22 results on '"Praetner M"'
Search Results
2. Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue
- Author
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Lerchenberger, M, Uhl, B, Stark, K, Zuchtriegel, G, Eckart, A, Miller, M, Puhr-Westerheide, D, Praetner, M, Rehberg, M, Khandoga, A, Lauber, K, Massberg, S, Krombach, F, Reichel, CA, Lerchenberger, M, Uhl, B, Stark, K, Zuchtriegel, G, Eckart, A, Miller, M, Puhr-Westerheide, D, Praetner, M, Rehberg, M, Khandoga, A, Lauber, K, Massberg, S, Krombach, F, and Reichel, CA
- Published
- 2015
3. Plasminogen Activator Inhibitor-1 (PAI-1) reguliert Leukozytenakkumulation und mikrovaskuläre Dysfunktion im postischämischen Gewebe über low density lipoprotein receptor-related protein-1 (LRP-1)
- Author
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Reichel, C, Praetner, M, Uhl, B, Lerchenberger, M, and Krombach, F
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Einleitung: Ischämie-Reperfusion (I/R) wird als Hauptursache für Gewebedysfunktion nach Transplantation angesehen. Der Verlust der mikrovaskulären Integrität und die Akkumulation von Leukozyten im reperfundierten Gewebe sind maßgeblich an der Pathogenese des I/R-Schadens[for full text, please go to the a.m. URL], 83. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie
- Published
- 2012
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4. EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction
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Mielenz, D, Reichel, M, Jia, T, Quinlan, E B, Stöckl, T, Mettang, M, Zilske, D, Kirmizi-Alsan, E, Schönberger, P, Praetner, M, Huber, S E, Amato, D, Schwarz, M, Purohit, P, Brachs, S, Spranger, J, Hess, A, Büttner, C, Ekici, A B, Perez-Branguli, F, Winner, B, Rauschenberger, V, Banaschewski, T, Bokde, A L W, Büchel, C, Conrod, P J, Desrivières, S, Flor, H, Frouin, V, Gallinat, J, Garavan, H, Gowland, P, Heinz, A, Martinot, J-L, Lemaitre, H, Nees, F, Paus, T, Smolka, M N, Schambony, A, Bäuerle, T, Eulenburg, V, Alzheimer, C, Lourdusamy, A, Schumann, G, and Müller, C P
- Abstract
In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with β-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.
- Published
- 2018
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5. Quantum Dots Modulate Leukocyte Adhesion and Transmigration Depending on Their Surface Modification
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Rehberg, M., primary, Praetner, M., additional, Leite, C. F., additional, Reichel, C. A., additional, Bihari, P., additional, Mildner, K., additional, Duhr, S., additional, Zeuschner, D., additional, and Krombach, F., additional
- Published
- 2010
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6. Optimized dispersion of nanoparticles for biological in vitro and in vivo studies
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Coester Conrad, Reichel Christoph A, Khandoga Alexander G, Praetner Marc, Schultes Stephan, Vippola Minnamari, Bihari Peter, Tuomi Timo, Rehberg Markus, and Krombach Fritz
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Toxicology. Poisons ,RA1190-1270 ,Industrial hygiene. Industrial welfare ,HD7260-7780.8 - Abstract
Abstract Background The aim of this study was to establish and validate a practical method to disperse nanoparticles in physiological solutions for biological in vitro and in vivo studies. Results TiO2 (rutile) dispersions were prepared in distilled water, PBS, or RPMI 1640 cell culture medium. Different ultrasound energies, various dispersion stabilizers (human, bovine, and mouse serum albumin, Tween 80, and mouse serum), various concentrations of stabilizers, and different sequences of preparation steps were applied. The size distribution of dispersed nanoparticles was analyzed by dynamic light scattering and zeta potential was measured using phase analysis light scattering. Nanoparticle size was also verified by transmission electron microscopy. A specific ultrasound energy of 4.2 × 105 kJ/m3 was sufficient to disaggregate TiO2 (rutile) nanoparticles, whereas higher energy input did not further improve size reduction. The optimal sequence was first to sonicate the nanoparticles in water, then to add dispersion stabilizers, and finally to add buffered salt solution to the dispersion. The formation of coarse TiO2 (rutile) agglomerates in PBS or RPMI was prevented by addition of 1.5 mg/ml of human, bovine or mouse serum albumin, or mouse serum. The required concentration of albumin to stabilize the nanoparticle dispersion depended on the concentration of the nanoparticles in the dispersion. TiO2 (rutile) particle dispersions at a concentration lower than 0.2 mg/ml could be stabilized by the addition of 1.5 mg/ml albumin. TiO2 (rutile) particle dispersions prepared by this method were stable for up to at least 1 week. This method was suitable for preparing dispersions without coarse agglomerates (average diameter < 290 nm) from nanosized TiO2 (rutile), ZnO, Ag, SiOx, SWNT, MWNT, and diesel SRM2975 particulate matter. Conclusion The optimized dispersion method presented here appears to be effective and practicable for preparing dispersions of nanoparticles in physiological solutions without creating coarse agglomerates.
