377 results on '"Zakrzewicz, A."'
Search Results
2. Learning From User-Specified Optimizer Hints in Database Systems
- Author
-
Zakrzewicz Maciej
- Subjects
database systems ,query optimization ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
Recently, numerous machine learning (ML) techniques have been applied to address database performance management problems, including cardinality estimation, cost modeling, optimal join order prediction, hint generation, etc. In this paper, we focus on query optimizer hints employed by users in their queries in order to mask some Query Optimizer deficiencies. We treat the query optimizer hints, bound to previous queries, as significant additional query metadata and learn to automatically predict which new queries will pose similar performance challenges and should therefore also be supported by query optimizer hints. To validate our approach, we have performed a number of experiments using real-life SQL workloads and we achieved promising results.
- Published
- 2024
- Full Text
- View/download PDF
3. Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP
- Author
-
Hongtao Liu, Dariusz Zakrzewicz, Kamil Nosol, Rossitza N. Irobalieva, Somnath Mukherjee, Rose Bang-Sørensen, Nora Goldmann, Sebastian Kunz, Lorenzo Rossi, Anthony A. Kossiakoff, Stephan Urban, Dieter Glebe, Joachim Geyer, and Kaspar P. Locher
- Subjects
Science - Abstract
Abstract Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor’s extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.
- Published
- 2024
- Full Text
- View/download PDF
4. IgG against the Membrane-Proximal Portion of the Desmoglein 3 Ectodomain Induces Loss of Keratinocyte Adhesion, a Hallmark in Pemphigus Vulgaris
- Author
-
Hudemann, Christoph, Exner, Yvonne, Pollmann, Robert, Schneider, Karina, Zakrzewicz, Anna, Feldhoff, Simon, Schmidt, Thomas, Spindler, Volker, Rafei-Shamsabadi, David, Völlner, Frauke, Waschke, Jens, Tikkanen, Ritva, Hertl, Michael, and Eming, Rüdiger
- Published
- 2023
- Full Text
- View/download PDF
5. Activation of endothelial NO synthase and P2X7 receptor modification mediates the cholinergic control of ATP-induced interleukin-1β release by mononuclear phagocytes
- Author
-
Katrin Richter, Nilay Asci, Vijay K. Singh, Sanaria Hawro Yakoob, Marion Meixner, Anna Zakrzewicz, Juliane Liese, Andreas Hecker, Sigrid Wilker, Sabine Stumpf, Klaus-Dieter Schlüter, Marius Rohde, Axel Gödecke, Winfried Padberg, Ivan Manzini, Günther Schmalzing, and Veronika Grau
- Subjects
inflammation ,P2X7 receptor ,CHRNA7 ,CHRNA9 ,CHRNA10 ,endothelial NO synthase ,Immunologic diseases. Allergy ,RC581-607 - Abstract
ObjectiveThe pro-inflammatory cytokine interleukin-1β (IL-1β) plays a central role in host defense against infections. High systemic IL-1β levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1β release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1β release by human monocytes via nicotinic acetylcholine receptor (nAChR) subunits α7, α9 and/or α10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R).MethodsDifferent human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1β was measured in cell culture supernatants. Patch-clamp and intracellular Ca2+ imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain.ResultsThe inhibitory effect of nAChR agonists on the BzATP-induced IL-1β release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal via eNOS to inhibit the BzATP-induced IL-1β release. Moreover, NO donors (SNAP, S-nitroso-N-acetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1β release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, Xenopus laevis oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification.ConclusionWe provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1β release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders.
- Published
- 2023
- Full Text
- View/download PDF
6. Reviews with revenue in reputation: Credibility management method for consumer-opinion platforms
- Author
-
Leszczyński, Konrad and Zakrzewicz, Maciej
- Published
- 2019
- Full Text
- View/download PDF
7. Atherogenesis and plaque rupture, surface/interface-related phenomena
- Author
-
Siegel, G., Berkholz, J., Klüßendorf, D., Knosalla, C., Zakrzewicz, A., Ermilov, E., Malmsten, M., and Lindman, B.
- Published
- 2018
- Full Text
- View/download PDF
8. Tyrosine 146 of the Human Na+/Taurocholate Cotransporting Polypeptide (NTCP) Is Essential for Its Hepatitis B Virus (HBV) Receptor Function and HBV Entry into Hepatocytes
- Author
-
Dariusz Zakrzewicz, Regina Leidolf, Sebastian Kunz, Simon Franz Müller, Anita Neubauer, Silke Leiting, Nora Goldmann, Felix Lehmann, Dieter Glebe, and Joachim Geyer
- Subjects
bile acid ,HBV ,infection ,NTCP ,preS1 ,receptor ,Microbiology ,QR1-502 - Abstract
Na+/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1) is a hepatic bile acid uptake carrier participating in the enterohepatic circulation of bile acids. Apart from its transporter function, NTCP acts as the high-affinity liver-specific receptor for the hepatitis B virus (HBV), which attaches via its preS1-peptide domain of the large surface protein to NTCP, subsequently leading to endocytosis of the virus/NTCP-receptor complex. Although the process of NTCP-dependent HBV infection of hepatocytes has received much attention over the last decade, the precise molecular sites of the virus/NTCP interaction have not been fully identified. Inspection of the primary protein sequence of human NTCP revealed 139YIYSRGIY146 as a highly conserved tyrosine-rich motif. To study the role of Y139, Y141 and Y146 amino acids in NTCP biology, the aforementioned residues were substituted with alanine, phenylalanine or glutamate (mimicking phosphorylation) using site-directed mutagenesis. Similar to wt NTCP, the Y139A, Y141A, Y146A, Y141F, Y146F, and Y146E mutants were expressed at the plasma membrane of HEK293 cells and exhibited intact bile acid transport function. Y146A, Y146E, and Y146F demonstrated transport kinetics comparable to wild-type NTCP with Km values of 57.3–112.4 µM and Vmax values of 6683–7579 pmol/mg protein/min. Only Y141E was transport deficient, most likely due to an intracellular accumulation of the mutant protein. Most importantly, Y146A and Y146E mutation completely abrogated binding of the viral preS1-peptide to NTCP, while the Y146F mutant of NTCP showed some residual binding competence for preS1. Consequently, the NTCP mutants Y146A and Y146E, when expressed in HepG2 hepatoma cells, showed complete loss of susceptibility for in vitro HBV infection. In conclusion, tyrosine 146, and to some extent tyrosine 141, both belonging to the tyrosine-rich motif 139YIYSRGIY146 of human NTCP, are newly identified amino acid residues that play an essential role in the interaction of HBV with its receptor NTCP and, thus, in the process of virus entry into hepatocytes.
