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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  10. Kongress für Infektionskrankheiten und Tropenmedizin (KIT 2010); 20100623-20100626; Köln; DOCP98 /20100602/
    Publication Date: 2010-06-02
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    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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  • 3
    Keywords: IN-VITRO ; HEPATOCELLULAR-CARCINOMA ; IDENTIFICATION ; PATHOGENESIS ; SMOKERS ; NONALCOHOLIC STEATOHEPATITIS ; FATTY LIVER-DISEASE ; HYALINE BODIES ; LIPOTOXICITY ; AKR1B10
    Abstract: BACKGROUND: Pathogenesis and factors for determining progression of alcoholic and non-alcoholic steatosis to steatohepatitis with risk of further progression to liver cirrhosis and cancer are poorly understood. In the present study, we aimed to identify potential molecular signatures for discrimination of steatohepatitis from steatosis. METHODOLOGY AND RESULTS: Global microarray gene expression analysis was applied to unravel differentially expressed genes between steatohepatitis compared to steatosis and control samples. For functional annotation as well as the identification of disease-relevant biological processes of the differentially expressed genes the gene ontology (GO) database was used. Selected candidate genes (n = 46) were validated in 87 human liver samples from two sample cohorts by quantitative real-time PCR (qRT-PCR). The GO analysis revealed that genes down-regulated in steatohepatitis were mainly involved in metabolic processes. Genes up-regulated in steatohepatitis samples were associated with cancer progression and proliferation. In surgical liver resection samples, 39 genes and in percutaneous liver biopsies, 30 genes were significantly up-regulated in steatohepatitis. Furthermore, immunohistochemical investigation of human liver tissue revealed a significant increase of AKR1B10 protein expression in steatohepatitis. CONCLUSIONS: The development of steatohepatitis is characterized by distinct molecular changes. The most striking examples in this respect were KRT23 and AKR1B10, which we found to be highly differentially expressed in steatohepatitis compared to steatosis and normal liver. We propose that KRT23 and AKR1B10 may serve as future potential biomarkers for steatohepatitis as well as markers for progression to HCC.
    Type of Publication: Journal article published
    PubMed ID: 23071592
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; FACTOR RECEPTOR ; INHIBITION ; MODEL ; PATHWAY ; PATHWAYS ; DISEASE ; liver ; GENE ; GENES ; transcription ; MICE ; TUMOR-NECROSIS-FACTOR ; DOWN-REGULATION ; GROWTH-FACTOR RECEPTOR ; ALPHA ; ACID ; MOUSE ; resistance ; INDUCED APOPTOSIS ; UP-REGULATION ; NECROSIS-FACTOR-ALPHA ; inactivation ; DAMAGE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; PHENOTYPE ; MOUSE MODEL ; INJURY ; EPIDERMAL-GROWTH-FACTOR ; INCREASED EXPRESSION ; signaling ; CYTOKINE ; FAS ; BILE ; INTERLEUKIN-6 ; KNOCKOUT MICE ; methods ; BARRIER ; NECROSIS ; Stat3 ; CHOLESTASIS ; interleukin 6 ; FACTOR-RECEPTOR ; Conditional mouse model ; BILE-ACIDS ; PRIMARY HEPATOCYTES
    Abstract: BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. METHODS: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC. RESULTS: We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Delta hc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Delta hc) mice were more sensitive to cholic acid-induced liver damage than control mice. CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes
    Type of Publication: Journal article published
    PubMed ID: 20193684
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  • 5
    ISSN: 1432-1440
    Keywords: α1-Antitrypsin deficiency ; Glomerulonephritis ; Cirrhosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An association of α1-antitrypsin deficiency with glomerulonephritis is rare and has so far been observed only in children or young adults. We report a 63-year-old man with severe α1-antitrypsin deficiency associated with pulmonary emphysema, cirrhosis of the liver, and mesangioproliferative glomerulonephritis with nephrotic syndrome. Following initial presentation with nephropathy, further work-up revealed α1-antitrypsin deficiency of proteinase inhibitor Z. In the absence of glomerular α1-antitrypsin deposits the relationship between renal disease and α1-antitrypsin deficiency remains unclear. α1-Antitrypsin deficiency should be considered in adults with abnormal renal function and chronic liver disease.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0030-493X
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Cross sections for charge transfer reactions of organic ions containing oxygen have been obtained using time-of-flight techniques. Charge transfer cross sections have been determined for reactions of 2.0 to 3.4 keV ions produced by electron impact ionization of oxygen containing molecules such as methanol, ethanal and ethanol. Experimental cross section magnitudes have been correlated with reaction energy defects computed from ion recombination energies and target ionization energies. Large cross sections are observed for reacting systems with small energy defects.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-09-02
