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Search Results: 1 - 10 of 558 matches for " Detlef Schuppan "
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Discovery of a Novel and Rich Source of Gluten-Degrading Microbial Enzymes in the Oral Cavity
Eva J. Helmerhorst,Maram Zamakhchari,Detlef Schuppan,Frank G. Oppenheim
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013264
Abstract: Celiac disease is a T cell mediated-inflammatory enteropathy caused by the ingestion of gluten in genetically predisposed individuals carrying HLA-DQ2 or HLA-DQ8. The immunogenic gliadin epitopes, containing multiple glutamine and proline residues, are largely resistant to degradation by gastric and intestinal proteases. Salivary microorganisms however exhibit glutamine endoprotease activity, discovered towards glutamine- and proline-rich salivary proteins. The aim was to explore if gliadins can serve as substrates for oral microbial enzymes.
Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives
Michael H?pfner, Detlef Schuppan, Hans Scherübl
World Journal of Gastroenterology , 2008,
Abstract: The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options. Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies, which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors. This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors. In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e. combining growth factor (receptor)-targeting agents with chemo- or biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.
Targeted medical therapy of biliary tract cancer: Recent advances and future perspectives
Michael H?pfner, Detlef Schuppan, Hans Scherübl
World Journal of Gastroenterology , 2008,
Abstract: The limited efficacy of cytotoxic therapy for advanced biliary tract and gallbladder cancers emphasizes the need for novel and more effective medical treatment options. A better understanding of the specific biological features of these neoplasms led to the development of new targeted therapies, which take the abundant expression of several growth factors and cognate tyrosine kinase receptors into account. This review will briefly summarize the status and future perspectives of antiangiogenic and growth factor receptor-based pharmacological approaches for the treatment of biliary tract and gallbladder cancers. In view of multiple novel targeted approaches, the rationale for innovative therapies, such as combinations of growth factor (receptor)-targeting agents with cytotoxic drugs or with other novel anticancer drugs will be highlighted.
Role of the receptor for advanced glycation end products in hepatic fibrosis
Christina Lohwasser, Daniel Neureiter, Yury Popov, Michael Bauer, Detlef Schuppan
World Journal of Gastroenterology , 2009,
Abstract: AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE) in the pathogenesis of liver fibrogenesis.METHODS: In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells (HSC) were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin (AGE-BSA) and Nε-(carboxymethyl) lysine (CML)-BSA, or with tumor necrosis factor-α (TNF-α). In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro.RESULTS: In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α. RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1(I) mRNA by AGE-BSA.CONCLUSION: Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.
Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer
Michael H?pfner, Detlef Schuppan, Hans Scherübl
World Journal of Gastroenterology , 2008,
Abstract: Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer (HCC). Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors (“small molecule inhibitors”) and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin (mTOR) upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation. mTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.
Identification of Rothia Bacteria as Gluten-Degrading Natural Colonizers of the Upper Gastro-Intestinal Tract
Maram Zamakhchari, Guoxian Wei, Floyd Dewhirst, Jaeseop Lee, Detlef Schuppan, Frank G. Oppenheim, Eva J. Helmerhorst
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024455
Abstract: Background Gluten proteins, prominent constituents of barley, wheat and rye, cause celiac disease in genetically predisposed subjects. Gluten is notoriously difficult to digest by mammalian proteolytic enzymes and the protease-resistant domains contain multiple immunogenic epitopes. The aim of this study was to identify novel sources of gluten-digesting microbial enzymes from the upper gastro-intestinal tract with the potential to neutralize gluten epitopes. Methodology/Principal Findings Oral microorganisms with gluten-degrading capacity were obtained by a selective plating strategy using gluten agar. Microbial speciations were carried out by 16S rDNA gene sequencing. Enzyme activities were assessed using gliadin-derived enzymatic substrates, gliadins in solution, gliadin zymography, and 33-mer α-gliadin and 26-mer γ-gliadin immunogenic peptides. Fragments of the gliadin peptides were separated by RP-HPLC and structurally characterized by mass spectrometry. Strains with high activity towards gluten were typed as Rothia mucilaginosa and Rothia aeria. Gliadins (250 μg/ml) added to Rothia cell suspensions (OD620 1.2) were degraded by 50% after ~30 min of incubation. Importantly, the 33-mer and 26-mer immunogenic peptides were also cleaved, primarily C-terminal to Xaa-Pro-Gln (XPQ) and Xaa-Pro-Tyr (XPY). The major gliadin-degrading enzymes produced by the Rothia strains were ~70–75 kDa in size, and the enzyme expressed by Rothia aeria was active over a wide pH range (pH 3–10). Conclusion/Significance While the human digestive enzyme system lacks the capacity to cleave immunogenic gluten, such activities are naturally present in the oral microbial enzyme repertoire. The identified bacteria may be exploited for physiologic degradation of harmful gluten peptides.
Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells
Masahiko Koda, Michael Bauer, Anja Krebs, Eckhart G Hahn, Detlef Schuppan, Yoshikazu Murawaki
Comparative Hepatology , 2006, DOI: 10.1186/1476-5926-5-5
Abstract: First passage HSC predominantly expressed endothelin A receptor (ETAR) mRNA and 4th passage HSC predominantly expressed the endothelin B receptor (ETBR) mRNA. ET-1 had no effect on DNA synthesis in 1st passage HSC, but reduced DNA synthesis in 4th passage HSC by more than 50%. Inhibition of proliferation by endothelin-1 was abrogated by ETBR specific antagonist BQ788, indicating a prominent role of ETBR in growth inhibition. ET-1 did not prevent apoptosis induced by serum deprivation or Fas ligand in 1st or 4th passage HSC. However, ET-1 increased procollagen α1(I), transforming growth factor β-1 and matrix metalloproteinase (MMP)-2 mRNA transcripts in a concentration-dependent manner in 1st, but not in 4th passage HSC. Profibrogenic gene expression was abrogated by ETAR antagonist BQ123. Both BQ123 and BQ788 attenuated the increase of MMP-2 expression by ET-1.We show that ET-1 stimulates fibrogenic gene expression for 1st passage HSC and it inhibits HSC proliferation for 4th passage HSC. These data indicate the profibrogenic and antifibrogenic action of ET-1 for HSC are involved in the process of liver fibrosis.Hepatic stellate cells (HSC) are responsible for the storage of retinoid and the control of sinusoidal blood flow in normal liver. In liver injury, HSC number is markedly increased and transformed into myofibroblast-like cells, termed activated HSC. Activated HSC produce extracellular matrix components, matrix metalloproteinases and their inhibitors [1-3]. All of them decreasing during the resolution of the fibrotic tissue.Endothelin (ET)-1, a 21 amino acid peptide, plays multifunctional roles in a variety of tissues and cells [4,5]. In the liver, ET-1 induces vascular constriction and stimulates glycogenolysis and the synthesis of lipid mediators [6,7]. ET-1 is secreted by sinusoidal endothelial cells and by activated HSC [8], and activated HSC that express high numbers of ET receptors [1] respond to ET-1 with spreading and expression of α-smooth muscle act
Elevated transaminases as a predictor of coma in a patient with anorexia nervosa: a case report and review of the literature
Shuhei Yoshida, Masahiko Shimada, Miroslaw Kornek, Seong-Jun Kim, Katsunosuke Shimada, Detlef Schuppan
Journal of Medical Case Reports , 2010, DOI: 10.1186/1752-1947-4-307
Abstract: A 37-year-old Japanese woman showed features of acute liver failure and hepatic coma which were not associated with hypoglycemia or hyper-ammonemia. Our patient's consciousness was significantly improved with the recovery of liver function and normalization of transaminase levels after administration of nutritional support.Our case report demonstrates that transaminase levels had an inverse relationship with the consciousness of our patient, although the pathogenesis of coma remains largely unknown. This indicates that transaminase levels can be one of the key predictors of impending coma in patients with anorexia nervosa. Therefore, frequent monitoring of transaminase levels combined with rigorous treatment of the underlying nutritional deficiency and psychiatric disorder are necessary to prevent this severe complication.Anorexia nervosa (AN) is a difficult-to-treat psychosomatic disease. Mild liver injury is regularly detected as a complication of AN [1-5]. Although severe acute liver injury has been previously described in a patient with AN, the underlying pathogenetic mechanisms remain largely unclear. Furthermore, only a few cases of AN with deep coma have been reported, mostly due to hypoglycemic coma [6-9].Our case report describes a patient with AN who