenal System immunology, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Toll-Like Receptors metabolism, Hypothalamo-Hypophyseal System physiology, Inflammation physiopathology, Myeloid Differentiation Factor 88 physiology, Pituitary-Adrenal System physiology
- Abstract
Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.
- Published
- 2013
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24. Impact of Hey2 and COUP-TFII on genes involved in arteriovenous differentiation in primary human arterial and venous endothelial cells.
- Author
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Korten S, Brunssen C, Poitz DM, Großklaus S, Brux M, Schnittler HJ, Strasser RH, Bornstein SR, Morawietz H, and Goettsch W
- Subjects
- Biomarkers metabolism, Cells, Cultured, Down-Regulation physiology, Endothelium, Vascular cytology, Ephrin-B2 metabolism, Humans, Receptors, Notch metabolism, Signal Transduction physiology, Umbilical Arteries cytology, Umbilical Veins cytology, Up-Regulation physiology, Vascular Endothelial Growth Factor A metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, COUP Transcription Factor II metabolism, Cell Differentiation physiology, Endothelium, Vascular metabolism, Repressor Proteins metabolism, Umbilical Arteries metabolism, Umbilical Veins metabolism
- Abstract
Arteries and veins show marked differences in their anatomy, physiology and genetic expression pattern. In this study, we analyzed impact of overexpression or downregulation of arterial marker gene Hey2 and venous marker gene COUP-TFII in human venous and arterial endothelial cells on genes involved in arteriovenous differentiation. Lentiviral overexpression of venous marker gene COUP-TFII in arterial endothelial cells led to downregulation of NICD4, arterial marker gene Hey2 and EphrinB2. Downregulation of Hey2 could be mediated by direct binding of COUP-TFII to Hey2 promoter as shown by ChIP, EMSA and promoter analysis. Downregulation of Hey2 by shRNA causes downregulation of EphrinB2 expression. Overexpression of arterial marker Hey2 in venous endothelial cells did not change expression pattern of COUP-TFII. Downregulation of venous marker gene COUP-TFII in venous endothelial cells resulted in upregulation of VEGF-A, Dll4 and EphrinB2 expression. Our data support an important role of Hey2 and COUP-TFII in arteriovenous differentiation of human endothelial cells.
- Published
- 2013
- Full Text
- View/download PDF
25. Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction.
- Author
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Kanczkowski W, Chatzigeorgiou A, Grossklaus S, Sprott D, Bornstein SR, and Chavakis T
- Subjects
- Adrenal Gland Diseases genetics, Adrenal Gland Diseases pathology, Adrenal Gland Diseases physiopathology, Adrenal Glands drug effects, Adrenal Glands pathology, Adrenocorticotropic Hormone metabolism, Animals, Apoptosis drug effects, Calcium-Binding Proteins, Carrier Proteins genetics, Cell Adhesion Molecules, Cells, Cultured, Corticosterone metabolism, Gene Expression drug effects, Humans, Hypothalamo-Hypophyseal System physiopathology, Inflammation pathology, Intercellular Signaling Peptides and Proteins, Lipopolysaccharides toxicity, Mice, Mice, Inbred C57BL, Mice, Knockout, Pituitary-Adrenal System physiopathology, Stress, Physiological, Systemic Inflammatory Response Syndrome genetics, Systemic Inflammatory Response Syndrome pathology, Systemic Inflammatory Response Syndrome physiopathology, Adrenal Glands physiopathology, Carrier Proteins physiology, Inflammation physiopathology
- Abstract
Inflammation in the course of systemic inflammatory response syndrome (SIRS) or sepsis often results in dysregulation of the hypothalamic-pituitary-adrenal axis; however, the underlying mechanisms are not well understood. The adrenal gland is highly vascularized; thus, we hypothesized that endothelial dysfunction may actively participate in inflammation-related adrenal insufficiency. To address this hypothesis, we used the properties of developmental endothelial locus-1 (Del-1), which is an endothelial-derived anti-inflammatory factor that antagonizes integrin-dependent leukocyte adhesion. Here we identified that Del-1 is expressed in the adrenal gland and that its expression was down-regulated upon SIRS induction by systemic lipopolysaccharide administration. Furthermore, we observed increased leukocyte accumulation, inflammation, and higher apoptosis in the adrenal glands of Del-1-deficient mice as compared with wild-type mice. Strikingly, Del-1 deficiency was also associated with reduced corticosterone and ACTH levels 24 hours after lipopolysaccharide administration. Together, these data suggest that Del-1 may act as a gatekeeper of adrenal gland inflammation and may regulate the integrity of the hypothalamic-pituitary-adrenal axis stress response, thereby modulating adrenal (dys)function in the course of SIRS.
