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Search Results: 1 - 10 of 26260 matches for " Martin Zeitz "
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Innate and adaptive immunity in inflammatory bowel disease
Britta Siegmund,Martin Zeitz
World Journal of Gastroenterology , 2011, DOI: 10.3748/wjg.v17.i27.3178
Abstract: Inflammatory bowel diseases are the consequence of a dysregulated mucosal immune system. The mucosal immune system consists of two arms, innate and adaptive immunity, that have been studied separately for a long time. Functional studies from in vivo models of intestinal inflammation as well as results from genome-wide association studies strongly suggest a cross-regulation of both arms. The present review will illustrate this interaction by selecting examples from innate immunity and adaptive immunity, and their direct impact on each other. Broadening our view by focusing on the cross-regulated areas of the mucosal immune system will not only facilitate our understanding of disease, but furthermore will allow identification of future therapeutic targets.
Combined Pulse Electroporation – A Novel Strategy for Highly Efficient Transfection of Human and Mouse Cells
Thorsten Stroh,Ulrike Erben,Anja A. Kühl,Martin Zeitz,Britta Siegmund
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009488
Abstract: The type of a nucleic acid and the type of the cell to be transfected generally affect the efficiency of electroporation, the versatile method of choice for gene regulation studies or for recombinant protein expression. We here present a combined square pulse electroporation strategy to reproducibly and efficiently transfect eukaryotic cells. Cells suspended in a universal buffer system received an initial high voltage pulse that was continuously combined with a subsequent low voltage pulse with independently defined electric parameters of the effective field and the duration of each pulse. At comparable viable cell recoveries and transfection efficiencies of up to 95% of all cells, a wide variety of cells especially profited from this combined pulse strategy by high protein expression levels of individual cells after transfection. Long-term silencing of gene expression by transfected small interfering RNA was most likely due to the uptake of large nucleic acid amounts as shown by direct detection of fluorochromated small interfering RNA. The highly efficient combined pulse electroporation strategy enables for external regulation of the number of naked nucleic acid molecules taken up and can be easily adapted for cells considered difficult to transfect.
Feedback Mechanism for Microtubule Length Regulation by Stathmin Gradients
Maria Zeitz,Jan Kierfeld
Quantitative Biology , 2014, DOI: 10.1016/j.bpj.2014.10.056
Abstract: We formulate and analyze a theoretical model for the regulation of microtubule (MT) polymerization dynamics by the signaling proteins Rac1 and stathmin. In cells, the MT growth rate is inhibited by cytosolic stathmin, which, in turn, is inactivated by Rac1. Growing MTs activate Rac1 at the cell edge, which closes a positive feedback loop. We investigate both tubulin sequestering and catastrophe promotion as mechanisms for MT growth inhibition by stathmin. For a homogeneous stathmin concentration in the absence of Rac1, we find a switch-like regulation of the MT mean length by stathmin. For constitutively active Rac1 at the cell edge, stathmin is deactivated locally, which establishes a spatial gradient of active stathmin. In this gradient, we find a stationary bimodal MT length distributions for both mechanisms of MT growth inhibition by stathmin. One subpopulation of the bimodal length distribution can be identified with fast growing and long pioneering MTs in the region near the cell edge, which have been observed experimentally. The feedback loop is closed through Rac1 activation by MTs. For tubulin sequestering by stathmin, this establishes a bistable switch with two stable states: one stable state corresponds to upregulated MT mean length and bimodal MT length distributions, i.e., pioneering MTs; the other stable state corresponds to an interrupted feedback with short MTs. Stochastic effects as well as external perturbations can trigger switching events. For catastrophe promoting stathmin we do not find bistability.
Reversibility of Red blood Cell deformation
Maria Zeitz,Pierre Sens
Quantitative Biology , 2011, DOI: 10.1103/PhysRevE.85.051904
Abstract: The ability of cells to undergo reversible shape changes is often crucial to their survival. For Red Blood Cells (RBCs), irreversible alteration of the cell shape and flexibility often causes anemia. Here we show theoretically that RBCs may react irreversibly to mechanical perturbations because of tensile stress in their cytoskeleton. The transient polymerization of protein fibers inside the cell seen in sickle cell anemia or a transient external force can trigger the formation of a cytoskeleton-free membrane protrusion of micrometer dimensions. The complex relaxation kinetics of the cell shape is shown to be responsible for selecting the final state once the perturbation is removed, thereby controlling the reversibility of the deformation. In some case, tubular protrusion are expected to relax via a peculiar "pearling instability".
Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42
Martin Ruehl, Marion Muche, Christian Freise, Ulrike Erben, Ulf Neumann, Detlef Schuppan, Yury Popov, Walburga Dieterich, Martin Zeitz, Richard W Farndale, Rajan Somasundaram
Fibrogenesis & Tissue Repair , 2011, DOI: 10.1186/1755-1536-4-1
Abstract: In situ zymography and immunohistology showed association of enzymatically inactive prodomain-containing proMMP-2 and proMMP-9 but not of their activated forms to fibrillar collagen structures, which are not substrates of these gelatinases. In solid-phase binding studies with human collagens and collagen fragments, up to 45% of [125I]-labeled proMMP-2 and proMMP-9 but not of active (act)MMP-2 and actMMP-9 were retained by natural collagenous molecules and by synthetic analogs containing repeated Gly-Pro-Hyp triplets (GPO). Surface plasmon resonance yielded binding constants for the interaction of collagen type I (CI) with proMMP-2 and proMMP-9 in a nanomolar range. Values for actMMP-2 and actMMP-9 were 30-40 times higher. Tenfold molar excesses of (GPO)10 reduced the interaction of CI with pro- and actMMP-2 by 22- or 380-fold and resulted in prodomain release accompanied by high enzymatic activation and activity. Pointing to gelatine substrate displacement, higher (GPO)10 concentrations blocked the enzymatic activity. The MMP-2 prodomain-derived collagen-binding domain peptide (P33-42) binds to the collagen-binding domain of MMP-2, thereby preserving enzymatic inactivity. Synthetic P33-42 peptide competed with proMMP-2 binding to CI and prevented (GPO)10-mediated proMMP-2 activation. In contrast to (GPO)10, P33-42 did not activate proMMP-2, making triple helical and hydroxyproline-containing (GPO)10 unique in modulating gelatinase availability and activity.These findings suggest novel strategies using collagen analogs for the resolution of liver fibrosis via fibrotic matrix-sequestered gelatinases.Matrix metalloproteinases (MMPs) form a large family of zinc-dependent metalloendopeptidases that degrade extracellular matrix (ECM) molecules, including various collagens, gelatine, elastin, fibronectin and aggrecan [1]. The diversity of MMP-binding partners and of MMP substrates suggests a central role for MMPs in the "protease web" beyond their proteolytic activity. MMP
A hepatoprotective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines
Christian Freise, Martin Ruehl, Ulrike Erben, Ulf Neumann, Daniel Seehofer, Ki Kim, Wolfram Trowitzsch-Kienast, Thorsten Stroh, Martin Zeitz, Rajan Somasundaram
BMC Complementary and Alternative Medicine , 2011, DOI: 10.1186/1472-6882-11-39
Abstract: Four human HCC cell lines representing diverse stages of differentiation were treated with L.obtusiloba extract, standardized according to its known suppressive effects on proliferation and TGF-β-expression. Beside measurement of proliferation, invasion and apoptosis, effects on signal transduction and NF-κB-activity were determined.L.obtusiloba extract inhibited proliferation and induced apoptosis in all HCC cell lines and provoked a reduced basal and IGF-1-induced activation of the IGF-1R signaling cascade and a reduced transcriptional NF-κB-activity, particularly in the poorly differentiated SK-Hep1 cells. Pointing to anti-angiogenic effects, L.obtusiloba extract attenuated the basal and IGF-1-induced expression of hypoxia inducible factor-1α, vascular endothelial growth factor, peroxisome proliferator-activated receptor-γ, cyclooxygenase-2 and inducible nitric oxide synthase.The traditional application of the extract is confirmed by our experimental data. Due to its potential to inhibit critical receptor tyrosine kinases involved in HCC progression via the IGF-1 signaling pathway and NF-κB, the standardized L.obtusiloba extract should be further analysed for its active compounds and explored as (complementary) treatment option for HCC.Hepatocellular carcinoma (HCC) results from chronic liver disease and is