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- 2008
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7. Platelets mediate acute hepatic microcirculatory injury in a protease-activated-receptor-4-dependent manner after extended liver resection.
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Zhang Y, Huber P, Praetner M, Zöllner A, Holdt L, Khandoga A, and Lerchenberger M
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- Mice, Animals, Hepatectomy, Microcirculation, Mice, Inbred C57BL, Liver, Peptide Hydrolases, Intercellular Adhesion Molecule-1, Reperfusion Injury
- Abstract
Background: Small-for-size syndrome (SFSS) is a major complication following extended liver resection. The role of platelets in the early development of SFSS remains to be cleared. We aimed to investigate the impact of platelets and PAR-4, a receptor for platelet activation, on the acute phase microcirculatory injury after liver resection by in vivo microscopy analyzing the changes in leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis-induced perfusion failure., Methods: Sixty-percent partial hepatectomy (PH) models using C57BL/6 mice receiving platelet depletion with anti-GPIbα, PAR-4 blockade with tcY-NH2, or vehicle treatment with saline were used. Sham-operated animals served as controls. Epifluorescence microscopic analysis was performed 2 h after PH to quantify the leukocyte recruitment and microcirculatory changes. Sinusoidal neutrophil recruitment, platelet-neutrophil interaction, and microthrombosis were evaluated using two-photon microscopy. ICAM-1 expression and liver liver injury were assessed in tissue/blood samples., Results: The increments of leukocyte recruitment in post-sinusoidal venules and sinusoidal perfusion failure, the upregulation of ICAM-1 expression, and the deterioration of liver function 2 h after 60% PH were alleviated in the absence of platelets or by PAR-4 blockade. Intensified platelet-neutrophil interaction and microthrombosis in sinusoids were observed 2 h after 60% PH, which significantly attenuated after PAR-4 blockade., Conclusion: Platelets play a critical role in acute liver injury after extended liver resection within 2 h. The deactivation of platelets via PAR-4 blockade ameliorated liver function deterioration by suppressing early leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis in hepatic sinusoids., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest. Animal experiments were performed according to the German legislation on the protection of animals (Protocol Nr.: 02–17-132)., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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8. Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males.
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Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, Eulenburg V, Granzow J, Hofer M, Hohenschild J, Huber SE, Kämpf S, Kogias G, Lacatusu L, Lugmair C, Taku SM, Meixner D, Sembritzki NK, Praetner M, Rhein C, Sauer C, Scholz J, Ulrich F, Valenta F, Weigand E, Werner M, Tay N, Mc Veigh CJ, Haase J, Wang AL, Abdel-Hafiz L, Huston JP, Smaga I, Frankowska M, Filip M, Lourdusamy A, Kirchner P, Ekici AB, Marx LM, Suresh NP, Frischknecht R, Fejtova A, Saied EM, Arenz C, Bozec A, Wank I, Kreitz S, Hess A, Bäuerle T, Ledesma MD, Mitroi DN, Miranda AM, Oliveira TG, Lenz B, Schumann G, Kornhuber J, and Müller CP
- Subjects
- Male, Mice, Animals, Female, Alcohol Drinking, Anxiety metabolism, Brain metabolism, Ethanol, Sphingomyelin Phosphodiesterase genetics, Sphingomyelin Phosphodiesterase metabolism, Emotions
- Abstract
Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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9. Serine proteases mediate leukocyte recruitment and hepatic microvascular injury in the acute phase following extended hepatectomy.