- Published
- 2022
- Full Text
- View/download PDF
9. The Properties of Materials and Structures of Fluted PVC Panels for the Transmission of Airborne Sound
- Author
-
Joanna Maria Kopania, Wojciech Zakrzewicz, Przemysław Kubiak, Adam Mrowicki, Michał Głogowski, Jacek Gralewski, Grzegorz Bogusławski, Kamil Wójciak, and Patryk Gaj
- Subjects
PVC panels ,transmission loss ,absorption coefficient ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
The primary goal of this research was to study transmission loss and absorption of fluted PVC panels using experimental and theoretical methods. During these studies, the link between panel size, thickness, transmission loss, and absorption was considered. We measured the transmission loss and absorption in reverberation rooms according to ISO standards. Hansen’s theoretical model was also used to predict the transmission loss. Agreement between TL prediction according to Hansen’s model and measured results for some of the studied panels were observed. However, the analytical prediction, according to Hansen’s model, for heavy fluted PVC panels must be used with caution. The absorption properties of the studied fluted PVC panels are also connected with their resonance, and, in addition, the resonance frequency is associated with the space between the ribs and wave propagation in the panel’s plane.
- Published
- 2022
- Full Text
- View/download PDF
10. Correction: Zakrzewicz et al. Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus? Cells 2022, 11, 942
- Author
-
Anna Zakrzewicz, Celina Würth, Benedikt Beckert, Simon Feldhoff, Katrien Vanderheyden, Stian Foss, Jan Terje Andersen, Hans de Haard, Peter Verheesen, Vladimir Bobkov, and Ritva Tikkanen
- Subjects
n/a ,Cytology ,QH573-671 - Abstract
The authors wish to make the following changes to their paper [...]
- Published
- 2022
- Full Text
- View/download PDF
11. ZNF580 – a brake on Interleukin-6
- Author
-
Philipp Stenzel, Kaj Nagorsen, Jonathan Bernd, Ulrike Leppert, Andreas Zakrzewicz, and Janine Berkholz
- Subjects
ZNF580 ,Interleukin 6 ,Monocytes ,LPS ,Sepsis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Background Zinc finger protein 580 (ZNF580) was reported to modulate angiogenesis, endothelial homeostasis and blood pressure control. ZNF580 regulated genes include VEGF-A and IL-8. However, it is unknown if ZNF580 could play a role during inflammation. The aim of this study was to find out if ZNF580 affects the expression of IL-6, if it occurs in monocytic cells and responds to inflammatory mediators. Results Overexpression of ZNF580 reduced LPS-induced promotor activity of IL-6. Consistently, overexpression of ZNF580 reduced by half the LPS-induced expression of IL-6. ZNF580 was strongly expressed in the nucleus of MonoMac6, a human monocytic cell line. LPS-stimulated IL-6 secretion increased when ZNF580 was suppressed with siRNA. After stimulation of MonoMac6 with LPS for 24 h, ZNF580 negatively correlated with the amount of secreted IL-6. In response to LPS, ZNF580 was increased within the first 8 h, followed by a marked decrease after 16 h. This decrease coincided with sustained IL-6 production. Conclusion This study demonstrated that ZNF580 inhibits LPS-induced expression of IL-6. ZNF580 was highly expressed in monocytic cells and therefore may contribute to the modulation of its IL-6 production, at least in response to LPS. This suggests cooperation between ZNF580 and NFκB, which could play a role during sepsis.
- Published
- 2018
- Full Text
- View/download PDF
12. Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
- Author
-
Anna Zakrzewicz, Celina Würth, Benedikt Beckert, Simon Feldhoff, Katrien Vanderheyden, Stian Foss, Jan Terje Andersen, Hans de Haard, Peter Verheesen, Vladimir Bobkov, and Ritva Tikkanen
- Subjects
keratinocytes ,epidermis ,pemphigus vulgaris ,autoimmune disease ,autoantibodies ,Fc receptor neonatal ,Cytology ,QH573-671 - Abstract
Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with antibodies isolated from pemphigus vulgaris patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data suggest that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus.
- Published
- 2022
- Full Text
- View/download PDF
13. Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery
- Author
-
Dariusz Zakrzewicz and Joachim Geyer
- Subjects
HBV ,posttranslational modification ,Na+/taurocholate cotransporting polypeptide ,NTCP ,mutation ,bile acid transport ,Biology (General) ,QH301-705.5 - Abstract
Hepatitis B virus (HBV) infections are among the major public health concerns worldwide with more than 250 million of chronically ill individuals. Many of them are additionally infected with the Hepatitis D virus, a satellite virus to HBV. Chronic infection frequently leads to serious liver diseases including cirrhosis and hepatocellular carcinoma, the most common type of liver cancer. Although current antiviral therapies can control HBV replication and slow down disease progress, there is an unmet medical need to identify therapies to cure this chronic infectious disease. Lately, a noteworthy progress in fighting against HBV has been made by identification of the high-affinity hepatic host receptor for HBV and HDV, namely Na+/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1). Next to its primary function as hepatic uptake transporter for bile acids, NTCP is essential for the cellular entry of HBV and HDV into hepatocytes. Due to this high-ranking discovery, NTCP has become a valuable target for drug development strategies for HBV/HDV-infected patients. In this review, we will focus on a newly predicted three-dimensional NTCP model that was generated using computational approaches and discuss its value in understanding the NTCP’s membrane topology, substrate and virus binding taking place in plasma membranes. We will review existing data on structural, functional, and biological consequences of amino acid residue changes and mutations that lead to loss of NTCP’s transport and virus receptor functions. Finally, we will discuss new directions for future investigations aiming at development of new NTCP-based HBV entry blockers that inhibit HBV tropism in human hepatocytes.