the most common malignancy of the liver [1]. Chronic Hepatitis B or C leading to liver cirrhosis are major risk factors for the development of HCC [2]. Even in developing countries less than 40% of patients have a chance for cure when the tumor is diagnosed. In more advanced stages there are only reduced therapeutic options, since e.g. the use of more aggressive chemotherapeutic approaches is often limited by significant liver dysfunction/cirrhosis. Thus, the median survival in advanced HCC without therapy ranges from 4.2 to 7.9 months or even less [3,4]. Small molecules, targeting tumor angiogenesis, apoptosis or specific signal transduction pathways, have ga
Using Chemical Release Surveillance Data to Evaluate the Public Health Impacts of Chlorine and Its Alternatives  [PDF]
Perri Zeitz Ruckart, Ayana Anderson, Wanda Lizak Welles
Journal of Environmental Protection (JEP) , 2012, DOI: 10.4236/jep.2012.312177
Abstract: Background: More than 80 million Americans may be at risk of a chemical exposure because they live near one of the 101 most hazardous chemical facilities or near routes used to transport hazardous chemicals. One approach to hazard reduction is to use less toxic alternatives. Chlorine, one of the chemicals posing the greatest public health danger, has several alternatives depending on the application. Methods: We analyzed data collected during 1993-2008 by 17 state health departments participating in the Agency for Toxic Substances and Disease Registry’s (ATSDR) active chemical incident surveillance program. We conducted descriptive analyses to evaluate whether five chlorine alternatives (calcium hypochlorite, hydrogen peroxide, sodium chlorate, sodium hydrosulfite, and sodium hypochlorite) resulted in less severe incidents. We used chi square and z-score analyses to test significance, where appropriate. Results: During 1993-2008, 2040 incidents involved chlorine, and 1246 incidents involved chlorine alternatives. Nearly 30% of chlorine releases resulted in injured persons, as compared to 13% of chlorine alternatives that resulted in injury. Although similar proportions of persons injured in chlorine or chlorine alternative releases were treated on scene (18% and 14%, respectively) and at a hospital (58% and 60%, respectively), there was a greater proportion of hospital admissions following chlorine releases than there was following releases of chlorine alternatives (10 % vs. 4%) (p < 0.01). There were significantly fewer victims per release for hydrogen peroxide (0.2) than there were for chlorine (1.3) in paper manufacturing (p < 0.01). Conclusion: Exposures to these five potential chlorine alternatives resulted in a lower proportion of exposed persons requiring hospital admission. To reduce acute public health injuries associated with chemical exposures, users should consider a chlorine alternative when such a substitution is reasonable.
Characterization of Chromosomal Instability in Murine Colitis-Associated Colorectal Cancer
Marco Gerling,Rainer Glauben,Jens K. Habermann,Anja A. Kühl,Christoph Loddenkemper,Hans-Anton Lehr,Martin Zeitz,Britta Siegmund
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022114
Abstract: Patients suffering from ulcerative colitis (UC) bear an increased risk for colorectal cancer. Due to the sparsity of colitis-associated cancer (CAC) and the long duration between UC initiation and overt carcinoma, elucidating mechanisms of inflammation-associated carcinogenesis in the gut is particularly challenging. Adequate murine models are thus highly desirable. For human CACs a high frequency of chromosomal instability (CIN) reflected by aneuploidy could be shown, exceeding that of sporadic carcinomas. The aim of this study was to analyze mouse models of CAC with regard to CIN. Additionally, protein expression of p53, beta-catenin and Ki67 was measured to further characterize murine tumor development in comparison to UC-associated carcinogenesis in men.