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Zhang Y, Huber P, Praetner M, Zöllner A, Holdt L, Khandoga A, and Lerchenberger M
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- Mice, Animals, Serine Proteases metabolism, Fibrinolysin metabolism, Mice, Inbred C57BL, Liver metabolism, Leukocytes, Microcirculation, Hepatectomy, Intercellular Adhesion Molecule-1 metabolism
- Abstract
Objective: Post-hepatectomy liver failure (PHLF) is the main limitation of extended liver resection. The molecular mechanism and the role of leukocytes in the development of PHLF remain to be unveiled. We aimed to address the impact of serine proteases (SPs) on the acute phase after liver resection by intravitally analyzing leukocyte recruitment and changes in hemodynamics and microcirculation of the liver., Methods: C57BL/6 mice undergoing 60% partial hepatectomy were treated with aprotinin (broad-spectrum SP inhibitor), tranexamic acid (plasmin inhibitor), or vehicle. Sham-operated animals served as controls. In vivo fluorescence microscopy was used to quantify leukocyte-endothelial interactions immediately after, as well as 120 min after partial hepatectomy in postsinusoidal venules, along with measurement of sinusoidal perfusion rate and postsinusoidal shear rate. Recruitment of leukocytes, neutrophils, T cells, and parameters of liver injury were assessed in tissue/blood samples., Results: Leukocyte recruitment, sinusoidal perfusion failure rate, and shear rate were significantly increased in mice after 60% partial hepatectomy compared to sham-operated animals. The inhibition of SPs or plasmin significantly attenuated leukocyte recruitment and improved the perfusion rate in the remnant liver. ICAM-1 expression and neutrophil recruitment significantly increased after 60% partial hepatectomy and were strongly reduced by plasmin inhibition., Conclusions: Endothelial activation and leukocyte recruitment in the liver in response to the increment of sinusoidal shear rate were hallmarks in the acute phase after liver resection. SPs mediated leukocyte recruitment and contributed to the impairment of sinusoidal perfusion in an ICAM-1-dependent manner in the acute phase after liver resection., (© 2022 The Authors. Microcirculation published by John Wiley & Sons Ltd.)
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- 2023
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10. Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.
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Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, Eulenburg V, Granzow J, Hofer M, Hohenschild J, Huber SE, Kämpf S, Kogias G, Lacatusu L, Lugmair C, Taku SM, Meixner D, Tesch N, Praetner M, Rhein C, Sauer C, Scholz J, Ulrich F, Valenta F, Weigand E, Werner M, Tay N, Mc Veigh CJ, Haase J, Wang AL, Abdel-Hafiz L, Huston JP, Smaga I, Frankowska M, Filip M, Lourdusamy A, Kirchner P, Ekici AB, Marx LM, Suresh NP, Frischknecht R, Fejtova A, Saied EM, Arenz C, Bozec A, Wank I, Kreitz S, Hess A, Bäuerle T, Ledesma MD, Mitroi DN, Miranda AM, Oliveira TG, Gulbins E, Lenz B, Schumann G, Kornhuber J, and Müller CP
- Subjects
- Animals, Comorbidity, Humans, Mice, Morbidity, Alcoholism genetics, Bone Diseases genetics, Depressive Disorder, Major genetics, Sphingomyelin Phosphodiesterase genetics
- Abstract
Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias., (© 2021. The Author(s).)
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- 2021
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11. Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson's Disease Receiving Additional Antidepressant Treatment with Moclobemide.
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Praetner M, Schiele T, Werle L, Kuffer J, Nischwitz S, Keck ME, and Kloiber S
- Abstract
Background: The pharmacological treatment options of Parkinson's disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation . In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient's psychovegetative symptoms subsided., Conclusions: The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression., Competing Interests: The authors report no competing interests/conflicts of interest., (Copyright © 2021 Marc Praetner et al.)
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- 2021
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12. Enhanced Alcohol Preference and Anxiolytic Alcohol Effects in Niemann-Pick Disease Model in Mice.