- Published
- 2022
- Full Text
- View/download PDF
14. SLPI Inhibits ATP-Mediated Maturation of IL-1β in Human Monocytic Leukocytes: A Novel Function of an Old Player
- Author
-
Anna Zakrzewicz, Katrin Richter, Dariusz Zakrzewicz, Kathrin Siebers, Jelena Damm, Alisa Agné, Andreas Hecker, J. Michael McIntosh, Walee Chamulitrat, Gabriela Krasteva-Christ, Ivan Manzini, Ritva Tikkanen, Winfried Padberg, Sabina Janciauskiene, and Veronika Grau
- Subjects
annexin II ,calcium-independent phospholipase A2β ,caspase-1 ,IL-1β ,inflammasome ,SLPI ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Interleukin-1β (IL-1β) is a potent, pro-inflammatory cytokine of the innate immune system that plays an essential role in host defense against infection. However, elevated circulating levels of IL-1β can cause life-threatening systemic inflammation. Hence, mechanisms controlling IL-1β maturation and release are of outstanding clinical interest. Secretory leukocyte protease inhibitor (SLPI), in addition to its well-described anti-protease function, controls the expression of several pro-inflammatory cytokines on the transcriptional level. In the present study, we tested the potential involvement of SLPI in the control of ATP-induced, inflammasome-dependent IL-1β maturation and release. We demonstrated that SLPI dose-dependently inhibits the ATP-mediated inflammasome activation and IL-1β release in human monocytic cells, without affecting the induction of pro-IL-1β mRNA by LPS. In contrast, the ATP-independent IL-1β release induced by the pore forming bacterial toxin nigericin is not impaired, and SLPI does not directly modulate the ion channel function of the human P2X7 receptor heterologously expressed in Xenopus laevis oocytes. In human monocytic U937 cells, however, SLPI efficiently inhibits ATP-induced ion-currents. Using specific inhibitors and siRNA, we demonstrate that SLPI activates the calcium-independent phospholipase A2β (iPLA2β) and leads to the release of a low molecular mass factor that mediates the inhibition of IL-1β release. Signaling involves nicotinic acetylcholine receptor subunits α7, α9, α10, and Src kinase activation and results in an inhibition of ATP-induced caspase-1 activation. In conclusion, we propose a novel anti-inflammatory mechanism induced by SLPI, which inhibits the ATP-dependent maturation and secretion of IL-1β. This novel signaling pathway might lead to development of therapies that are urgently needed for the prevention and treatment of systemic inflammation.
- Published
- 2019
- Full Text
- View/download PDF
15. Structural Microangiopathies in Skeletal Muscle Related to Systemic Vascular Pathologies in Humans
- Author
-
Oliver Baum, Jonathan Bernd, Samuel Becker, Adolfo Odriozola, Benoît Zuber, Stefan A. Tschanz, Andreas Zakrzewicz, Stuart Egginton, and Janine Berkholz
- Subjects
capillaries ,human pathologies ,morphometry ,skeletal muscle ,transmission electron microscopy ,Physiology ,QP1-981 - Abstract
It is unclear how microangiopathic changes in skeletal muscle vary among systemic vascular pathologies. We therefore analyzed the capillary fine structure in skeletal muscle from patients with arterial hypertension (HYPT), diabetes mellitus type 2 (T2DM) or intermittent claudication – peripheral arterial disease (IC/PAD). Tablet-based image analysis (TBIA) was carried out to largely re-evaluate 5,000 transmission electron micrographs of capillaries from 126 vastus lateralis biopsies of 75 individuals (HYPT, T2DM or IC/PAD patients as well as healthy individuals before and after endurance exercise training) used in previous morphometric studies, but assessed using stereological counting grids of different sizes. Serial block-face scanning electron microscopy (SBFSEM) of mouse skeletal muscle was used for validation of the particular fine structural events observed in human biopsies. The peri-capillary basement membrane (BM) was 38.5 and 45.5% thicker (P < 0.05) in T2DM and IC/PAD patients than in the other groups. A 17.7–39.6% lower (P < 0.05) index for intraluminal endothelial cell (EC) surface enlargement by projections was exclusively found in T2DM patients by TBIA morphometry. The proportion of capillaries with disrupted BM between pericytes (PC) and EC was higher (P < 0.05) in HYPT (33.2%) and T2DM (38.7%) patients than in the control group. Empty EC-sockets were more frequent (P < 0.05) in the three patient groups (20.6% in HYPT, 27.1% in T2DM, 30.0% in IC/PAD) than in the healthy individuals. SBFSEM confirmed that EC-sockets may exhibit close proximity to the capillary lumen. Our comparative morphometric analysis demonstrated that structural arrangement of skeletal muscle capillaries is more affected in T2DM than in HYPT or IC/PAD, although some similar elements of remodeling were found. The increased frequency of empty EC-sockets in the three patient groups indicates that the PC-EC interaction is commonly disturbed in these systemic vascular pathologies.
- Published
- 2020
- Full Text
- View/download PDF
16. The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells
- Author
-
Ahmed Shamloul, Gustav Steinemann, Kerrin Roos, Celine Huajia Liem, Jonathan Bernd, Thorsten Braun, Andreas Zakrzewicz, and Janine Berkholz
- Subjects
Smyd1 ,lipopolysaccharide ,sepsis ,IL-6 ,NF-κB ,histone methylation ,Cytology ,QH573-671 - Abstract
The lysine methyltransferase Smyd1 with its characteristic catalytic SET-domain is highly enriched in the embryonic heart and skeletal muscles, participating in cardiomyogenesis, sarcomere assembly and chromatin remodeling. Recently, significant Smyd1 levels were discovered in endothelial cells (ECs) that responded to inflammatory cytokines. Based on these biochemical properties, we hypothesized that Smyd1 is involved in inflammation-triggered signaling in ECs and therefore, investigated its role within the LPS-induced signaling cascade. Human endothelial cells (HUVECs and EA.hy926 cells) responded to LPS stimulation with higher intrinsic Smyd1 expression. By transfection with expression vectors containing gene inserts encoding either intact Smyd1, a catalytically inactive Smyd1-mutant or Smyd1-specific siRNAs, we show that Smyd1 contributes to LPS-triggered expression and secretion of IL-6 in EA.hy926 cells. Further molecular analysis revealed this process to be based on two signaling pathways: Smyd1 increased the activity of NF-κB and promoted the trimethylation of lysine-4 of histone-3 (H3K4me3) within the IL-6 promoter, as shown by ChIP-RT-qPCR combined with IL-6-promoter-driven luciferase reporter gene assays. In summary, our experimental analysis revealed that LPS-binding to ECs leads to the up-regulation of Smyd1 expression to transduce the signal for IL-6 up-regulation via activation of the established NF-κB pathway as well as via epigenetic trimethylation of H3K4.
- Published
- 2021
- Full Text
- View/download PDF
17. Knockout of the CMP–Sialic Acid Transporter SLC35A1 in Human Cell Lines Increases Transduction Efficiency of Adeno-Associated Virus 9: Implications for Gene Therapy Potency Assays
- Author
-
Antje Banning, Anna Zakrzewicz, Xin Chen, Steven J. Gray, and Ritva Tikkanen
- Subjects
human gene therapy ,AAV ,sialic acid ,sialylation ,SLC35A1 ,glycosylation ,Cytology ,QH573-671 - Abstract
Recombinant adeno-associated viruses (AAV) have emerged as an important tool for gene therapy for human diseases. A prerequisite for clinical approval is an in vitro potency assay that can measure the transduction efficiency of each virus lot produced. The AAV serotypes are typical for gene therapy bind to different cell surface structures. The binding of AAV9 on the surface is mediated by terminal galactose residues present in the asparagine-linked carbohydrates in glycoproteins. However, such terminal galactose residues are rare in cultured cells. They are masked by sialic acid residues, which is an obstacle for the infection of many cell lines with AAV9 and the respective potency assays. The sialic acid residues can be removed by enzymatic digestion or chemical treatment. Still, such treatments are not practical for AAV9 potency assays since they may be difficult to standardize. In this study, we generated human cell lines (HEK293T and HeLa) that become permissive for AAV9 transduction after a knockout of the CMP–sialic acid transporter SLC35A1. Using the human aspartylglucosaminidase (AGA) gene, we show that these cell lines can be used as a model system for establishing potency assays for AAV9-based gene therapy approaches for human diseases.
