Leibniz Institute For Altersforschung

Jena, Germany

Leibniz Institute For Altersforschung

Jena, Germany
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Tietze D.,TU Darmstadt | Tischler M.,TU Darmstadt | Voigt S.,TU Darmstadt | Imhof D.,Friedrich - Schiller University of Jena | And 3 more authors.
Chemistry - A European Journal | Year: 2010

During recent years several peptide-based Ni superoxide dismutase (NiSOD) models have been developed. These NiSOD models show an important structural difference compared to the native NiSOD enzyme, which could cause a completely different mechanism of superoxide dismutation. In the native enzyme the peptide bond between Leu4 and Pro5 is cis-configured, while the NiSOD models exhibit a trans-configured peptide bond between these two residues. To shed light on how the configuration of this single peptide bond influences the activity of the NiSOD model peptides, a new cisprolyl bond surrogate was developed. As surrogate we chose a leucine/alanine-based disubstituted 1,2,3-triazole, which was incorporated into the NiSOD model peptide replacing resi-dues Leu4 and Pro5. The yielded 1,5disubstituted triazole nickel peptide exhibited high SOD activity, which was approximately the same activity as its parent trans-configured analogue. Hence, the conformation of the prolyl peptide bond apparently has of minor importance for the catalytic activity of the metallopeptides as postulated in literature. Furthermore, it is shown that the triazole metallopeptide is forming a stable cyanide adduct as a substrate analogue model complex. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA. Weinheim.


Thiele W.,University of Heidelberg | Thiele W.,Karlsruhe Institute of Technology | Krishnan J.,Karlsruhe Institute of Technology | Rothley M.,University of Heidelberg | And 8 more authors.
Blood | Year: 2012

VEGFR-3 is a transmembrane receptor tyrosine kinase that is activated by its ligands VEGF-C and VEGF-D. Although VEGFR-3 has been linked primarily to the regulation of lymphangiogenesis, in the present study, we demonstrate a role for VEGFR-3 in megakaryopoiesis. Using a human erythroleukemia cell line and primary murine BM cells, we show that VEGFR-3 is expressed on megakaryocytic progenitor cells through to the promegakaryoblast stage. Functionally, specific activation of VEGFR-3 impaired the transition to polyploidy of CD41+ cells in primary BM cultures. Blockade of VEGFR-3 promoted endoreplication consistently. In vivo, long-term activation or blockade of VEGFR-3 did not affect steady-state murine megakaryopoiesis or platelet counts significantly. However, activation of VEGFR-3 in sublethally irradiated mice resulted in significantly elevated numbers of CD41+ cells in the BM and a significant increase in diploid CD41+ cells, whereas the number of polyploid CD41+ cells was reduced significantly. Moreover, activation of VEGFR-3 increased platelet counts in thrombopoietin-treated mice significantly and modulated 5-fluorouracil - induced thrombocytosis strongly, suggesting a regulatory role for VEGFR-3 in megakaryopoiesis. © 2012 by The American Society of Hematology.


Song L.,TU Munich | Wormann S.,TU Munich | Ai J.,TU Munich | Neuhofer P.,TU Munich | And 13 more authors.
Gastroenterology | Year: 2016