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Kalinichenko LS, Mühle C, Eulenburg V, Praetner M, Reichel M, Gulbins E, Kornhuber J, and Müller CP
- Abstract
Major depression and alcohol use disorder are severe psychiatric diseases affecting the world's population with high comorbidity level. However, the pathogenesis of this comorbidity remains unclear, and no selective treatment for this condition is available. A pathogenic pathway and a possible therapeutic target for the treatment of depression-alcoholism comorbidity based on the hyperfunction of acid sphingomyelinase (Asm) were recently suggested. Here we analyzed the effects of alcohol on the depression/anxiety state of homozygous Asm-knockout mice (Asm - /-), which can be considered as a model of an early stage of Niemann-Pick disease, as well as their drinking pattern under normal and stress conditions. It was observed that forced treatment with alcohol (2 g/kg, i.p.) reduces the anxiety level of Asm-/- mice as measured in the elevated plus maze (EPM) test, but enhances the depression level in the forced swim test (FST). The analysis of drinking pattern of these animals in a free-choice alcohol drinking paradigm revealed higher alcohol intake and preference in Asm-/- mice compared to wild type (wt) littermates. However, this difference was overwritten by the stress exposure. Stronger sedating effects of alcohol were observed in Asm-/- mice compared to wt animals in the loss of righting reflex test after single and repeated alcohol injections (3 g/kg, i.p.). Altogether, the present findings might indicate an Asm involvement in the mechanisms of comorbidity between alcoholism and anxiety/depression.
- Published
- 2019
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13. Delayed hemolysis, elevated liver enzymes, low platelet count syndrome in succession of switches of preventive anticoagulant treatment in a 41-year-old patient with a history of recurrent assisted implantation failures: a case report.
- Author
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Mikolaiczik K, Praetner M, Rüth M, and Mark K
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- Adult, Female, Humans, Infant, Low Birth Weight, Infant, Newborn, Pregnancy, Premature Birth, Treatment Outcome, Anticoagulants therapeutic use, Aspirin therapeutic use, Cesarean Section, HELLP Syndrome drug therapy, HELLP Syndrome physiopathology, HELLP Syndrome prevention & control, Heparin, Low-Molecular-Weight therapeutic use, Sperm Injections, Intracytoplasmic
- Abstract
Background: For the past decades the mean age of primiparae in Western societies is constantly increasing. At the same time, there is a growing demand for assisted reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection. Subsequently, a higher prevalence of pregnancy-associated diseases such as gestational hypertension and preeclampsia is observed. To improve pregnancy rates after in vitro fertilization/intracytoplasmic sperm injection and to reduce the risk of pregnancy-associated diseases with a cardiovascular pathophysiology, two anticoagulants are the focus of current research: low molecular weight heparin and acetylsalicylic acid (aspirin)., Case Presentation: A 41-year-old white woman, gravida 3, para 0, received low molecular weight heparin to reduce the risk of abortion after five unsuccessful intracytoplasmic sperm injections and two miscarriages. She autonomously discontinued the medication with low molecular weight heparin at 12 weeks and 2 days of gestation and took aspirin instead until 24 weeks and 2 days of gestation as preeclampsia prophylaxis. However, the pregnancy ended with an urgent cesarean section at 27 weeks and 4 days of gestation due to a fast progressing hemolysis, elevated liver enzyme levels, and low blood platelet count syndrome, a potentially life-threatening variant of preeclampsia., Conclusion: Based on the current demographic trend toward late-in-life pregnancy it is mandatory to establish clear guidelines concerning preventive treatment options of preeclampsia for patients with risk factors. The establishment of a special first-trimester screening for these women should be discussed. Moreover, it is necessary to raise the awareness among physicians of these contemporary issues to guarantee the best possible medical care.
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- 2019
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14. Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia-Reperfusion.
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Praetner M, Zuchtriegel G, Holzer M, Uhl B, Schaubächer J, Mittmann L, Fabritius M, Fürst R, Zahler S, Funken D, Lerchenberger M, Khandoga A, Kanse S, Lauber K, Krombach F, and Reichel CA
- Subjects
- Abdominal Muscles metabolism, Abdominal Muscles pathology, Animals, CD18 Antigens metabolism, Capillary Permeability, Cell Line, Disease Models, Animal, Humans, Kinetics, Leukocyte Rolling, Liver metabolism, Liver pathology, Low Density Lipoprotein Receptor-Related Protein-1, Male, Mice, Inbred C57BL, Mice, Knockout, Microvessels pathology, Neutrophil Activation, Neutrophils transplantation, Plasminogen Activator Inhibitor 1 deficiency, Plasminogen Activator Inhibitor 1 genetics, Protein Conformation, Receptors, LDL metabolism, Reperfusion Injury pathology, Signal Transduction, Tumor Suppressor Proteins metabolism, Abdominal Muscles blood supply, Liver blood supply, Microvessels metabolism, Neutrophil Infiltration, Neutrophils metabolism, Plasminogen Activator Inhibitor 1 metabolism, Reperfusion Injury metabolism
- Abstract
Objective: Ischemia-reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure., Approach and Results: Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of β2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor-related protein-1 and mitogen-activated protein kinase-dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis., Conclusions: Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury., (© 2018 American Heart Association, Inc.)