- Published
- 2021
- Full Text
- View/download PDF
18. Surfactant inhibits ATP-induced release of interleukin-1β via nicotinic acetylcholine receptors[S]
- Author
-
Sören Backhaus, Anna Zakrzewicz, Katrin Richter, Jelena Damm, Sigrid Wilker, Gabriele Fuchs-Moll, Mira Küllmar, Andreas Hecker, Ivan Manzini, Clemens Ruppert, J. Michael McIntosh, Winfried Padberg, and Veronika Grau
- Subjects
CHRNA7 ,CHRNA9 ,CHRNA10 ,dipalmitoylphosphatidylcholine ,inflammasome ,monocyte ,Biochemistry ,QD415-436 - Abstract
Interleukin (IL)-1β is a potent pro-inflammatory cytokine of innate immunity involved in host defense. High systemic IL-1β levels, however, cause life-threatening inflammatory diseases, including systemic inflammatory response syndrome. In response to various danger signals, the pro-form of IL-1β is synthesized and stays in the cytoplasm unless a second signal, such as extracellular ATP, activates the inflammasome, which enables processing and release of mature IL-1β. As pulmonary surfactant is known for its anti-inflammatory properties, we hypothesize that surfactant inhibits ATP-induced release of IL-1β. Lipopolysaccharide-primed monocytic U937 cells were stimulated with an ATP analog in the presence of natural or synthetic surfactant composed of recombinant surfactant protein (rSP)-C, palmitoylphosphatidylglycerol, and dipalmitoylphosphatidylcholine (DPPC). Both surfactant preparations dose-dependently inhibited IL-1β release from U937 cells. DPPC was the active constituent of surfactant, whereas rSP-C and palmitoylphosphatidylglycerol were inactive. DPPC was also effective in primary mononuclear leukocytes isolated from human blood. Experiments with nicotinic antagonists, siRNA technology, and patch-clamp experiments suggested that stimulation of nicotinic acetylcholine receptors (nAChRs) containing subunit α9 results in a complete inhibition of the ion channel function of ATP receptor, P2X7. In conclusion, the surfactant constituent, DPPC, efficiently inhibits ATP-induced inflammasome activation and maturation of IL-1β in human monocytes by a mechanism involving nAChRs.
- Published
- 2017
- Full Text
- View/download PDF
19. The Comparative Study on the Li-S and Li-ion Batteries Cooperating with the Photovoltaic Array
- Author
-
Krystian Siczek, Krzysztof Siczek, Piotr Piersa, Łukasz Adrian, Szymon Szufa, Andrzej Obraniak, Przemysław Kubiak, Wojciech Zakrzewicz, and Grzegorz Bogusławski
- Subjects
photovoltaic array ,Li-ion battery ,Li-S battery ,boost converter ,boost inverter ,Technology - Abstract
The stationary photovoltaic array can be used to charge the different vehicle batteries and, in parallel, be used as a power source for the utility grid or standalone devices placed such as in campers. The main objective of the study was to compare chosen electrical characteristics of two assemblies with each containing the same PV array, boost converter and inverter, and a different battery, such as the Li-S one and the Li-ion one, respectively. Differences occurring during modelling of Li-ion and Li-S batteries were discussed. The model of the chosen photovoltaic array was used during analysis. The models based on electrical equivalent circuits for Li-ion battery and of Li-S battery were utilized during calculations. The models of the boost converter and boost inverter of known topology parameters were utilized during simulations. In the chosen performances (courses of voltages and currents versus time) obtained from the simulation of the sets composed of the Li-S battery cooperating with the boost inverter or the boost converter, only small differences or no differences occurred when compared to the case of the Li-ion battery.
- Published
- 2020
- Full Text
- View/download PDF
20. Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1β by Monocytic Cells
- Author
-
Anca-Laura Amati, Anna Zakrzewicz, Kathrin Siebers, Sigrid Wilker, Sarah Heldmann, Dariusz Zakrzewicz, Andreas Hecker, J. Michael McIntosh, Winfried Padberg, and Veronika Grau
- Subjects
Pathology ,RB1-214 - Abstract
Chemokines and ATP are among the mediators of inflammatory sites that can enter the circulation via damaged blood vessels. The main function of chemokines is leukocyte mobilization, and ATP typically triggers inflammasome assembly. IL-1β, a potent inflammasome-dependent cytokine of innate immunity, is essential for pathogen defense. However, excessive IL-1β may cause life-threatening systemic inflammation. Here, we hypothesize that chemokines control ATP-dependent secretion of monocytic IL-1β. Lipopolysaccharide-primed human monocytic U937 cells were stimulated with the P2X7 agonist BzATP for 30 min to induce IL-1β release. CCL3, CCL4, and CCL5 dose dependently inhibited BzATP-stimulated release of IL-1β, whereas CXCL16 was ineffective. The effect of CCL3 was confirmed for primary mononuclear leukocytes. It was blunted after silencing CCR1 or calcium-independent phospholipase A2 (iPLA2) by siRNA and was sensitive to antagonists of nicotinic acetylcholine receptors containing subunits α7 and α9. U937 cells secreted small factors in response to CCL3 that mediated the inhibition of IL-1β release. We suggest that CCL chemokines inhibit ATP-induced release of IL-1β from U937 cells by a triple-membrane-passing mechanism involving CCR, iPLA2, release of small mediators, and nicotinic acetylcholine receptor subunits α7 and α9. We speculate that whenever chemokines and ATP enter the circulation concomitantly, systemic release of IL-1β is minimized.