Background & Aims Under conditions of inflammation in the absence of micro-organisms (sterile inflammation), necrotic cells release damage-associated molecular patterns that bind to Toll-like receptors on immune cells to activate a signaling pathway that involves activation of IκB kinase and nuclear factor κB (NF-κB). Little is known about the mechanisms that control NF-κB activity during sterile inflammation. We analyzed the contribution of B-cell CLL/lymphoma 3 (BCL3), a transcription factor that associates with NF-κB, in control of sterile inflammation in the pancreas and biliary system of mice. Methods Acute pancreatitis (AP) was induced in C57BL/6 (control) and Bcl3-/- mice by intraperitoneal injection of cerulein or pancreatic infusion of sodium taurocholate. We also studied Mdr2-/- mice, which develop spontaneous biliary inflammation, as well as Bcl3-/-Mdr2-/- mice. We performed immunohistochemical analyses of inflamed and noninflamed regions of pancreatic tissue from patients with AP or primary sclerosing cholangitis (PSC), as well as from mice. Immune cells were characterized by fluorescence-activated cell sorting analysis. Control or Bcl3-/- mice were irradiated, injected with bone marrow from Bcl3-/- or control mice, and AP was induced. Results Pancreatic or biliary tissues from patients with AP or PSC had higher levels of BCL3 and phosphorylated RelA and IκBα in inflamed vs noninflamed regions. Levels of BCL3 were higher in pancreata from control mice given cerulein than from mice without AP, and were higher in biliary tissues from Mdr2-/- mice than from control mice. Bcl3-/- mice developed more severe AP after administration of cerulein or sodium taurocholate than control mice; pancreata from the Bcl3-/- mice with AP had greater numbers of macrophages, myeloid-derived suppressor cells, dendritic cells, and granulocytes than control mice with AP. Activation of NF-κB was significantly prolonged in Bcl3-/- mice with AP, compared with control mice with AP. Bcl3-/-Mdr2-/- mice developed more severe cholestasis and had increased markers of liver injury and increased proliferation of biliary epithelial cells and hepatocytes than Mdr2-/- mice. In experiments with bone marrow chimeras, expression of BCL3 by acinar cells, but not myeloid cells, was required for reduction of inflammation during development of AP. BCL3 inhibited ubiquitination and proteasome-mediated degradation of p50 homodimers, which prolonged binding of NF-κB heterodimers to DNA. Conclusions BCL3 is up-regulated in inflamed pancreatic or biliary tissues from mice and patients with AP or cholangitis. Its production appears to reduce the inflammatory response in these tissues via blocking ubiquitination and proteasome-mediated degradation of p50 homodimers. © 2016 AGA Institute.


PubMed | Otto Von Guericke University of Magdeburg, Leibniz Institute For Altersforschung, TU Munich, University of Leipzig and Heinrich Heine University Düsseldorf
Type: Journal Article | Journal: Gastroenterology | Year: 2016

Under conditions of inflammation in the absence of micro-organisms (sterile inflammation), necrotic cells release damage-associated molecular patterns that bind to Toll-like receptors on immune cells to activate a signaling pathway that involves activation of IB kinase and nuclear factor B (NF-B). Little is known about the mechanisms that control NF-B activity during sterile inflammation. We analyzed the contribution of B-cell CLL/lymphoma 3 (BCL3), a transcription factor that associates with NF-B, in control of sterile inflammation in the pancreas and biliary system of mice.Acute pancreatitis (AP) was induced in C57BL/6 (control) and Bcl3(-/-) mice by intraperitoneal injection of cerulein or pancreatic infusion of sodium taurocholate. We also studied Mdr2(-/-) mice, which develop spontaneous biliary inflammation, as well as Bcl3(-/-)Mdr2(-/-) mice. We performed immunohistochemical analyses of inflamed and noninflamed regions of pancreatic tissue from patients with AP or primary sclerosing cholangitis (PSC), as well as from mice. Immune cells were characterized by fluorescence-activated cell sorting analysis. Control or Bcl3(-/-) mice were irradiated, injected with bone marrow from Bcl3(-/-) or control mice, and AP was induced.Pancreatic or biliary tissues from patients with AP or PSC had higher levels of BCL3 and phosphorylated RelA and IB in inflamed vs noninflamed regions. Levels of BCL3 were higher in pancreata from control mice given cerulein than from mice without AP, and were higher in biliary tissues from Mdr2(-/-) mice than from control mice. Bcl3(-/-) mice developed more severe AP after administration of cerulein or sodium taurocholate than control mice; pancreata from the Bcl3(-/-) mice with AP had greater numbers of macrophages, myeloid-derived suppressor cells, dendritic cells, and granulocytes than control mice with AP. Activation of NF-B was significantly prolonged in Bcl3(-/-) mice with AP, compared with control mice with AP. Bcl3(-/-)Mdr2(-/-) mice developed more severe cholestasis and had increased markers of liver injury and increased proliferation of biliary epithelial cells and hepatocytes than Mdr2(-/-) mice. In experiments with bone marrow chimeras, expression of BCL3 by acinar cells, but not myeloid cells, was required for reduction of inflammationduring development of AP. BCL3 inhibited ubiquitination and proteasome-mediated degradation of p50 homodimers, which prolonged binding of NF-B heterodimers to DNA.BCL3 is up-regulated in inflamed pancreatic orbiliary tissues from mice and patients with AP or cholangitis. Its production appears to reduce the inflammatory response in these tissues via blocking ubiquitination and proteasome-mediated degradation of p50 homodimers.