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- 2018
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15. Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis.
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Müller CP, Kalinichenko LS, Tiesel J, Witt M, Stöckl T, Sprenger E, Fuchser J, Beckmann J, Praetner M, Huber SE, Amato D, Mühle C, Büttner C, Ekici AB, Smaga I, Pomierny-Chamiolo L, Pomierny B, Filip M, Eulenburg V, Gulbins E, Lourdusamy A, Reichel M, and Kornhuber J
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- Animals, Choice Behavior drug effects, Conditioning, Operant drug effects, Depression genetics, Ethanol blood, Food Preferences drug effects, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Reflex, Righting drug effects, Reflex, Righting genetics, Signal Transduction drug effects, Signal Transduction genetics, Sphingomyelin Phosphodiesterase genetics, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Antidepressive Agents therapeutic use, Depression drug therapy, Ethanol therapeutic use, Homeostasis genetics, Sphingolipids metabolism, Sphingomyelin Phosphodiesterase metabolism
- Abstract
Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking-but not forced alcohol exposure-reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism.
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- 2017
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16. Intercellular Transport of Nanomaterials is Mediated by Membrane Nanotubes In Vivo.
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Rehberg M, Nekolla K, Sellner S, Praetner M, Mildner K, Zeuschner D, and Krombach F
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- Animals, Biological Transport, Green Fluorescent Proteins metabolism, Macrophages metabolism, Mice, Microscopy, Confocal, Microscopy, Fluorescence, Nanotubes
- Abstract
So-called membrane nanotubes are cellular protrusions between cells whose functions include cell communication, environmental sampling, and protein transfer. It has been previously reported that systemically administered carboxyl-modified quantum dots (cQDs) are rapidly taken up by perivascular macrophages in skeletal muscle of healthy mice. Expanding these studies, it is found, by means of in vivo fluorescence microscopy on the mouse cremaster muscle, rapid uptake of cQDs not only by perivascular macrophages but also by tissue-resident cells, which are localized more than 100 μm distant from the closest vessel. Confocal microscopy on muscle tissue, immunostained for the membrane dye DiI, reveals the presence of continuous membranous structures between MHC-II-positive, F4/80-positive cells. These structures contain microtubules, components of the cytoskeleton, which clearly colocalize with cQDs. The cQDs are exclusively found inside endosomal vesicles. Most importantly, by using in vivo fluorescence microscopy, this study detected fast (0.8 μm s(-1) , mean velocity), bidirectional movement of cQDs in such structures, indicating transport of cQD-containing vesicles along microtubule tracks by the action of molecular motors. The findings are the first to demonstrate membrane nanotube function in vivo and they suggest a previously unknown route for the distribution of nanomaterials in tissue., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
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- 2016
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17. Carbon-based nanomaterials accelerate arteriolar thrombus formation in the murine microcirculation independently of their shape.
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Holzer M, Bihari P, Praetner M, Uhl B, Reichel C, Fent J, Vippola M, Lakatos S, and Krombach F
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- Animals, Arterioles drug effects, Arterioles pathology, Blood Platelets drug effects, Blood Platelets metabolism, Endothelial Cells cytology, Endothelial Cells drug effects, Humans, Leukocytes cytology, Leukocytes drug effects, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Scanning, P-Selectin genetics, P-Selectin metabolism, Thrombosis chemically induced, Microcirculation drug effects, Nanotubes, Carbon toxicity, Soot toxicity
- Abstract
Although carbon-based nanomaterials (CBNs) have been shown to exert prothrombotic effects in microvessels, it is poorly understood whether CBNs also have the potential to interfere with the process of leukocyte-endothelial cell interactions and whether the shape of CBNs plays a role in these processes. Thus, the aim of this study was to compare the acute effects of two differently shaped CBNs, fiber-shaped single-walled carbon nanotubes (SWCNT) and spherical ultrafine carbon black (CB), on thrombus formation as well as on leukocyte-endothelial cell interactions and leukocyte transmigration in the murine microcirculation upon systemic administration in vivo. Systemic administration of both SWCNT and CB accelerated arteriolar thrombus formation at a dose of 1 mg kg(-1) body weight, whereas SWCNT exerted a prothrombotic effect also at a lower dose (0.1 mg kg(-1) body weight). In vitro, both CBNs induced P-selectin expression on human platelets and formation of platelet-granulocyte complexes. In contrast, injection of fiber-shaped SWCNT or of spherical CB did not induce leukocyte-endothelial cell interactions or leukocyte transmigration. In vitro, both CBNs slightly increased the expression of activation markers on human monocytes and granulocytes. These findings suggest that systemic administration of CBNs accelerates arteriolar thrombus formation independently of the CBNs' shape, but does not induce leukocyte-endothelial cell interactions or leukocyte transmigration., (Copyright © 2014 John Wiley & Sons, Ltd.)