- Published
- 2017
- Full Text
- View/download PDF
21. ZNF580 – a brake on Interleukin-6
- Author
-
Stenzel, Philipp, Nagorsen, Kaj, Bernd, Jonathan, Leppert, Ulrike, Zakrzewicz, Andreas, and Berkholz, Janine
- Published
- 2018
- Full Text
- View/download PDF
22. Adaptation of Asymptotic Trust Algorithm : Reputation on Internet Forums
- Author
-
Leszczyński, Konrad, Zakrzewicz, Maciej, Morzy, Tadeusz, editor, Härder, Theo, editor, and Wrembel, Robert, editor
- Published
- 2013
- Full Text
- View/download PDF
23. C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation
- Author
-
Katrin Richter, Sabrina Sagawe, Andreas Hecker, Mira Küllmar, Ingolf Askevold, Jelena Damm, Sarah Heldmann, Michael Pöhlmann, Sophie Ruhrmann, Michael Sander, Klaus-Dieter Schlüter, Sigrid Wilker, Inke R. König, Wolfgang Kummer, Winfried Padberg, Arik J. Hone, J. Michael McIntosh, Anna Teresa Zakrzewicz, Christian Koch, and Veronika Grau
- Subjects
C-reactive protein ,interleukin-1β ,NLRP3 inflammasome ,monocytes ,nicotinic acetylcholine receptors ,sterile inflammation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Blood levels of the acute phase reactant C-reactive protein (CRP) are frequently measured as a clinical marker for inflammation, but the biological functions of CRP are still controversial. CRP is a phosphocholine (PC)-binding pentraxin, mainly produced in the liver in response to elevated levels of interleukin-1β (IL-1β) and of the IL-1β-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1β levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feedback regulator of monocytic IL-1β maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1β release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC50 = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits α7, α9, and α10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChRs, suggesting that CRP is a potent nicotinic agonist controlling innate immunity without entailing the risk of adverse effects in the nervous system. In a prospective study on multiple trauma patients, IL-1β plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and TNF-α positively correlated. In conclusion, PC-laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and might protect against trauma-associated sterile inflammation.
- Published
- 2018
- Full Text
- View/download PDF
24. Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors
- Author
-
Kathrin Siebers, Bijan Fink, Anna Zakrzewicz, Alisa Agné, Katrin Richter, Sebastian Konzok, Andreas Hecker, Sven Zukunft, Mira Küllmar, Jochen Klein, J. Michael McIntosh, Thomas Timm, Katherina Sewald, Winfried Padberg, Nupur Aggarwal, Walee Chamulitrat, Sentot Santoso, Wendy Xia, Sabina Janciauskiene, and Veronika Grau
- Subjects
CD36 ,CHRNA7 ,CHRNA9 ,CHRNA10 ,inflammasome ,interleukin-1β ,Immunologic diseases. Allergy ,RC581-607 - Abstract
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
- Published
- 2018
- Full Text
- View/download PDF
25. Electrostatic Force Method : Trust Management Method Inspired by the Laws of Physics
- Author
-
Leszczyński, Konrad, Zakrzewicz, Maciej, Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Nierstrasz, Oscar, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Sudan, Madhu, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Vardi, Moshe Y., Series editor, Weikum, Gerhard, Series editor, Furnell, Steven, editor, Lambrinoudakis, Costas, editor, and Pernul, Günther, editor
- Published
- 2011
- Full Text
- View/download PDF
26. Hidden and Indirect (Probabilistically Estimated) Reputations - Hiper Method
- Author
-
Leszczyński Konrad and Zakrzewicz Maciej
- Subjects
trust management method ,reputation system ,e-commerce ,online auctions ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
It is a challenge to design a well balanced reputation system for an environment with millions of users. A reputation system must also represent user reputation as a value which is simple and easy to compare and will give users straightforward suggestions who to trust. Since reputation systems rely on feedbacks given by users, it is necessary to collect unbiased feedbacks
- Published
- 2015
- Full Text
- View/download PDF
27. Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders
- Author
-
Dariusz Zakrzewicz, Anna Zakrzewicz, Klaus T. Preissner, Philipp Markart, and Malgorzata Wygrecka
- Subjects
protein arginine methylation ,PRMT ,chronic lung disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease.
- Published
- 2012
- Full Text
- View/download PDF
28. Interactions of Na+/taurocholate cotransporting polypeptide with host cellular proteins upon hepatitis B and D virus infection: novel potential targets for antiviral therapy.
- Author
-
Zakrzewicz, Dariusz and Geyer, Joachim
- Subjects
- *
HEPATITIS D , *HEPATITIS B , *VIRAL tropism , *BILE salts , *DRUG development - Abstract
Na+/taurocholate cotransporting polypeptide (NTCP) is a member of the solute carrier (SLC) family 10 transporters (gene symbol SLC10A1) and is responsible for the sodium-dependent uptake of bile salts across the basolateral membrane of hepatocytes. In addition to its primary transporter function, NTCP is the high-affinity hepatic receptor for hepatitis B (HBV) and hepatitis D (HDV) viruses and, therefore, is a prerequisite for HBV/HDV virus entry into hepatocytes. The inhibition of HBV/HDV binding to NTCP and internalization of the virus/NTCP receptor complex has become a major concept in the development of new antiviral drugs called HBV/HDV entry inhibitors. Hence, NTCP has emerged as a promising target for therapeutic interventions against HBV/HDV infections in the last decade. In this review, recent findings on protein–protein interactions (PPIs) between NTCP and cofactors relevant for entry of the virus/NTCP receptor complex are summarized. In addition, strategies aiming to block PPIs with NTCP to dampen virus tropism and HBV/HDV infection rates are discussed. Finally, this article suggests novel directions for future investigations evaluating the functional contribution of NTCP-mediated PPIs in the development and progression of HBV/HDV infection and subsequent chronic liver disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
29. Canonical and Novel Non-Canonical Cholinergic Agonists Inhibit ATP-Induced Release of Monocytic Interleukin-1β via Different Combinations of Nicotinic Acetylcholine Receptor Subunits α7, α9 and α10
- Author
-
Anna Zakrzewicz, Katrin Richter, Alisa Agné, Sigrid Wilker, Kathrin Siebers, Bijan Fink, Gabriela Krasteva-Christ, Mike Althaus, Winfried Padberg, Arik J. Hone, J. Michael McIntosh, and Veronika Grau
- Subjects
acetylcholine ,CHRNA ,glycerophosphocholine ,inflammasome ,interleukin-1beta ,lysophosphatidylcholine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Recently, we discovered a cholinergic mechanism that inhibits the adenosine triphosphate (ATP)-dependent release of interleukin-1β (IL-1β) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of α7, α9 and/or α10 subunits. Furthermore, we identified phosphocholine (PC) and dipalmitoylphosphatidylcholine (DPPC) as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, PC does not provoke ion channel responses at conventional nAChRs composed of subunits α9 and α10. The purpose of this study is to determine the composition of nAChRs necessary for nicotinic signaling in monocytic cells and to test the hypothesis that common metabolites of phosphatidylcholines, lysophosphatidylcholine (LPC) and glycerophosphocholine (G-PC), function as nAChR agonists. In peripheral blood mononuclear cells from nAChR gene-deficient mice, we demonstrated that inhibition of ATP-dependent release of IL-1β by acetylcholine (ACh), nicotine and PC depends on subunits α7, α9 and α10. Using a panel of nAChR antagonists and siRNA technology, we confirmed the involvement of these subunits in the control of IL-1β release in the human monocytic cell line U937. Furthermore, we showed that LPC (C16:0) and G-PC efficiently inhibit ATP-dependent release of IL-1β. Of note, the inhibitory effects mediated by LPC and G-PC depend on nAChR subunits α9 and α10, but only to a small degree on α7. In Xenopuslaevis oocytes heterologously expressing different combinations of human α7, α9 or α10 subunits, ACh induced canonical ion channel activity, whereas LPC, G-PC and PC did not. In conclusion, we demonstrate that canonical nicotinic agonists and PC elicit metabotropic nAChR activity in monocytes via interaction of nAChR subunits α7, α9 and α10. For the metabotropic signaling of LPC and G-PC, nAChR subunits α9 and α10 are needed, whereas α7 is virtually dispensable. Furthermore, molecules bearing a PC group in general seem to regulate immune functions without perturbing canonical ion channel functions of nAChR.