    Description: The ATP-binding cassette transporter ABCB4/MDR3 is critical for biliary phosphatidylcholine (PC) excretion at the canalicular membrane of hepatocytes. Defective ABCB4 gene expression and protein function result in various cholestatic liver and bile duct injuries. Thyroid hormone receptor (THR) is a major regulator of hepatic lipid metabolism; we explored its potential role in ABCB4 regulation. Thyroid hormone T3 stimulation to human hepatocyte models showed direct transcriptional activation of ABCB4 in a dose- and time-dependent manner. To determine whether THRβ1 (the main THR isoform of the liver) is involved in regulation, we tested THRβ1-specific agonists (e.g., GC-1, KB-141); these agonists resulted in greater stimulation than the native hormone. KB-141 activated hepatic ABCB44 expression in mice, which enhanced biliary PC secretion in vivo. We also identified THR response elements 6 kb upstream of the ABCB4 locus that were conserved in humans and mice. Thus, T3-via THRβ1 as a novel transcriptional activator regulates ABCB4 to increase ABCB4 protein levels at the canalicular membrane and promote PC secretion into bile. These findings may have important implications for understanding thyroid hormone function as a potential modifier of bile duct homeostasis and provide pharmacologic opportunities to improve liver function in hepatobiliary diseases caused by low ABCB4 expression.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 8
    Publication Date: 2018-01-10
    Description: The German cytologist Theodor Boveri proposed about 100 years ago that cancer is caused by an abnormal distribution of microscopic bodies called chromosomes. At that time, researchers had no idea of the cellular component for inheritance and challenged his hypothesis. Meanwhile, genomic instability is viewed as a hallmark of cancer 1 and an alternative model for cancer formation was put forward that proposed acquisition of a ‘mutator’ phenotype as the initiating event. Although supported by the vast plasticity of sequence changes and chromosomal aberrations in individual cells of single tumours, these observations did not solve the issue whether the ‘mutator’ phenotype is a precondition or a consequence of tumourigenesis. The ‘mutator’ phenotype is causative for genomic instability, an umbrella term for small DNA structure variations, microsatellite instability and chromosomal instability (CIN). 2 The latter affects chromosome number and structure and is a characteristic feature of many cancer types...
    Keywords: Gut
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 9
    Publication Date: 2011-06-18
    Description: Cachexia is a multifactorial wasting syndrome most common in patients with cancer that is characterized by the uncontrolled loss of adipose and muscle mass. We show that the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (Atgl) or hormone-sensitive lipase (Hsl) ameliorates certain features of cancer-associated cachexia (CAC). In wild-type C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue (WAT), and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased WAT lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected although to a lesser degree. Thus, functional lipolysis is essential in the pathogenesis of CAC. Pharmacological inhibition of metabolic lipases may help prevent cachexia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das, Suman K -- Eder, Sandra -- Schauer, Silvia -- Diwoky, Clemens -- Temmel, Hannes -- Guertl, Barbara -- Gorkiewicz, Gregor -- Tamilarasan, Kuppusamy P -- Kumari, Pooja -- Trauner, Michael -- Zimmermann, Robert -- Vesely, Paul -- Haemmerle, Guenter -- Zechner, Rudolf -- Hoefler, Gerald -- F 3001/Austrian Science Fund FWF/Austria -- F 3002/Austrian Science Fund FWF/Austria -- F 3013/Austrian Science Fund FWF/Austria -- Z 136/Austrian Science Fund FWF/Austria -- New York, N.Y. -- Science. 2011 Jul 8;333(6039):233-8. doi: 10.1126/science.1198973. Epub 2011 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Pathology, Medical University of Graz, Graz, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21680814" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/*enzymology/pathology ; Animals ; Blood Glucose/metabolism ; Body Mass Index ; Body Weight ; Cachexia/*enzymology/etiology/pathology ; Cytokines/blood ; Fatty Acids/blood ; Glycerol/metabolism ; Humans ; Lipase/deficiency/genetics/*metabolism ; *Lipolysis ; Melanoma, Experimental ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/pathology ; Myocardium/pathology ; Neoplasms/complications/*enzymology/pathology ; Neoplasms, Experimental/complications/*enzymology/pathology ; Peptides/metabolism ; Sterol Esterase/deficiency/genetics/*metabolism ; Triglycerides/blood ; Weight Loss
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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