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- 2014
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18. Tissue plasminogen activator promotes postischemic neutrophil recruitment via its proteolytic and nonproteolytic properties.
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Uhl B, Zuchtriegel G, Puhr-Westerheide D, Praetner M, Rehberg M, Fabritius M, Hessenauer M, Holzer M, Khandoga A, Fürst R, Zahler S, Krombach F, and Reichel CA
- Subjects
- Animals, Capillary Permeability, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelial Cells metabolism, Fibrinogen metabolism, Fibrinolysin metabolism, Gelatinases metabolism, Hemodynamics, Humans, Male, Mast Cells metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcirculation, Microvessels metabolism, Microvessels physiopathology, Mutation, Neutrophils drug effects, Neutrophils immunology, Recombinant Proteins administration & dosage, Reperfusion Injury genetics, Reperfusion Injury immunology, Reperfusion Injury physiopathology, Time Factors, Tissue Plasminogen Activator administration & dosage, Tissue Plasminogen Activator deficiency, Tissue Plasminogen Activator genetics, Transendothelial and Transepithelial Migration, Chemotaxis, Leukocyte drug effects, Muscles blood supply, Neutrophil Infiltration drug effects, Neutrophils enzymology, Reperfusion Injury enzymology, Tissue Plasminogen Activator metabolism
- Abstract
Objective: Neutrophil infiltration of the postischemic tissue considerably contributes to organ dysfunction on ischemia/reperfusion injury. Beyond its established role in fibrinolysis, tissue-type plasminogen activator (tPA) has recently been implicated in nonfibrinolytic processes. The role of this serine protease in the recruitment process of neutrophils remains largely obscure., Approach and Results: Using in vivo microscopy on the postischemic cremaster muscle, neutrophil recruitment and microvascular leakage, but not fibrinogen deposition at the vessel wall, were significantly diminished in tPA(-/-) mice. Using cell transfer techniques, leukocyte and nonleukocyte tPA were found to mediate ischemia/reperfusion-elicited neutrophil responses. Intrascrotal but not intra-arterial application of recombinant tPA induced a dose-dependent increase in the recruitment of neutrophils, which was significantly higher compared with stimulation with a tPA mutant lacking catalytic activity. Whereas tPA-dependent transmigration of neutrophils was selectively reduced on the inhibition of plasmin or gelatinases, neutrophil intravascular adherence was significantly diminished on the blockade of mast cell activation or lipid mediator synthesis. Moreover, stimulation with tPA caused a significant elevation in the leakage of fluorescein isothiocyanate dextran to the perivascular tissue, which was completely abolished on neutrophil depletion. In vitro, tPA-elicited macromolecular leakage of endothelial cell layers was abrogated on the inhibition of its proteolytic activity., Conclusions: Endogenously released tPA promotes neutrophil transmigration to reperfused tissue via proteolytic activation of plasmin and gelatinases. As a consequence, tPA on transmigrating neutrophils disrupts endothelial junctions allowing circulating tPA to extravasate to the perivascular tissue, which, in turn, amplifies neutrophil recruitment through the activation of mast cells and release of lipid mediators., (© 2014 American Heart Association, Inc.)
- Published
- 2014
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19. Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue.
