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  • 1
    Keywords: DISEASE ; METABOLISM ; ALPHA ; ACID ; inactivation ; DIFFERENTIAL EXPRESSION ; 5-LIPOXYGENASE ; MOLECULAR-MECHANISMS ; prostaglandins ; NONALCOHOLIC FATTY LIVER
    Abstract: BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. METHODOLOGY AND RESULTS: In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. CONCLUSIONS: We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J on the one hand and PWD/PhJ on the other.
    Type of Publication: Journal article published
    PubMed ID: 25347188
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  • 2
    Keywords: NF-KAPPA-B ; OXIDATIVE STRESS ; PROTEASOME ; MOUSE-LIVER ; MURINE PERITONEAL-MACROPHAGES ; INTERACTING PROTEIN P62 ; CHAIN BINDING-PROTEIN ; A170 STRESS PROTEIN ; KINASE-C ISOFORMS ; INCLUSION-BODIES
    Abstract: Mallory bodies (MBs) consist of abnormal keratins, ubiquitin, heat shock proteins, and the protein p62. p62 is encoded by an immediate-early response gene that rapidly responds to a variety of extracellular signals involved in cell proliferation, differentiation, and particularly oxidative stress. It acts as an adapter in signal transduction and binds noncovalently to ubiquitin, possibly being involved in the regulation of the fate of ubiquitinated proteins by segregation (i.e., sequestosome or aggresome formation). The presence of p62 together with ubiquitinated abnormal keratins in the MB characterizes MBs as a disease-associated type of sequestosome. A detailed study on the expression of p62 and its relationship to MB formation in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-treated mouse liver is reported based on immunohistochemical, immunoblot, and Northern blot analyses. The results indicate that p62 is rapidly induced in hepatocytes of intoxicated animals preceding MB formation. As suggested by experiments with short-term DDC-treated naive mice and mice refed DDC after recovery from long-term DDC treatment (primed mice), p62 does not exert an initiating effect on MB formation but the appearance of MBs requires the presence of abnormal keratins, which associate with p62 after ubiquitination. The rapid induction of p62 and its association with MBs further support the role of oxidative stress in MB formation. In conclusion, the constant presence of p62 in MBs suggests that binding of p62 to abnormal keratins may allow hepatocytes to dispose potentially harmful proteins in a biologically inert manner.
    Type of Publication: Journal article published
    PubMed ID: 11981755
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  • 3
    Keywords: MICE ; intermediate filaments ; FACTOR-KAPPA-B ; OXIDATIVE STRESS ; UBIQUITIN ; SH2 DOMAIN ; PARKINSONS-DISEASE ; MURINE PERITONEAL-MACROPHAGES ; PHOSPHOTYROSINE-INDEPENDENT LIGAND ; MALLORY BODIES
    Abstract: Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.
    Type of Publication: Journal article published
    PubMed ID: 11786419
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  • 4
    ISSN: 0309-1651
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0309-1651
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters A 78 (1980), S. 22-24 
    ISSN: 0375-9601
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-2307
    Keywords: Endocrine tissues ; Endocrine tumours ; Cytoskeleton ; Immunohistochemistry ; Gel-electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The presence and distribution of intermediate filament proteins, such as cytokeratins, vimentin, neurofilament proteins and glial fibrillary acidic protein were assessed immunohistochemically in pituitary adenomas, medullary thyroid carcinomas, endocrine pancreatic tumours, gastric, intestinal and bronchial carcinoids, parathyroid adenomas, pheochromocytomas, paragangliomas and related non-neoplastic tissues. In some cases, immunohistochemical results were correlated with cytoskeletal proteins as analysed by SDS-polyacrylamide gel electrophoresis. Cytokeratin antibodies with broad range of immunoreactivity (i.e. to murine liver cytokeratin component D) reacted with epithelial cells in all non-neoplastic endocrine tissues and related neuroendocrine tumours studied, except for adrenal medulla, pheochromocytoma and paraganglioma, independently of hormone production and biological behaviour. In contrast, antibodies to epidermis-derived cytokeratins failed to stain endocrine tissues and tumours. Paranuclear cytokeratin accumulations were seen in bronchial, gastric, and intestinal carcinoids and seem to be a common feature of neuroendocrine tumours. One-and two-dimensional SDS-polyacrylamide gel electrophoresis of non-neoplastic endocrine tissues and related tumours revealed two major keratin polypeptides corresponding to cytokeratins No. 8 and 18 of the cytokeratin catalog of human cells (Moll et al. 1982). According to this cytokeratin polypeptide composition, endocrine tissues and related tumours conform to the “simple type” of epithelia. Vimentin-related immunoreactivity was restricted to stromal cells and to folliculo-stellate cells in normal pituitary gland, Schwann cells in carcinoids and satellite cells in normal adrenal medulla and in pheochromocytomas. Neurofilament protein- (70 kD)-antibodies only stained nerve fibers in normal tissues and at the periphery of carcinoid tumour cell complexes, and, to a variable degree, cells in nontumorous adrenal medulla, pheochromocytomas and paragangliomas. Furthermore, neurofilament reactivity was observed along with cytokeratin expression in two bronchial carcinoids.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-2307
