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94 Publications visible to you, out of a total of 94
Second exposure to acetaminophen overdose is associated with liver fibrosis in mice

Abstract (Expand)

Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in response as a result of repeated exposures of acetaminophen (APAP) compared to a single … dose is not well-studied. Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP admin-istrations. Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels revealed that the fulminant liver damage was reduced after the second APAP administration compared to that observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracel-lular matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase. From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed after a second challenge. Therefore, further studies are required to mechanistically understand the so called “liver memory”

Author: Mohammad AlWahsh, Amnah Othman, Lama Hamadneh, Ahmad Telfah, Jörg Lambert, Suhair Hikmat, Amin Alassi, Fatma El Zahraa Mohamed, Roland Hergenröder, Tariq Al-Qirim, Steven Dooley, Seddik Hammad

Date Published: 6th Feb 2019

Publication Type: Not specified

Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

Abstract

Not specified

Authors: Ersin Karatayli, Rabea A. Hall, Susanne N. Weber, Steven Dooley, Frank Lammert

Date Published: 1st Feb 2019

Publication Type: Not specified

Data Formats for Systems Biology and Quantitative Modeling

Abstract (Expand)

Data standards support the reliable exchange of information, the interoperability of tools, and the reproducibility of scientific results. In systems biology standards are agreed ways of structuring, … describing, and associating models and data, as well as their respective parts, graphical visualization, and information about applied experimental or computational methods. Such standards also assist with describing how constituent parts interact together, or are linked, and how they are embedded in their environmental and experimental context. Here the focus will be on standards for formatting models and their content, and on metadata checklists and ontologies that support modeling.

Author: Martin Golebiewski

Date Published: 2019

Publication Type: InBook

Pipe-3D: A Pipeline Based on Immunofluorescence, 3D Confocal Imaging, Reconstructions, and Morphometry for Biliary Network Analysis in Cholestasis

Abstract

Not specified

Authors: Amruta Damle-Vartak, Brigitte Begher-Tibbe, Georgia Gunther, Fabian Geisler, Nachiket Vartak, Jan G. Hengstler

Date Published: 2019

Publication Type: Book

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Abstract

Not specified

Authors: Matthias Reichert, Frank Lammert

Date Published: 24th Oct 2018

Publication Type: Not specified

Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours.

Abstract (Expand)

BACKGROUND: Although metabolism is profoundly altered in human liver cancer, the extent to which experimental models, e.g. cell lines, mimic those alterations is unresolved. Here, we aimed to determine … the resemblance of hepatocellular carcinoma (HCC) cell lines to human liver tumours, specifically in the expression of deregulated metabolic targets in clinical tissue samples. METHODS: We compared the overall gene expression profile of poorly-differentiated (HLE, HLF, SNU-449) to well-differentiated (HUH7, HEPG2, HEP3B) HCC cell lines in three publicly available microarray datasets. Three thousand and eighty-five differentially expressed genes in >/=2 datasets (P < 0.05) were used for pathway enrichment and gene ontology (GO) analyses. Further, we compared the topmost gene expression, pathways, and GO from poorly differentiated cell lines to the pattern from four human HCC datasets (623 tumour tissues). In well- versus poorly differentiated cell lines, and in representative models HLE and HUH7 cells, we specifically assessed the expression pattern of 634 consistently deregulated metabolic genes in human HCC. These data were complemented by quantitative PCR, proteomics, metabolomics and assessment of response to thirteen metabolism-targeting compounds in HLE versus HUH7 cells. RESULTS: We found that poorly-differentiated HCC cells display upregulated MAPK/RAS/NFkB signaling, focal adhesion, and downregulated complement/coagulation cascade, PPAR-signaling, among pathway alterations seen in clinical tumour datasets. In HLE cells, 148 downregulated metabolic genes in liver tumours also showed low gene/protein expression - notably in fatty acid beta-oxidation (e.g. ACAA1/2, ACADSB, HADH), urea cycle (e.g. CPS1, ARG1, ASL), molecule transport (e.g. SLC2A2, SLC7A1, SLC25A15/20), and amino acid metabolism (e.g. PHGDH, PSAT1, GOT1, GLUD1). In contrast, HUH7 cells showed a higher expression of 98 metabolic targets upregulated in tumours (e.g. HK2, PKM, PSPH, GLUL, ASNS, and fatty acid synthesis enzymes ACLY, FASN). Metabolomics revealed that the genomic portrait of HLE cells co-exist with profound reliance on glutamine to fuel tricarboxylic acid cycle, whereas HUH7 cells use both glucose and glutamine. Targeting glutamine pathway selectively suppressed the proliferation of HLE cells. CONCLUSIONS: We report a yet unappreciated distinct expression pattern of clinically-relevant metabolic genes in HCC cell lines, which could enable the identification and therapeutic targeting of metabolic vulnerabilities at various liver cancer stages.