- Author
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Lerchenberger M, Uhl B, Stark K, Zuchtriegel G, Eckart A, Miller M, Puhr-Westerheide D, Praetner M, Rehberg M, Khandoga AG, Lauber K, Massberg S, Krombach F, and Reichel CA
- Subjects
- Aminocaproates pharmacology, Animals, Aprotinin pharmacology, Chemotaxis, Leukocyte drug effects, Immune System Diseases metabolism, Immune System Diseases pathology, Inflammation metabolism, Leukocyte Disorders metabolism, Leukocyte Disorders pathology, Male, Matrix Metalloproteinases metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neutrophil Infiltration drug effects, Neutrophil Infiltration immunology, Peritonitis immunology, Peritonitis pathology, Tranexamic Acid pharmacology, Transcellular Cell Migration drug effects, Transcellular Cell Migration immunology, Chemotaxis, Leukocyte physiology, Inflammation immunology, Matrix Metalloproteinases physiology, Neutrophil Infiltration physiology
- Abstract
In vitro studies suggest that leukocytes locomote in an ameboid fashion independently of pericellular proteolysis. Whether this motility pattern applies for leukocyte migration in inflamed tissue is still unknown. In vivo microscopy on the inflamed mouse cremaster muscle revealed that blockade of serine proteases or of matrix metalloproteinases (MMPs) significantly reduces intravascular accumulation and transmigration of neutrophils. Using a novel in vivo chemotaxis assay, perivenular microinjection of inflammatory mediators induced directional interstitial migration of neutrophils. Blockade of actin polymerization, but not of actomyosin contraction abolished neutrophil interstitial locomotion. Multiphoton laser scanning in vivo microscopy showed that the density of the interstitial collagen network increases in inflamed tissue, thereby providing physical guidance to infiltrating neutrophils. Although neutrophils locomote through the interstitium without pericellular collagen degradation, inhibition of MMPs, but not of serine proteases, diminished their polarization and interstitial locomotion. In this context, blockade of MMPs was found to modulate expression of adhesion/signaling molecules on neutrophils. Collectively, our data indicate that serine proteases are critical for neutrophil extravasation, whereas these enzymes are dispensable for neutrophil extravascular locomotion. By contrast, neutrophil interstitial migration strictly relies on actin polymerization and does not require the pericellular degradation of collagen fibers but is modulated by MMPs.
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- 2013
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20. The contribution of the capillary endothelium to blood clearance and tissue deposition of anionic quantum dots in vivo.
- Author
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Praetner M, Rehberg M, Bihari P, Lerchenberger M, Uhl B, Holzer M, Eichhorn ME, Fürst R, Perisic T, Reichel CA, Welsch U, and Krombach F
- Subjects
- Animals, Anions, Endothelial Cells cytology, Endothelial Cells metabolism, Endothelial Cells ultrastructure, Hemodynamics, Injections, Intra-Arterial, Kinetics, Male, Mice, Mice, Inbred C57BL, Microscopy, Microvessels cytology, Microvessels metabolism, Muscle, Skeletal blood supply, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, Myocardium cytology, Myocardium metabolism, Myocardium ultrastructure, Photons, Tissue Distribution, Endothelium, Vascular metabolism, Quantum Dots
- Abstract
The increasing interest in biomedical applications of semiconductor quantum dots (QDs) is closely linked to the use of surface modifications to target specific sites of the body. The immense surface area of vascular endothelium is a possible interaction platform with systemically administered QDs. Therefore, the aim of this study was to investigate the microvascular distribution of neutral, cationic, and anionic QDs in vivo. QDs with carboxyl-, amine- and polyethylene glycol surface coatings were injected into the blood circulation of mice. In vivo microscopy of the cremaster muscle, two-photon microscopy of skeletal and heart muscle, as well as quantitative fluorescence measurements of blood, excreta, and tissue samples were performed. Transmission electron microscopy was used to detect QDs at the cellular level. The in vitro association of QDs with cultured endothelial cells was investigated by flow cytometry and confocal microscopy. Anionic QDs exhibited a very low residence time in the blood stream, preferably accumulated in organs with a prominent mononuclear phagocytic component, but were also found in other tissues with low phagocytic properties where they were predominantly associated with capillary endothelium. This deposition behavior was identified as a new, phagocyte-independent principle contributing to the rapid clearance of anionic QDs from the circulation., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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21. Single-walled carbon nanotubes activate platelets and accelerate thrombus formation in the microcirculation.