    Keywords: Gastrointestinal carcinomas ; Tissue polypeptide antigen (TPA) ; Cytokeratins ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The presence and distribution of tissue polypeptide antigen (TPA) were assessed in gastrointestinal carcinomas of different origin, morphology and degree of differentiation. Immunocytochemistry was employed, using the PAP technique on formalin-fixed, paraffin-embedded material and compared with the results obtained with antibodies to cytokeratins. Like cytokeratins, TPA was a reliable marker of epithelial differentiation and showed tissue distribution patterns similar to cytokeratins, as revealed by antibodies with broad-range cytokeratin immunoreactivity. In most carcinomas, TPA-specific immunostaining was less intense than in non-neoplastic tissue. No direct relationship between intensity of TPA staining and morphological degree of differentiation and proliferation was found. TPA staining was most pronounced at the periphery of the cells. In stratified epithelium, i.e. oesophageal mucosa, basally located cells exceeded superficial cells in TPA immunoreactivity in contrast to the cytokeratin antibodies which decorated the more superficially placed cell layers. TPA and cytokeratin staining patterns were similar in neoplastic and non-neoplastic gastric, intestinal mucosa, as well as in biliary tract epithelium. Antral and cardial mucoid glands of the stomach as well as gastric carcinomas of the pylorocardial type remained unstained with both types of antibodies. Similar staining with TPA and cytokeratin antibodies was also observed in pancreatic and liver tissue. In this study, hepatocytes were, although weakly, stained by TPA antibodies and an identical staining was found with benign and malignant hepatocellular neoplasms. Ductal and ductular TPA-staining was most conspicuous and so was the immunoreactivity of cholangiocellular carcinomas. A comparison between TPA and cytokeratins was also made by immunoblotting which revealed immunoreactivity of antibodies to TPA with cytokeratin polypeptides of different species (man, mouse) and organs (epidermis, liver), particularly with the cytokeratin component 8 of human liver and the related component A of mouse liver. The significance of this finding is uncertain until the pertinent epitopes have been revealed by monoclonal mapping of the components which exhibit similar molecular weights by SDS polyacrylamide gel electrophoresis.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-2307
    Keywords: Thyroid ; Mixed medullary-papillary carcinoma ; Common stem cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We present three thyroid carcinomas displaying medullary and papillary components. In two cases the papillary component was characterized by typical papillae with a fibrovascular core; in one a follicular variant of papillary carcinoma was found. The papillary component was dominant in two and the medullary in one case. One tumour showed clear-cut borders between the two components, the others displayed an intermingled pattern. Both tumour components were seen in lymph node metastases with immunostaining with antibodies to calcitonin, chromogranin A, carcinoembryonic antigen, other neuroendocrine markers and thyroglobulin. At least two of our cases are true mixed carcinomas probably arising from a common stem cell.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1433-0385
    Keywords: Key words: Schistosoma japonicum ; Rectal carcinoma ; Etiology ; Inflammatory chronic large-bowel disease ; Precancerous condition. ; Schlüsselwörter: Schistosomiasis japonicum ; Rectumcarcinom ; Ätiologie ; chronisch entzündliche Dickdarmerkrankung ; fakultative Präcancerose.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung. Bei einem 39 jährigen österreichischen Staatsbürger chinesischer Herkunft wurden nach einer Latenzzeit von etwa 20 Jahren nicht nur in dem chirurgisch entfernten Rectumcarcinom, sondern auch in der das Carcinom umgebenden chronisch entzündlich veränderten Rectumschleimhaut mit verschiedenen Schweregraden der Dysplasie und in einem tumorös befallenen benachbarten Lymphknoten, Wurmeier nachgewiesen und daher ein kausaler Zusammenhang angenommen. Während aber der ätiologische Zusammenhang einer chronischen Infektion mit Schistosoma haematobium und dem gehäuften endemischen Auftreten von Blasenkrebs als gesichert gilt, wird bei den intestinalen Formen der chronischen Schistosomiasis eine erhöhte Carcinomkoinzidenz kontrovers beurteilt. Ätiologisch und pathogenetisch ist die Kausalität zwischen Wurmeiablage und späterem Carcinom ähnlich zu sehen wie bei anderen entzündlichen Dickdarmerkrankungen, wo es über die Sequenz chronische Entzündung/schwere Dysplasie zur späteren Carcinomentstehung kommen kann. Neben einer Übersicht über die Parasitologie und Pathologie dieser Trematodenerkrankung wird der ätiologische und pathogenetische Zusammenhang zwischen Rectumcarcinom und Schistosomiasis japonicum anhand entsprechender Literaturstellen hergestellt.
    Notes: Summary. After a latency period of 20 years, in a 39-year-old Austrian citizen of Chinese origin, a surgically removed rectal carcinoma, as well as the neighboring chronic inflammatory rectal mucosa with various degrees of dysplasia and one positive neighboring lymph node, showed helminthiasis in the histopathological examination, convincing us of a link between carcinoma and chronic helminthiasis. Whereas the etiological context between chronic infection by Schistosoma haematobium and endemic frequent urinary bladder carcinoma is considered a matter of fact, whether of not the incidence of intestinal carcinoma is increased in connection with chronic intestinal schistosomiasis is controversial. The etiological and pathogenetic link between helminthiasis and carcinoma should be considered in the same way as for other related inflammatory large-bowel diseases. In the sequence chronic inflammation – severe dysplasia, the formation of carcinoma could possibly occur. Besides a survey of trematodes parasitology and pathology, the link between rectal carcinoma and Schistosomiasis japonicum is pointed out by means of appropriate literature investigations.
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