Authors: Z. C. Nwosu, N. Battello, M. Rothley, W. Pioronska, B. Sitek, M. P. Ebert, U. Hofmann, J. Sleeman, S. Wolfl, C. Meyer, D. A. Megger, S. Dooley

Date Published: 5th Sep 2018

Publication Type: Not specified

MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis.

Abstract (Expand)

MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in … human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-beta) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-kappaB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-beta signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-beta and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.

Authors: L. Tao, D. Xue, D. Shen, W. Ma, J. Zhang, X. Wang, W. Zhang, L. Wu, K. Pan, Y. Yang, Z. C. Nwosu, S. Dooley, E. Seki, C. Liu

Date Published: 12th Aug 2018

Publication Type: Not specified

Inverse agonist of ERRgamma reduces cannabinoid receptor type 1-mediated induction of fibrinogen synthesis in mice with a high-fat diet-intoxicated liver.

Abstract (Expand)

Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood … vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRgamma as key regulator of hepatocytic fibrinogen gene expression in human. In a therapeutic approach, we now tested ERRgamma inverse agonist GSK5182 as regulator of fibrinogen levels in mouse hyperfibrinogenemia caused by diet-induced obesity and in mouse hepatocytes. ACEA, a CB1R agonist, up-regulated transcription of mouse fibrinogen via induction of ERRgamma, whereas knockdown of ERRgamma attenuated the effect of ACEA (10 microM) on fibrinogen expression in AML12 mouse hepatocytes. Deletion analyses of the mouse fibrinogen gamma (FGG) gene promoter and ChIP assays revealed binding sites for ERRgamma on the mouse FGG promoter. ACEA or adenovirus ERRgamma injection induced FGA, FGB and FGG mRNA and protein expression in mouse liver, while ERRgamma knockdown with Ad-shERRgamma attenuated ACEA-mediated induction of fibrinogen gene expression. Moreover, mice maintained on a high-fat diet (HFD) expressed higher levels of fibrinogen, whereas cannabinoid receptor type 1 (CB1R)-KO mice fed an HFD had nearly normal fibrinogen levels. Finally, GSK5182 (40 mg/kg) strongly inhibits the ACEA (10 mg/kg) or HFD-mediated induction of fibrinogen level in mice. Taken together, targeting ERRgamma with its inverse agonist GSK5182 represents a promising therapeutic strategy for ameliorating hyperfibrinogenemia.

Authors: Y. Zhang, D. K. Kim, Y. S. Jung, Y. H. Kim, Y. S. Lee, J. Kim, W. I. Jeong, I. K. Lee, S. J. Cho, S. Dooley, C. H. Lee, H. S. Choi

Date Published: 19th Jul 2018

Publication Type: Not specified

Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation

Abstract (Expand)

Tamoxifen (TAM) is commonly used for cell type specific Cre recombinase-induced gene inactivation and in cell fate tracing studies. Inducing a gene knockout by TAM and using non-TAM exposed mice as … controls lead to a situation where differences are interpreted as consequences of the gene knockout but in reality result from TAM-induced changes in hepatic metabolism. The degree to which TAM may compromise the interpretation of animal experiments with inducible gene expression still has to be elucidated. Here, we report that TAM strongly attenuates CCl4-induced hepatotoxicity in male C57Bl/6N mice, even after a 10 days TAM exposure-free period. TAM decreased (p < 0.0001) the necrosis index and the level of aspartate- and alanine transaminases in CCl4-treated compared to vehicle-exposed mice. TAM pretreatment also led to the downregulation of CYP2E1 (p = 0.0045) in mouse liver tissue, and lowered its activity in CYP2E1 expressing HepG2 cell line. Furthermore, TAM increased the level of the antioxidant ascorbate, catalase, SOD2, and methionine, as well as phase II metabolizing enzymes GSTM1 and UGT1A1 in CCl4-treated livers. Finally, we found that TAM increased the presence of resident macrophages and recruitment of immune cells in necrotic areas of the livers as indicated by F4/80 and CD45 staining. In conclusion, we reveal that TAM increases liver resistance to CCl4-induced toxicity. This finding is of high relevance for studies using the tamoxifen-inducible expression system particularly if this system is used in combination with hepatotoxic compounds such as CCl4.

