Leibniz Center for Medicine and Biosciences

Borstel-Hohenraden, Germany

Leibniz Center for Medicine and Biosciences

Borstel-Hohenraden, Germany
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Muller-Fielitz H.,University of Lübeck | Lau M.,University of Lübeck | Johren O.,University of Lübeck | Stellmacher F.,Leibniz Center for Medicine and Biosciences | And 2 more authors.
British Journal of Pharmacology | Year: 2012

Background and purpose Plasma aldosterone levels correlate positively with obesity, suggesting a link between the hypertension associated with obesity and increased mineralocorticoid levels. We tested the hypothesis that aldosterone is involved in the BP response to angiotensin II (AngII) in obese rats. Experimental Approach Lean (LZR) and obese (OZR) Zucker rats were treated with AngII (9 Âμg·h-1; 4 weeks), and BP and plasma AngII and aldosterone were determined. KEy Results Chronic AngII increased the BP in OZR markedly more so than in LZR. Plasma AngII levels in LZR and OZR were similar after AngII treatment. The AngII stimulated a rise in plasma aldosterone that was sixfold more in OZR than in LZR. The thickness of the zona glomerulosa of the adrenal glands was selectively increased by AngII in OZR. Adrenal mRNA levels of CYP11B2 aldosterone synthase and the AT1B receptor were selectively increased in AngII-treated OZR. The BP response to chronic AngII stimulation was diminished in OZR after adrenalectomy when plasma aldosterone was absent. Acute bolus injections of AngII did not increase the BP response or aldosterone release in OZR. Conclusions and Implications The AngII-induced BP response is enhanced in obesity and this is associated with a specific increase in circulating aldosterone. Due to the AngII-induced growth of the zona glomerulosa in OZR, the AT1B receptors and aldosterone synthase may be selectively enhanced in obesity under concomitant AngII stimulation, increasing the adrenal synthesis of aldosterone. Our results confirm functionally that aldosterone plays a major role in obesity-related hypertension. © 2012 The British Pharmacological Society.

Turska-Szewczuk A.,Maria Curie Sklodowska University | Lindner B.,Research Center Borstel | Komaniecka I.,Maria Curie Sklodowska University | Kozinska A.,National Veterinary Research Institute | And 4 more authors.
Marine Drugs | Year: 2013

Chemical analyses and mass spectrometry were used to study the structure of the lipopolysaccharide (LPS) isolated from Aeromonas bestiarum strain K296, serotype O18. ESI-MS revealed that the most abundant A. bestiarum LPS glycoforms have a hexa-acylated or tetra-acylated lipid A with conserved architecture of the backbone, consisting of a 1,4′-bisphosphorylated β-(1→6)- linked D-GlcN disaccharide with an AraN residue as a non-stoichiometric substituent and a core oligosaccharide composed of Kdo1Hep 6Hex1HexN1P1. 1D and 2D NMR spectroscopy revealed that the O-specific polysaccharide (OPS) of A. bestiarum K296 consists of a branched tetrasaccharide repeating unit containing two 6-deoxy-L-talose (6dTalp), one Manp and one Gal pNAc residues; thus, it is similar to that of the OPS of A. hydrophila AH-3 (serotype O34) in both the sugar composition and the glycosylation pattern. Moreover, 3-substituted 6dTalp was 2-O-acetylated and additional O-acetyl groups were identified at O-2 and O-4 (or O-3) positions of the terminal 6dTalp. Western blots with polyclonal rabbit sera showed that serotypes O18 and O34 share some epitopes in the LPS. The very weak reaction of the anti-O34 serum with the O-deacylated LPS of A. bestiarum K296 might have been due to the different O-acetylation pattern of the terminal 6dTalp. The latter suggestion was further confirmed by NMR. © 2013 by the authors; licensee MDPI.