Oral and Fecal Campylobacter concisus Strains Perturb Barrier Function by Apoptosis Induction in HT-29/B6 Intestinal Epithelial Cells
Hans Linde Nielsen, Henrik Nielsen, Tove Ejlertsen, J?rgen Engberg, Dorothee Günzel, Martin Zeitz, Nina A. Hering, Michael Fromm, J?rg-Dieter Schulzke, Roland Bücker
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023858
Abstract: Campylobacter concisus infections of the gastrointestinal tract can be accompanied by diarrhea and inflammation, whereas colonization of the human oral cavity might have a commensal nature. We focus on the pathophysiology of C. concisus and the effects of different clinical oral and fecal C. concisus strains on human HT-29/B6 colon cells. Six oral and eight fecal strains of C. concisus were isolated. Mucus-producing HT-29/B6 epithelial monolayers were infected with the C. concisus strains. Transepithelial electrical resistance (Rt) and tracer fluxes of different molecule size were measured in Ussing chambers. Tight junction (TJ) protein expression was determined by Western blotting, and subcellular TJ distribution was analyzed by confocal laser-scanning microscopy. Apoptosis induction was examined by TUNEL-staining and Western blot of caspase-3 activation. All strains invaded confluent HT-29/B6 cells and impaired epithelial barrier function, characterized by a time- and dose-dependent decrease in Rt either after infection from the apical side but even more from the basolateral compartment. TJ protein expression changes were sparse, only in apoptotic areas of infected monolayers TJ proteins were redistributed. Solely the barrier-forming TJ protein claudin-5 showed a reduced expression level to 66±8% (P<0.05), by expression regulation from the gene. Concomitantly, Lactate dehydrogenase release was elevated to 3.1±0.3% versus 0.7±0.1% in control (P<0.001), suggesting cytotoxic effects. Furthermore, oral and fecal C. concisus strains elevated apoptotic events to 5-fold. C. concisus-infected monolayers revealed an increased permeability for 332 Da fluorescein (1.74±0.13 vs. 0.56±0.17 10?6 cm/s in control, P<0.05) but showed no difference in permeability for 4 kDa FITC-dextran (FD-4). The same was true in camptothecin-exposed monolayers, where camptothecin was used for apoptosis induction. In conclusion, epithelial barrier dysfunction by oral and fecal C. concisus strains could mainly be assigned to apoptotic leaks together with moderate TJ changes, demonstrating a leak-flux mechanism that parallels the clinical manifestation of diarrhea.
Aetiology of community-acquired, acute gastroenteritis in hospitalised adults: a prospective cohort study
Andreas Jansen, Klaus Stark, Jan Kunkel, Eckart Schreier, Ralf Ignatius, Oliver Liesenfeld, Dirk Werber, Ulf B G?bel, Martin Zeitz, Thomas Schneider
BMC Infectious Diseases , 2008, DOI: 10.1186/1471-2334-8-143
Abstract: From August 2005 to August 2007, we conducted a prospective cohort study among patients ≥18 y hospitalized with community-acquired gastroenteritis in a university hospital in Berlin, Germany. Stool specimens were examined for 26 gastrointestinal pathogens, supplemented by serologic tests for antibodies to Campylobacter spp., Yersinia spp., and Entamoeba histolytica. Patient data on demographics and clinical presentation were recorded and analyzed. Coexisting medical conditions were assessed using the Charlson Comorbidity Index score.Of 132 patients presenting with acute community-acquired gastroenteritis, 104 were included in the study. A non-infectious aetiology was diagnosed in 8 patients (8%). In 79 (82%) of the remaining 96 patients at least one microorganism was identified. Campylobacter spp. (35%) was detected most frequently, followed by norovirus (23%), Salmonella spp. (20%), and rotavirus (15%). In 46% of the patients with Campylobacter spp. infection, the diagnosis was made solely by serology. More than one pathogen was found in seventeen (22%) patients. Simultaneous infection was significantly more likely in patients with rotavirus and salmonella infections (RR 3.6; 95% CI: 1.8–7.4; RR 2.5; 95%CI: 1.2–5.5). Length of hospital stay (median: 5.5 days) was independent of the pathogen, but was associated with coexisting medical conditions (OR 4,8; 95%CI:2,0–11,6).Known enteric pathogens were detected in 82% of adult patients who were hospitalized with acute gastroenteritis. We found that currently used culture-based methods may miss a substantial proportion of Campylobacter infections, and additional serological testing for Campylobacter should be considered. Viral infections emerged as an important cause of severe gastroenteritis in adults, and viral-bacterial co-infections in adults are probably underrecognized so far. The presence of coexisting medical conditions – but not the etiological agent – was a predictor for the duration of the hospital stay.Infect
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