Authors: Seddik Hammad, Amnah Othman, Christoph Meyer, Ahmad Telfah, Joerg Lambert, Bedair Dewidar, Julia Werle, Zeribe Chike Nwosu, Abdo Mahli, Christof Dormann, Yan Gao, Kerry Gould, Mei Han, Xiaodong Yuan, Mikheil Gogiashvili, Roland Hergenröder, Claus Hellerbrand, Maria Thomas, Matthias Philip Ebert, Salah Amasheh, Jan G. Hengstler, Steven Dooley

Date Published: 4th Jul 2018

Publication Type: Not specified

Galunisertib modifies the liver fibrotic composition in the Abcb4Ko mouse model

Abstract (Expand)

Transforming growth factor (TGF)-β stimulates extracellular matrix (ECM) deposition during development of liver fibrosis and cirrhosis, the most important risk factor for the onset of hepatocellular … carcinoma. In liver cancer, TGF-β is responsible for a more aggressive and invasive phenotype, orchestrating remodeling of the tumor microenvironment and triggering epithelial-mesenchymal transition of cancer cells. This is the scientific rationale for targeting the TGF-β pathway via a small molecule, galunisertib (intracellular inhibitor of ALK5) in clinical trials to treat liver cancer patients at an advanced disease stage. In this study, the hypothesis that galunisertib modifies the tissue microenvironment via inhibition of the TGF-β pathway is tested in an experimental preclinical model. At the age of 6 months, Abcb4ko mice-a well-established model for chronic liver disease development and progression-are treated twice daily with galunisertib (150 mg/kg) via oral gavage for 14 consecutive days. Two days after the last treatment, blood plasma and livers are harvested for further assessment, including fibrosis scoring and ECM components. The reduction of Smad2 phosphorylation in both parenchymal and non-parenchymal liver cells following galunisertib administration confirms the treatment effectiveness. Damage-related galunisertib does not change cell proliferation, macrophage numbers and leucocyte recruitment. Furthermore, no clear impact on the amount of fibrosis is evident, as documented by PicroSirius red and Gomori-trichome scoring. On the other hand, several fibrogenic genes, e.g., collagens (Col1α1 and Col1α2), Tgf-β1 and Timp1, mRNA levels are significantly downregulated by galunisertib administration when compared to controls. Most interestingly, ECM/stromal components, fibronectin and laminin-332, as well as the carcinogenic β-catenin pathway, are remarkably reduced by galunisertib-treated Abcb5ko mice. In conclusion, TGF-β inhibition by galunisertib interferes, to some extent, with chronic liver progression, not by reducing the stage of liver fibrosis as measured by different scoring systems, but rather by modulating the biochemical composition of the deposited ECM, likely affecting the fate of non-parenchymal cells.

Authors: Seddik Hammad, Elisabetta Cavalcanti, Julia Werle, Maria Lucia Caruso, Anne Dropmann, Antonia Ignazzi, Matthias Philip Ebert, Steven Dooley, Gianluigi Giannelli

Date Published: 28th May 2018

Publication Type: Not specified

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2017.

Abstract (Expand)

Standards are essential to the advancement of Systems and Synthetic Biology. COMBINE provides a formal body and a centralised platform to help develop and disseminate relevant standards and related … resources. The regular special issue of the Journal of Integrative Bioinformatics aims to support the exchange, distribution and archiving of these standards by providing unified, easily citable access. This paper provides an overview of existing COMBINE standards and presents developments of the last year.