rapidly developed deep coma associated with acute liver failure, which was rapidly improved by initiation of total parenteral nutrition (TPN) and enteral feedings via a nasogastric (NG) tube.Our patient was a 37-year-old Japanese woman with a 12-year history of AN. She had been hospitalized frequently in the gastrointestinal unit for nutritional treatment, but she continuously rejected hospitalization in a psychiatric unit probably due to her denial of the illness, despite her frequent, self-induced vomiting. She had been admitted to the hospital three times previously because of general fatigue combined with acute liver failure. At these admissions, her Glasgow coma scale (GCS) was in the normal range of 12 t
Extracting Unsatisfiable Cores for LTL via Temporal Resolution
Viktor Schuppan
Computer Science , 2012, DOI: 10.1007/s00236-015-0242-1
Abstract: Unsatisfiable cores (UCs) are a well established means for debugging in a declarative setting. Still, there are few tools that perform automated extraction of UCs for LTL. Existing tools compute a UC as an unsatisfiable subset of the set of top-level conjuncts of an LTL formula. Using resolution graphs to extract UCs is common in other domains such as SAT. In this article we construct and optimize resolution graphs for temporal resolution as implemented in the temporal resolution-based solver TRP++, and we use them to extract UCs for propositional LTL. The resulting UCs are more fine-grained than the UCs obtained from existing tools because UC extraction also simplifies top-level conjuncts instead of treating them as atomic entities. For example, given an unsatisfiable LTL formula of the form $\phi \equiv ({\bf G} \psi) \wedge {\bf F} \psi'$ existing tools return $\phi$ as a UC irrespective of the complexity of $\psi$ and $\psi'$, whereas the approach presented in this article continues to remove parts not required for unsatisfiability inside $\psi$ and $\psi'$. Our approach also identifies groups of occurrences of a proposition that do not interact in a proof of unsatisfiability. We implement our approach in TRP++. Our experimental evaluation demonstrates that our approach (i) extracts UCs that are often significantly smaller than the input formula with an acceptable overhead and (ii) produces more fine-grained UCs than competing tools while remaining at least competitive in terms of run time and memory usage. The source code of our tool is publicly available.
Enhancing Unsatisfiable Cores for LTL with Information on Temporal Relevance
Viktor Schuppan
Computer Science , 2013, DOI: 10.4204/EPTCS.117.4
Abstract: LTL is frequently used to express specifications in many domains such as embedded systems or business processes. Witnesses can help to understand why an LTL specification is satisfiable, and a number of approaches exist to make understanding a witness easier. In the case of unsatisfiable specifications unsatisfiable cores (UCs), i.e., parts of an unsatisfiable formula that are themselves unsatisfiable, are a well established means for debugging. However, little work has been done to help understanding a UC of an unsatisfiable LTL formula. In this paper we suggest to enhance a UC of an unsatisfiable LTL formula with additional information about the time points at which the subformulas of the UC are relevant for unsatisfiability. For example, in "(G p) and (X not p)" the first occurrence of "p" is really only "relevant" for unsatisfiability at time point 1 (time starts at time point 0). We present a method to extract such information from the resolution graph of a temporal resolution proof of unsatisfiability of an LTL formula. We implement our method in TRP++, and we experimentally evaluate it. Source code of our tool is available.
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