Hoffmann J.,Heinrich Pette Institute | Schneider C.,Heinrich Pette Institute | Heinbockel L.,Leibniz Center for Medicine and Biosciences | Brandenburg K.,Leibniz Center for Medicine and Biosciences | And 2 more authors.
Antiviral Research | Year: 2014

Influenza A viruses are a continuous threat to human health as illustrated by the 2009 H1N1 pandemic. Since circulating influenza virus strains become increasingly resistant against currently available drugs, the development of novel antivirals is urgently needed. Here, we have evaluated a recently described new class of broad-spectrum antiviral peptides (synthetic anti-lipopolysaccharide peptides; SALPs) for their potential to inhibit influenza virus replication in vitro and in vivo. We found that particularly SALP PEP 19-2.5 shows high binding affinities for the influenza virus receptor molecule, N-Acetylneuraminic acid, leading to impaired viral attachment and cellular entry. As a result, replication of several influenza virus subtypes (H7N7, H3N2 and 2009 pandemic H1N1) was strongly reduced. Furthermore, mice co-treated with PEP 19-2.5 were protected against an otherwise 100% lethal H7N7 influenza virus infection. These findings show that SALPs exhibit antiviral activity against influenza viruses by blocking virus attachment and entry into host cells. Thus, SALPs present a new class of broad-spectrum antiviral peptides for further development for influenza virus therapy. © 2014 Published by Elsevier B.V.

Yildirim A.O.,University of Marburg | Yildirim A.O.,Institute of Lung Biology and Disease | Muyal V.,University of Marburg | John G.,Justus Liebig University | And 5 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy. Objectives: To investigate whether therapeutic application of palifermin (ΔN23-KGF) is able to induce a regenerative response in distal lungparenchyma after induction of pulmonaryemphysema. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg ΔN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase. Measurements and Main Results: Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase-induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. ΔN23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanceddifferentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-β1, TGF-β2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. ΔN23-KGF induced the expression of TGF-β1 in and release of active TGF-β1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-β1 but not ΔN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of ΔN23-KGF in LA-4/MLF cocultures. Conclusions: Our data demonstrate that therapeutic application of ΔN23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-β1.

Suomalainen M.,University of Helsinki | Lobo L.A.,University of Helsinki | Brandenburg K.,Leibniz Center for Medicine and Biosciences | Lindner B.,Leibniz Center for Medicine and Biosciences | And 5 more authors.
Infection and Immunity | Year: 2010

The Pla surface protease of Yersinia pestis activates human plasminogen and is a central virulence factor in bubonic and pneumonic plague. Pla is a transmembrane β-barrel protein and member of the omptin family of outer membrane proteases which require bound lipopolysaccharide (LPS) to be proteolytically active. Plasminogen activation and autoprocessing of Pla were dramatically higher in Y. pestis cells grown at 37°C than in cells grown at 20°C; the difference in enzymatic activity by far exceeded the increase in the cellular content of the Pla protein. Y. pestis modifies its LPS structure in response to growth temperature. We purified His6-Pla under denaturing conditions and compared various LPS types for their capacity to enhance plasmin formation by His6-Pla solubilized in detergent. Reactivation of His6-Pla was higher with Y. pestis LPSs isolated from bacteria grown at 37°C than with LPSs from cells grown at 25°C. Lack of O antigens and the presence of the outer core region as well as a lowered level of acylation in LPS were found to enhance the Pla-LPS interaction. Genetic substitution of arginine 138, which is part of a three-dimensional protein motif for binding to lipid A phosphates, decreased both the enzymatic activity of His6-Pla and the amount of Pla in Y. pestis cells, suggesting the importance of the Pla-lipid A phosphate interaction. The temperature-induced changes in LPS are known to help Y. pestis to avoid innate immune responses, and our results strongly suggest that they also potentiate Pla-mediated proteolysis. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Polansky J.K.,Helmholtz Center for Infection Research | Polansky J.K.,Leibniz Center for Medicine and Biosciences | Schreiber L.,Helmholtz Center for Infection Research | Thelemann C.,Charité - Medical University of Berlin | And 7 more authors.
Journal of Molecular Medicine | Year: 2010

The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage. © 2010 The Author(s).

Fischer N.,University of Hamburg | Schulz C.,University of Hamburg | Stieler K.,University of Hamburg | Hohn O.,Robert Koch Institute | And 3 more authors.
Emerging Infectious Diseases | Year: 2010

Xenotropic murine leukemia virus-related gammaretrovirus (XMRV) has been recently associated with prostate cancer and chronic fatigue syndrome. To identify nucleic acid sequences, we examined respiratory secretions by using PCR. XMRV-specifi c sequences were detected in 2%-3% of samples from 168 immunocompetent carriers and ≈10% of samples from 161 immunocompromised patients.