- Published
- 2017
- Full Text
- View/download PDF
30. Mast Cells and Fibroblasts Work in Concert to Aggravate Pulmonary Fibrosis: Role of Transmembrane SCF and the PAR-2/PKC-α/Raf-1/p44/42 Signaling Pathway
- Author
-
Wygrecka, Malgorzata, Dahal, Bhola K., Kosanovic, Djuro, Petersen, Frank, Taborski, Brigitte, von Gerlach, Susanne, Didiasova, Miroslava, Zakrzewicz, Dariusz, Preissner, Klaus T., Schermuly, Ralph T., and Markart, Philipp
- Published
- 2013
- Full Text
- View/download PDF
31. Tyrosine 146 of the Human Na+/Taurocholate Cotransporting Polypeptide (NTCP) Is Essential for Its Hepatitis B Virus (HBV) Receptor Function and HBV Entry into Hepatocytes
- Author
-
Zakrzewicz, Dariusz, Leidolf, Regina, Kunz, Sebastian, Müller, Simon Franz, Neubauer, Anita, Leiting, Silke, Goldmann, Nora, Lehmann, Felix, Glebe, Dieter, Geyer, Joachim, and Justus Liebig University Giessen
- Subjects
ddc:630 - Published
- 2022
- Full Text
- View/download PDF
32. Multitasking Na+/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery
- Author
-
Joachim Geyer and Dariusz Zakrzewicz
- Subjects
posttranslational modification ,QH301-705.5 ,Na+/taurocholate cotransporting polypeptide ,bile acid transport ,HBV ,Medicine (miscellaneous) ,virus diseases ,NTCP ,mutation ,Biology (General) ,digestive system ,General Biochemistry, Genetics and Molecular Biology - Abstract
Hepatitis B virus (HBV) infections are among the major public health concerns worldwide with more than 250 million of chronically ill individuals. Many of them are additionally infected with the Hepatitis D virus, a satellite virus to HBV. Chronic infection frequently leads to serious liver diseases including cirrhosis and hepatocellular carcinoma, the most common type of liver cancer. Although current antiviral therapies can control HBV replication and slow down disease progress, there is an unmet medical need to identify therapies to cure this chronic infectious disease. Lately, a noteworthy progress in fighting against HBV has been made by identification of the high-affinity hepatic host receptor for HBV and HDV, namely Na+/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1). Next to its primary function as hepatic uptake transporter for bile acids, NTCP is essential for the cellular entry of HBV and HDV into hepatocytes. Due to this high-ranking discovery, NTCP has become a valuable target for drug development strategies for HBV/HDV-infected patients. In this review, we will focus on a newly predicted three-dimensional NTCP model that was generated using computational approaches and discuss its value in understanding the NTCP’s membrane topology, substrate and virus binding taking place in plasma membranes. We will review existing data on structural, functional, and biological consequences of amino acid residue changes and mutations that lead to loss of NTCP’s transport and virus receptor functions. Finally, we will discuss new directions for future investigations aiming at development of new NTCP-based HBV entry blockers that inhibit HBV tropism in human hepatocytes.
- Published
- 2022
33. Comparison of alternative sources of farmland values
- Author
-
Zakrzewicz, Christopher, Wade Brorsen, B., and Briggeman, Brian C.
- Published
- 2012
- Full Text
- View/download PDF
34. Gene expression of human beta defensins-1 and -2 is significantly reduced in non-inflamed keratinized oral tissue of smokers
- Author
-
Wolgin, Michael, Liodakis, Stylianos, Ulrich, Ina, Zakrzewicz, Andreas, Kielbassa, Andrej M., and Pries, Axel R.
- Published
- 2012
- Full Text
- View/download PDF
35. Activation of endothelial NO synthase and P2X7 receptor modification mediates the cholinergic control of ATP-induced interleukin-1β release by mononuclear phagocytes.