- Author
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Bihari P, Holzer M, Praetner M, Fent J, Lerchenberger M, Reichel CA, Rehberg M, Lakatos S, and Krombach F
- Subjects
- Animals, Blood Cell Count, Blood Platelets metabolism, Granulocytes metabolism, Male, Mice, Mice, Inbred C57BL, P-Selectin metabolism, Titanium toxicity, Vehicle Emissions toxicity, Blood Platelets drug effects, Microcirculation drug effects, Nanotubes, Carbon toxicity, Platelet Activation drug effects, Thrombosis chemically induced
- Abstract
Objectives: Although ambient nanoparticles have been shown to exert prothrombotic effects, manufactured nanoparticles are in this aspect less well investigated. Thus, the aim of this study was to characterize the effects of diesel, titanium dioxide rutile, and single-walled carbon nanotube nanoparticles on (i) platelet activation in vitro and (ii) on macro- and microcirculatory thrombus formation in vivo., Methods: Platelet P-selectin expression was measured by flow cytometry after incubation of whole blood with diesel (0.1mg/mL), titanium dioxide (0.1mg/mL) or single-walled nanotubes (0.001-0.1mg/mL). Platelet-granulocyte complexes were analyzed in whole blood and platelet aggregometry was performed with platelet-rich plasma. Upon systemic administration of nanoparticles (1mg/kg) to anesthetized mice, ferric chloride-induced thrombus formation was measured in small mesenteric arteries using in vivo microscopy. In separate experiments, diesel (1mg/kg), titanium dioxide (1mg/kg), or single-walled nanotubes (0.01-1mg/kg) were injected into anesthetized mice and light/dye-induced thrombus formation was investigated in the cremasteric microcirculation., Results: Diesel and titanium dioxide nanoparticles did not activate platelets or exert prothrombotic effects. In contrast, single-walled nanotubes significantly increased platelet P-selectin expression, the number of platelet-granulocyte complexes, and platelet aggregability in vitro, and reduced the occlusion time in mesenteric arteries as well as in cremasteric arterioles., Conclusion: Our study shows that single-walled carbon nanotubes, but not diesel or titanium dioxide nanoparticles, induce platelet activation in vitro and exert prothrombotic effects in the microcirculation in vivo.
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- 2010
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22. Optimized dispersion of nanoparticles for biological in vitro and in vivo studies.
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Bihari P, Vippola M, Schultes S, Praetner M, Khandoga AG, Reichel CA, Coester C, Tuomi T, Rehberg M, and Krombach F
- Abstract
Background: The aim of this study was to establish and validate a practical method to disperse nanoparticles in physiological solutions for biological in vitro and in vivo studies., Results: TiO2 (rutile) dispersions were prepared in distilled water, PBS, or RPMI 1640 cell culture medium. Different ultrasound energies, various dispersion stabilizers (human, bovine, and mouse serum albumin, Tween 80, and mouse serum), various concentrations of stabilizers, and different sequences of preparation steps were applied. The size distribution of dispersed nanoparticles was analyzed by dynamic light scattering and zeta potential was measured using phase analysis light scattering. Nanoparticle size was also verified by transmission electron microscopy. A specific ultrasound energy of 4.2 x 105 kJ/m3 was sufficient to disaggregate TiO2 (rutile) nanoparticles, whereas higher energy input did not further improve size reduction. The optimal sequence was first to sonicate the nanoparticles in water, then to add dispersion stabilizers, and finally to add buffered salt solution to the dispersion. The formation of coarse TiO2 (rutile) agglomerates in PBS or RPMI was prevented by addition of 1.5 mg/ml of human, bovine or mouse serum albumin, or mouse serum. The required concentration of albumin to stabilize the nanoparticle dispersion depended on the concentration of the nanoparticles in the dispersion. TiO2 (rutile) particle dispersions at a concentration lower than 0.2 mg/ml could be stabilized by the addition of 1.5 mg/ml albumin. TiO2 (rutile) particle dispersions prepared by this method were stable for up to at least 1 week. This method was suitable for preparing dispersions without coarse agglomerates (average diameter < 290 nm) from nanosized TiO2 (rutile), ZnO, Ag, SiOx, SWNT, MWNT, and diesel SRM2975 particulate matter., Conclusion: The optimized dispersion method presented here appears to be effective and practicable for preparing dispersions of nanoparticles in physiological solutions without creating coarse agglomerates.
- Published
- 2008
- Full Text
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