- Published
- 2013
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26. Caveolin-1 opens endothelial cell junctions by targeting catenins.
- Author
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Kronstein R, Seebach J, Grossklaus S, Minten C, Engelhardt B, Drab M, Liebner S, Arsenijevic Y, Taha AA, Afanasieva T, and Schnittler HJ
- Subjects
- Animals, Antigens, CD metabolism, Base Sequence, CHO Cells, Cadherins metabolism, Caveolin 1 deficiency, Caveolin 1 genetics, Cell Line, Cricetinae, Cricetulus, DNA Primers genetics, Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Junctions drug effects, Mice, Mice, Knockout, Multiprotein Complexes metabolism, Mutant Proteins genetics, Mutant Proteins metabolism, Thrombin pharmacology, Catenins metabolism, Caveolin 1 metabolism, Endothelial Cells metabolism, Intercellular Junctions metabolism
- Abstract
Aims: A fundamental phenomenon in inflammation is the loss of endothelial barrier function, in which the opening of endothelial cell junctions plays a central role. However, the molecular mechanisms that ultimately open the cell junctions are largely unknown., Methods and Results: Impedance spectroscopy, biochemistry, and morphology were used to investigate the role of caveolin-1 in the regulation of thrombin-induced opening of cell junctions in cultured human and mouse endothelial cells. Here, we demonstrate that the vascular endothelial (VE) cadherin/catenin complex targets caveolin-1 to endothelial cell junctions. Association of caveolin-1 with VE-cadherin/catenin complexes is essential for the barrier function decrease in response to the pro-inflammatory mediator thrombin, which causes a reorganization of the complex in a rope ladder-like pattern accompanied by a loss of junction-associated actin filaments. Mechanistically, we show that in response to thrombin stimulation the protease-activated receptor 1 (PAR-1) causes phosphorylation of caveolin-1, which increasingly associates with β- and γ-catenin. Consequently, the association of β- and γ-catenin with VE-cadherin is weakened, thus allowing junction reorganization and a decrease in barrier function. Thrombin-induced opening of cell junctions is lost in caveolin-1-knockout endothelial cells and after expression of a Y/F-caveolin-1 mutant but is completely reconstituted after expression of wild-type caveolin-1., Conclusion: Our results highlight the pivotal role of caveolin-1 in VE-cadherin-mediated cell adhesion via catenins and, in turn, in barrier function regulation.
- Published
- 2012
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27. A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis.
- Author
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Langer HF, Orlova VV, Xie C, Kaul S, Schneider D, Lonsdorf AS, Fahrleitner M, Choi EY, Dutoit V, Pellegrini M, Grossklaus S, Nawroth PP, Baretton G, Santoso S, Hwang ST, Arnold B, and Chavakis T
- Subjects
- Animals, CHO Cells, Cell Adhesion Molecules analysis, Cell Adhesion Molecules antagonists & inhibitors, Cell Line, Tumor, Cell Movement, Cricetinae, Cricetulus, Endothelial Cells physiology, Humans, Mice, Mice, Inbred C57BL, Neoplasm Invasiveness, Cell Adhesion Molecules physiology, Immunoglobulins physiology, Lung Neoplasms secondary, Melanoma pathology
- Abstract
Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C(-/-) mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.
- Published
- 2011
- Full Text
- View/download PDF
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