- Author
-
Richter, Katrin, Asci, Nilay, Singh, Vijay K., Yakoob, Sanaria Hawro, Meixner, Marion, Zakrzewicz, Anna, Liese, Juliane, Hecker, Andreas, Wilker, Sigrid, Stumpf, Sabine, Schlüter, Klaus-Dieter, Rohde, Marius, Gödecke, Axel, Padberg, Winfried, Manzini, Ivan, Schmalzing, Günther, and Grau, Veronika
- Subjects
MACROPHAGES ,NITRIC-oxide synthases ,MONONUCLEAR leukocytes ,NICOTINIC acetylcholine receptors ,INTERLEUKIN-1 receptor antagonist protein ,NITRIC oxide ,CHOLINERGIC mechanisms - Abstract
Objective: The pro-inflammatory cytokine interleukin-1b (IL-1b) plays a central role in host defense against infections. High systemic IL-1b levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1b release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1b release by human monocytes via nicotinic acetylcholine receptor (nAChR) subunits a7, a9 and/or a10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R). Methods: Different human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1b was measured in cell culture supernatants. Patch-clamp and intracellular Ca2+ imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain. Results: The inhibitory effect of nAChR agonists on the BzATP-induced IL-1b release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal via eNOS to inhibit the BzATP-induced IL-1b release. Moreover, NO donors (SNAP, S-nitroso-Nacetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1b release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, Xenopus laevis oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification. Conclusion: We provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1b release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. Attenuation of Acute Rat Renal Allograft Rejection by Apolipoprotein E-Mimetic Peptide
- Author
-
Zakrzewicz, Anna, Kutlimuratov, Khusin, Atanasova, Srebrena, Zakrzewicz, Dariusz, Reichert, Martin, Schmitz, Jessica, Wilhelm, Jochen, Lochnit, Günter, Padberg, Winfried, and Grau, Veronika
- Published
- 2015
- Full Text
- View/download PDF
37. The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells
- Author
-
Berkholz, Ahmed Shamloul, Gustav Steinemann, Kerrin Roos, Celine Huajia Liem, Jonathan Bernd, Thorsten Braun, Andreas Zakrzewicz, and Janine
- Subjects
Smyd1 ,lipopolysaccharide ,sepsis ,IL-6 ,NF-κB ,histone methylation ,endothelial cells - Abstract
The lysine methyltransferase Smyd1 with its characteristic catalytic SET-domain is highly enriched in the embryonic heart and skeletal muscles, participating in cardiomyogenesis, sarcomere assembly and chromatin remodeling. Recently, significant Smyd1 levels were discovered in endothelial cells (ECs) that responded to inflammatory cytokines. Based on these biochemical properties, we hypothesized that Smyd1 is involved in inflammation-triggered signaling in ECs and therefore, investigated its role within the LPS-induced signaling cascade. Human endothelial cells (HUVECs and EA.hy926 cells) responded to LPS stimulation with higher intrinsic Smyd1 expression. By transfection with expression vectors containing gene inserts encoding either intact Smyd1, a catalytically inactive Smyd1-mutant or Smyd1-specific siRNAs, we show that Smyd1 contributes to LPS-triggered expression and secretion of IL-6 in EA.hy926 cells. Further molecular analysis revealed this process to be based on two signaling pathways: Smyd1 increased the activity of NF-κB and promoted the trimethylation of lysine-4 of histone-3 (H3K4me3) within the IL-6 promoter, as shown by ChIP-RT-qPCR combined with IL-6-promoter-driven luciferase reporter gene assays. In summary, our experimental analysis revealed that LPS-binding to ECs leads to the up-regulation of Smyd1 expression to transduce the signal for IL-6 up-regulation via activation of the established NF-κB pathway as well as via epigenetic trimethylation of H3K4.
- Published
- 2021
- Full Text
- View/download PDF
38. The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells
- Author
-
Shamloul, Ahmed, Steinemann, Gustav, Roos, Kerrin, Liem, Celine Huajia, Bernd, Jonathan, Braun, Thorsten, Zakrzewicz, Andreas, and Berkholz, Janine
- Subjects
Lipopolysaccharides ,QH301-705.5 ,Muscle Proteins ,Article ,NF-κB ,Epigenesis, Genetic ,Smyd1 ,sepsis ,NF-��B ,Human Umbilical Vein Endothelial Cells ,Humans ,histone methylation ,RNA, Small Interfering ,Biology (General) ,Promoter Regions, Genetic ,Inflammation ,IL-6 ,Interleukin-6 ,lipopolysaccharide ,NF-kappa B ,Endothelial Cells ,Gene Expression Regulation, Developmental ,DNA Methylation ,DNA-Binding Proteins ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,Signal Transduction ,Transcription Factors - Abstract
The lysine methyltransferase Smyd1 with its characteristic catalytic SET-domain is highly enriched in the embryonic heart and skeletal muscles, participating in cardiomyogenesis, sarcomere assembly and chromatin remodeling. Recently, significant Smyd1 levels were discovered in endothelial cells (ECs) that responded to inflammatory cytokines. Based on these biochemical properties, we hypothesized that Smyd1 is involved in inflammation-triggered signaling in ECs and therefore, investigated its role within the LPS-induced signaling cascade. Human endothelial cells (HUVECs and EA.hy926 cells) responded to LPS stimulation with higher intrinsic Smyd1 expression. By transfection with expression vectors containing gene inserts encoding either intact Smyd1, a catalytically inactive Smyd1-mutant or Smyd1-specific siRNAs, we show that Smyd1 contributes to LPS-triggered expression and secretion of IL-6 in EA.hy926 cells. Further molecular analysis revealed this process to be based on two signaling pathways: Smyd1 increased the activity of NF-kappa B and promoted the trimethylation of lysine-4 of histone-3 (H3K4me3) within the IL-6 promoter, as shown by ChIP-RT-qPCR combined with IL-6-promoter-driven luciferase reporter gene assays. In summary, our experimental analysis revealed that LPS-binding to ECs leads to the up-regulation of Smyd1 expression to transduce the signal for IL-6 up-regulation via activation of the established NF-��B pathway as well as via epigenetic trimethylation of H3K4.
- Published
- 2021
39. β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells
- Author
-
Sebastian Daniel Hiller, Sarah Heldmann, Katrin Richter, Innokentij Jurastow, Mira Küllmar, Andreas Hecker, Sigrid Wilker, Gabriele Fuchs-Moll, Ivan Manzini, Günther Schmalzing, Wolfgang Kummer, Winfried Padberg, J. Michael McIntosh, Jelena Damm, Anna Zakrzewicz, and Veronika Grau
- Subjects
β-NAD ,β-nicotinamide adenine dinucleotide ,CHRNA7 ,CHRNA9 ,CHRNA10 ,inflammasome ,interleukin-1β ,iPLA2β ,monocyte ,P2RY1 ,P2RY11 ,PLA2G6 ,U937 cells ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
While interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine essential for host defense, high systemic levels cause life-threatening inflammatory syndromes. ATP, a stimulus of IL-1β maturation, is released from damaged cells along with β-nicotinamide adenine dinucleotide (β-NAD). Here, we tested the hypothesis that β-NAD controls ATP-signaling and, hence, IL-1β release. Lipopolysaccharide-primed monocytic U937 cells and primary human mononuclear leukocytes were stimulated with 2′(3′)-O-(4-benzoyl-benzoyl)ATP trieethylammonium salt (BzATP), a P2X7 receptor agonist, in the presence or absence of β-NAD. IL-1β was measured in cell culture supernatants. The roles of P2Y receptors, nicotinic acetylcholine receptors (nAChRs), and Ca2+-independent phospholipase A2 (iPLA2β, PLA2G6) were investigated using specific inhibitors and gene-silencing. Exogenous β-NAD signaled via P2Y receptors and dose-dependently (IC50 = 15 µM) suppressed the BzATP-induced IL-1β release. Signaling involved iPLA2β, release of a soluble mediator, and nAChR subunit α9. Patch-clamp experiments revealed that β-NAD inhibited BzATP-induced ion currents. In conclusion, we describe a novel triple membrane-passing signaling cascade triggered by extracellular β-NAD that suppresses ATP-induced release of IL-1β by monocytic cells. This cascade links activation of P2Y receptors to non-canonical metabotropic functions of nAChRs that inhibit P2X7 receptor function. The biomedical relevance of this mechanism might be the control of trauma-associated systemic inflammation.
