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Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Algul H.,TU Munich | Siveke J.T.,TU Munich | Lesina M.,TU Munich | And 6 more authors.
Gastroenterology | Year: 2010

Background & Aims: Acute pancreatitis (AP) is a serious, unpredictable clinical problem, the pathophysiology of which is poorly understood. Here, we evaluate whether betacellulin (BTC), a ligand of the epidermal growth factor receptor also able to activate the proapoptotic ERBB4 receptor, can protect against experimental AP. Methods: AP was induced in transgenic mice overexpressing BTC (BTC-tg), control mice, or control mice after administration of recombinant BTC. The severity of pancreatitis was assessed by measurements of serum amylase and lipase and histologic grading. The involvement of the stress-activated protein kinase (SAPK) was evaluated by treating BTC-tg mice with an SAPK inhibitor before induction of AP. Results: BTC-tg mice showed increased apoptosis and proliferation in the exocrine pancreas, indicating an increased cell turnover. There was a marked, epidermal growth factor receptor-independent decrease in pancreas weight. After induction of AP by cerulein injection, BTC-tg mice showed a significantly lower increase in serum amylase and lipase levels as well as less pronounced tissue necrosis, edema, and inflammation, as compared to nontransgenic littermates. This protective effect, also confirmed in the l-arginine AP model, was associated with increased phosphorylation of SAPK and abrogated after treatment of BTC-tg mice with a SAPK inhibitor. Finally, the protective effect of BTC against AP was confirmed by treating nontransgenic mice with recombinant BTC. Conclusions: These findings indicate a potential application of the BTC/ERBB4 pathway for modulating the course of AP. © 2010 AGA Institute. Source

Schneider M.R.,Institute of Molecular Animal Breeding and Biotechnology | Kolligs F.T.,Ludwig Maximilians University of Munich
BioEssays | Year: 2015

Recent studies uncovered critical roles of the adhesion protein E-cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E-cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E-cadherin's functions beyond development, numerous mouse lines with tissue-specific disruption of Cdh1 have been generated. The consequences of E-cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue structure and function. This review focuses on these studies and discusses how they provided important insights into E-cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial-to-mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. © 2015 WILEY Periodicals, Inc. Source

Thoeringer C.K.,Max Planck Institute of Psychiatry | Henes K.,Max Planck Institute of Psychiatry | Eder M.,Max Planck Institute of Psychiatry | Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | And 5 more authors.
Neuropsychopharmacology | Year: 2012

Persistent dreadful memories and hyperarousal constitute prominent psychopathological features of posttraumatic stress disorder (PTSD). Here, we used a contextual fear conditioning paradigm to demonstrate that conditional genetic deletion of corticotropin-releasing hormone (CRH) receptor 1 within the limbic forebrain in mice significantly reduced remote, but not recent, associative and non-associative fear memories. Per os treatment with the selective CRHR1 antagonist DMP696 (3 mg/kg) attenuated consolidation of remote fear memories, without affecting their expression and retention. This could be achieved, if DMP696 was administered for 1 week starting as late as 24 h after foot shock. Furthermore, by combining electrophysiological recordings and western blot analyses, we demonstrate a delayed-onset and long-lasting increase in AMPA receptor (AMPAR) GluR1-mediated signaling in the dentate gyrus (DG) of the dorsal hippocampus 1 month after foot shock. These changes were absent from CRHR1-deficient mice and after DMP696 treatment. Inactivation of hippocampal GluR1-containing AMPARs by antisense oligonucleotides or philantotoxin 433 confirmed the behavioral relevance of AMPA-type glutamatergic neurotransmission in maintaining the high levels of remote fear in shocked mice with intact CRHR1 signaling. We conclude that limbic CRHR1 receptors enhance the consolidation of remote fear memories in the first week after foot shock by increasing the expression of Ca 2+-permeable GluR1-containing AMPARs in the DG. These findings suggest both receptors as rational targets for the prevention and therapy, respectively, of psychopathology associated with exaggerated fear memories, such as PTSD. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source

Paz A.H.,Federal University of Rio Grande do Sul | Salton G.D.,Federal University of Rio Grande do Sul | Ayala-Lugo A.,Federal University of Rio Grande do Sul | Gomes C.,Federal University of Rio Grande do Sul | And 7 more authors.
Stem Cells and Development | Year: 2011

Betacellulin (BTC), a ligand of the epidermal growth factor receptor, has been shown to promote growth and differentiation of pancreatic β-cells and to improve glucose metabolism in experimental diabetic rodent models. Mesenchymal stem cells (MSCs) have been already proved to be multipotent. Recent work has attributed to rat and human MSCs the potential to differentiate into insulin-secreting cells. Our goal was to transfect rat MSCs with a plasmid containing BTC cDNA to guide MSC differentiation into insulin-producing cells. Prior to induction of cell MSC transfection, MSCs were characterized by flow cytometry and the ability to in vitro differentiate into mesoderm cell types was evaluated. After rat MSC characterization, these cells were electroporated with a plasmid containing BTC cDNA. Transfected cells were cultivated in Dulbecco's modified Eagle medium high glucose (H-DMEM) with 10mM nicotinamide. Then, the capability of MSC-BTC to produce insulin in vitro and in vivo was evaluated. It was possible to demonstrate by radioimmunoassay analysis that 104 MSC-BTC cells produced up to 0.4ng/mL of insulin, whereas MSCs transfected with the empty vector (negative control) produced no detectable insulin levels. Moreover, MSC-BTC were positive for insulin in immunohistochemistry assay. In parallel, the expression of pancreatic marker genes was demonstrated by molecular analysis of MSC-BTC. Further, when MSC-BTC were transplanted to streptozotocin diabetic rats, BTC-transfected cells ameliorated hyperglycemia from over 500 to about 200mg/dL at 35 days post-cell transplantation. In this way, our results clearly demonstrate that BTC overabundance enhances glucose-induced insulin secretion in MSCs in vitro as well as in vivo. © 2011, Mary Ann Liebert, Inc. Source

Schafer M.,Institute of Molecular Health science | Willrodt A.-H.,Institute of Molecular Health science | Kurinna S.,Institute of Molecular Health science | Link A.S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 14 more authors.
EMBO Molecular Medicine | Year: 2014

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis. © 2014 The Authors. Source

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