Haass C.,German Center for Neurodegenerative Diseases | Haass C.,Ludwig Maximilians University of Munich | Kaether C.,Leibniz Institute For Altersforschung | Thinakaran G.,University of Chicago | Sisodia S.,University of Chicago
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Accumulations of insoluble deposits of amyloid β-peptide are major pathological hallmarks of Alzheimer disease. Amyloid β-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the β-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. β- and γ-secretase liberate by sequential cleavage the neurotoxic amyloid β-peptide, whereas α-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression. © 2012 Cold Spring Harbor Laboratory Press.all rights reserved.


Groth M.,Leibniz Institute For Altersforschung | Reichwald K.,Leibniz Institute For Altersforschung | Szafranski K.,Leibniz Institute For Altersforschung | Taudien S.,Leibniz Institute For Altersforschung | Platzer M.,Leibniz Institute For Altersforschung
BioSpektrum | Year: 2014

With the advent of next-generation sequencing technologies transcriptome sequencing (RNA-seq) became widely used to study the genetic background of ageing processes and related diseases. We describe the power of this method in the study of two novel age research model organisms, the short-lived killifish Nothobranchius furzeri and the long-lived naked mole rat Heterocephalus glaber. A third example illustrates the utility of RNA-seq in a multispecies approach elucidating the role of mild stress in healthy ageing. © 2014 Springer-Verlag Berlin Heidelberg.


Hartmann N.,Leibniz Institute For Altersforschung | Reichwald K.,Leibniz Institute For Altersforschung | Platzer M.,Leibniz Institute For Altersforschung | Englert C.,Leibniz Institute For Altersforschung
Biologie in Unserer Zeit | Year: 2013

Nothobranchius furzeri The African killifish Nothobranchius furzeri lives in seasonal ponds. Through diapauses it can survive the often very extended dry season. After hatching N. furzeri grows extremely fast and becomes sexually mature after 4-5 weeks. Certain strains of N. furzeri show an extremely short lifespan of only 3-4 months, which is the shortest lifespan of a vertebrate that can be kept in captivity. Despite its short lifespan N. furzeri shows typical signs of aging on a morphological, behavioral and molecular level. Old animals display shortening of telomeres and a loss of the number and activity of mitochondria. First crossing experiments between the short- and the long-living strains have revealed the existence of at least four genomic loci, which contribute to the differences in lifespan. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Mischo A.,Leibniz Institute For Altersforschung | Ohlenschlager O.,Leibniz Institute For Altersforschung | Ramachandran R.,Leibniz Institute For Altersforschung | Gorlach M.,Leibniz Institute For Altersforschung
Biomolecular NMR Assignments | Year: 2013

The resonance assignment of an amino-terminal pyroglutamic acid containing peptide derived from the E6 protein of human papillomavirus (HPV) type 51 in complex with PDZ domain 2 of hDlg/SAP-97 is reported. The assignments include 1H, 13C and 15N resonances for the protein and peptide in the complex and all of the peptide's pyroglutamic acid nuclei. © 2012 Springer Science+Business Media B.V.

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