- Published
- 2018
- Full Text
- View/download PDF
40. Reduced expression of arrestin beta 2 by graft monocytes during acute rejection of rat kidneys
- Author
-
Zakrzewicz, Anna, Krasteva, Gabriela, Wilhelm, Jochen, Dietrich, Hartmut, Wilker, Sigrid, Padberg, Winfried, Wygrecka, Malgorzata, and Grau, Veronika
- Published
- 2011
- Full Text
- View/download PDF
41. Leukocyte accumulation in graft blood vessels during self-limiting acute rejection of rat kidneys
- Author
-
Zakrzewicz, Anna, Wilhelm, Jochen, Blöcher, Sonja, Wilczynska, Joanna, Wilker, Sigrid, Dietrich, Hartmut, Weimer, Rolf, Padberg, Winfried, and Grau, Veronika
- Published
- 2011
- Full Text
- View/download PDF
42. Algorithms for spatial collocation pattern mining in a limited memory environment: a summary of results
- Author
-
Boinski, Pawel and Zakrzewicz, Maciej
- Published
- 2014
- Full Text
- View/download PDF
43. Tracking of fluorescence nanoparticles with nanometre resolution in a biological system: assessing local viscosity and microrheology
- Author
-
Marki, Alex, Ermilov, Eugeny, Zakrzewicz, Andreas, Koller, Akos, Secomb, Timothy W., and Pries, Axel R.
- Published
- 2014
- Full Text
- View/download PDF
44. Monocytic Tissue Transglutaminase in a Rat Model for Reversible Acute Rejection and Chronic Renal Allograft Injury
- Author
-
Anna Zakrzewicz, Srebrena Atanasova, Winfried Padberg, and Veronika Grau
- Subjects
Pathology ,RB1-214 - Abstract
Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer-344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase-3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase-3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self-limiting acute rejection.
- Published
- 2015
- Full Text
- View/download PDF
45. Quantitative assessment of arginine methylation in free versus protein-incorporated amino acids in vitro and in vivo using protein hydrolysis and high-performance liquid chromatography
- Author
-
Patrick Bulau, Dariusz Zakrzewicz, Kamila Kitowska, Birgit Wardega, Joachim Kreuder, and Oliver Eickelberg
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Arginine methylation constitutes a posttranslational modification dependent on the action of protein arginine methyltransferases (PRMTs). Using S-adenosylmethionine as a methyl donor, PRMTs catalyze the formation of monomethylarginine (L-NMMA), asymmetric dimethylarginine (ADMA), or symmetric dimethyl arginine (SDMA). Protein arginine methylation is involved in the regulation of signal transduction, RNA export, and cell proliferation, but a quantitative view of arginine methylation of the cell and tissue proteome remains to be performed. In this study, we developed a high-performance liquid chromatography (HPLC)-based method to accurately quantify methylated arginines in free and protein-incorporated amino acid pools of cell and tissue extracts, using protein precipitation and hydrolysis, HPLC separation, and fluorescence detection for the simultaneous quantification of L-arginine (L-Arg), L-NMMA, ADMA, and SDMA. This method permits accurate assessment of the degree of protein arginine methylation in complex biological samples. Using this method, we determined dynamic changes in protein methylation in vitro in cells subjected to proteasome inhibition. We furthermore demonstrate differential methylation patterns in heart and kidney lysates in vivo. Thus, the described method will greatly facilitate our understanding of the role of arginine methylation in physiology and pathophysiology and of the effects of pharmacological interventions on arginine methylation in select cell culture models.
- Published
- 2006
- Full Text
- View/download PDF
46. Transforming Growth Factor-β1 Induces Expression of Human Coagulation Factor XII via Smad3 and JNK Signaling Pathways in Human Lung Fibroblasts
- Author
-
Jablonska, Ewa, Markart, Philipp, Zakrzewicz, Dariusz, Preissner, Klaus T., and Wygrecka, Malgorzata
- Published
- 2010
- Full Text
- View/download PDF
47. Adaptive and innate immune responses in a rat orthotopic lung transplant model of chronic lung allograft dysfunction
- Author
-
Evers, Alena, Atanasova, Srebrena, Fuchs-Moll, Gabriele, Petri, Kathrin, Wilker, Sigrid, Zakrzewicz, Anna, Hirschburger, Markus, Padberg, Winfried, and Grau, Veronika
- Published
- 2015
- Full Text
- View/download PDF
48. Gene Expression of Human Beta-defensins in Healthy and Inflamed Human Dental Pulps
- Author
-
Paris, Sebastian, Wolgin, Michael, Kielbassa, Andrej Michael, Pries, Axel, and Zakrzewicz, Andreas
- Published
- 2009
- Full Text
- View/download PDF
49. A Role for the Epidermal Growth Factor-like Domain of P-Selectin in Ligand Recognition and Cell Adhesion
- Author
-
Kansas, Geoffrey S., Saunders, Kim B., Ley, Klaus, Zakrzewicz, Andreas, Gibson, Rosemary M., Furie, Barbara C., Furie, Bruce, and Tedder, Thomas F.
- Published
- 1994
50. The quality of life of Polish immigrant children in the Norwegian educational system The shift from Polish to the Norwegian educational system
- Author
-
Zakrzewicz, Natasza Izabela
- Abstract
This master thesis paper aims to examine the quality of life of Polish immigrant children in the Norwegian educational system. The study is based on two theoretical frameworks that are essential in describing and exploring multicultural education in the Norwegian context: Inclusive education and The Ecology of Human Development. The study applies a qualitative research approach by using online questionnaire targeted at Polish immigrant children who experienced shift between the Polish and the Norwegian educational system and their parents. The questions in the surveys were grouped into four topics: context, language, relationships, and educational achievements. The objective was to examine how Polish children and their parents feel about education in Poland and in Norway, what challenges they encounter and how do they feel about the shift between two different educational systems. The findings concluded that the majority of the survey’s participants are content with the shift from the Polish to the Norwegian educational system. They overall evaluate both Norwegian system as well as the teachers in Norway positively. Moreover, most of them feels comfortable using the Norwegian language and their relationships in Norway are satisfactory. Nevertheless, some expected challenges were voiced by the children and their parents. Some of the participants stated to have challenges with Norwegian language use and consequently this caused issues in all other aspects of their life in Norway, including the school context. It can be concluded that the quality of life of Polish immigrant children is satisfactory. Still, there is a need to remember that the majority does not mean all, and some children with a Polish (or any other non-Norwegian background) have special educational needs in the Norwegian educational system.
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.