Claes A.-K.,University of Toronto | Claes A.-K.,Leibniz Center for Medicine and Biosciences | Claes A.-K.,University of Kiel | Zhou J.Y.,University of Toronto | Philpott D.J.,University of Toronto
Physiology | Year: 2015

The NOD-like receptors (NLRs) are cytosolic pattern-recognition receptors, which are critically involved in mucosal immune defense. The association of the NLR, NOD2, with inflammatory bowel disease first pointed to the NLRs potential function as guardians of the intestinal barrier. Since then, several studies have emphasized the importance of NLRs in maintaining gut homeostasis and intestinal infections, and in shaping the microbiota. In this review, we will highlight the function of NLRs in intestinal inflammation. © 2015 Int.

Schromm A.B.,Emmy Noether Group of Immunobiophysics | Reiling N.,Leibniz Center for Medicine and Biosciences | Howe J.,Leibniz Center for Medicine and Biosciences | Wiesmuller K.-H.,EMC Microcollections GmbH | And 2 more authors.
Innate Immunity | Year: 2010

The innate immune response provides a critical first-line defense against Mycobacterium tuberculosis, an intracellular pathogen that represents a major health threat world-wide. A synthetic lipopeptide (LP) mimicking the lipid moiety of the cell-wall associated 19-kDa lipoprotein from M. tuberculosis has recently been assigned an important role in the induction of an antibacterial immune response in host macrophages. Here, we present experimental data on the biological activities and the biophysical mechanisms underlying cell activation by synthetic 19-kDa M. tuberculosis-derived lipopeptide (Mtb-LP). Investigation of the geometry of the LP (i.e. the molecular conformation and supramolecular aggregate structure) and the preference for membrane intercalation provide an explanation for the biological activities of the mycobacterial LP. Cell activation by low concentrations of Mtb-LP was enhanced by the lipopolysaccharideĝ€"binding protein and CD14. However, surprisingly, we found that activation of human macrophages to induce pro- as well as antiinflammatory mediators (tumor necrosis factor(TNF)-±, Interleukin(IL)-6, IL-8, and IL-10) in response to the Mtb-LP is strongly reduced in the presence of serum. This observation could be confirmed for the immune response of murine macrophages which showed a strongly enhanced TNF-± release in the absence of serum, suggesting that the molecular mechanisms of immune recognition of the Mtb-LP are tailored to the ambient conditions of the lung. © 2010 SAGE Publications.

PubMed | Aix - Marseille University, University of Navarra, University of Stockholm and Leibniz Center for Medicine and Biosciences
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2016

The structures of the lipooligosaccharides fromBrucella melitensismutants affected in the WbkD and ManBcoreproteins have been fully characterized using NMR spectroscopy. The results revealed that disruption ofwbkDgives rise to a rough lipopolysaccharide (R-LPS) with a complete core structure (-d-Glcp-(14)--Kdop-(24)[-d-GlcpN-(16)--d-GlcpN-(14)[-d-GlcpN-(16)]--d-GlcpN-(13)--d-Manp-(15)]--Kdop-(26)--d-GlcpN3N4P-(16)--d-GlcpN3N1P), in addition to components lacking one of the terminal -d-GlcpN and/or the -d-Glcpresidues (48 and 17%, respectively). These structures were identical to those of the R-LPS fromB. melitensisEP, a strain simultaneously expressing both smooth and R-LPS, also studied herein. In contrast, disruption ofmanBcoregives rise to a deep-rough pentasaccharide core (-d-Glcp-(14)--Kdop-(24)--Kdop-(26)--d-GlcpN3N4P-(16)--d-GlcpN3N1P) as the major component (63%), as well as a minor tetrasaccharide component lacking the terminal -d-Glcpresidue (37%). These results are in agreement with the predicted functions of the WbkD (glycosyltransferase involved in the biosynthesis of the O-antigen) and ManBcoreproteins (phosphomannomutase involved in the biosynthesis of a mannosyl precursor needed for the biosynthesis of the core and O-antigen). We also report that deletion ofB. melitensis wadCremoves the core oligosaccharide branch not linked to the O-antigen causing an increase in overall negative charge of the remaining LPS inner section. This is in agreement with the mannosyltransferase role predicted for WadC and the lack of GlcpN residues in the defective core oligosaccharide. Despite carrying the O-antigen essential inB. melitensisvirulence, the core deficiency in thewadCmutant structure resulted in a more efficient detection by innate immunity and attenuation, proving the role of the -d-GlcpN-(16)--d-GlcpN-(14)[-d-GlcpN-(16)]--d-GlcpN-(13)--d-Manp-(15) structure in virulence.

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