Authors: F. Schreiber, G. D. Bader, P. Gleeson, M. Golebiewski, M. Hucka, S. M. Keating, N. L. Novere, C. Myers, D. Nickerson, B. Sommer, D. Waltemath

Date Published: 30th Mar 2018

Publication Type: Not specified

Effects of Gene Variants Controlling Vitamin D Metabolism and Serum Levels on Hepatic Steatosis.

Abstract (Expand)

BACKGROUND/AIMS: Common genetic variations in vitamin D metabolism are associated with liver stiffness. Whether these genes are implicated in hepatic steatosis remains unclear. Here we aimed to analyse … the association of common vitamin D pathway gene variants with liver steatosis. METHODS: Liver steatosis was assessed non-invasively in 241 patients with chronic liver conditions by controlled attenuation parameter (CAP). The following polymorphisms were genotyped using TaqMan assays: group-specific component (GC) rs7041, 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657, -vitamin D receptor (VDR) rs7974353. Chemiluminescence immunoassay determined serum 25-hydroxyvitamin D (25(OH) D) concentrations. RESULTS: Vitamin D deficiency (defined by 25(OH)D concentrations <20 ng/mL) occurred in 66% of patients. Median CAP was 296 (100-400) dB/m. Patients with advanced steatosis (CAP >/=280 dB/m) had significantly (p = 0.033) lower 25(OH)D levels as compared to patients with CAP <280 dB/m. Moreover, the rare allele [T] in GC rs7041 was significantly (p = 0.018) associated with higher 25(OH)D levels in patients with CAP <280 dB/m. However, GC, DHCR7, CYP2R1, and VDR polymorphisms were not related to liver steatosis and obesity traits. CONCLUSIONS: Higher CAP values are associated with low serum 25(OH)D concentrations but not with common vitamin D pathway gene variants.

Authors: M. Jamka, A. Arslanow, A. Bohner, M. Krawczyk, S. N. Weber, F. Grunhage, F. Lammert, C. S. Stokes

Date Published: 8th Mar 2018

Publication Type: Not specified

Hepatic Smad7 overexpression causes severe iron overload in mice

Abstract

Not specified

Authors: Dilay Lai, Feng Teng, Seddik Hammad, Julia Werle, Thorsten Maas, Andreas Teufel, Martina U. Muckenthaler, Steven Dooley, Maja Vujić Spasić

Date Published: 1st Feb 2018

Publication Type: Not specified

Harmonizing semantic annotations for computational models in biology.

Abstract (Expand)

Life science researchers use computational models to articulate and test hypotheses about the behavior of biological systems. Semantic annotation is a critical component for enhancing the interoperability … and reusability of such models as well as for the integration of the data needed for model parameterization and validation. Encoded as machine-readable links to knowledge resource terms, semantic annotations describe the computational or biological meaning of what models and data represent. These annotations help researchers find and repurpose models, accelerate model composition and enable knowledge integration across model repositories and experimental data stores. However, realizing the potential benefits of semantic annotation requires the development of model annotation standards that adhere to a community-based annotation protocol. Without such standards, tool developers must account for a variety of annotation formats and approaches, a situation that can become prohibitively cumbersome and which can defeat the purpose of linking model elements to controlled knowledge resource terms. Currently, no consensus protocol for semantic annotation exists among the larger biological modeling community. Here, we report on the landscape of current annotation practices among the COmputational Modeling in BIology NEtwork community and provide a set of recommendations for building a consensus approach to semantic annotation.

Authors: M. L. Neal, M. Konig, D. Nickerson, G. Misirli, R. Kalbasi, A. Drager, K. Atalag, V. Chelliah, M. T. Cooling, D. L. Cook, S. Crook, M. de Alba, S. H. Friedman, A. Garny, J. H. Gennari, P. Gleeson, M. Golebiewski, M. Hucka, N. Juty, C. Myers, B. G. Olivier, H. M. Sauro, M. Scharm, J. L. Snoep, V. Toure, A. Wipat, O. Wolkenhauer, D. Waltemath

Date Published: 22nd Jan 2018

Publication Type: Not specified

Ethanol sensitizes hepatocytes for TGF-beta-triggered apoptosis.

Abstract (Expand)

Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-beta-a potent pro-fibrogenic cytokine-leads to disease progression. Our aim was to elucidate … the crosstalk of TGF-beta and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-beta and cell fate was determined. Fluidigm RNA analyses revealed transcriptional effects that regulate survival and apoptosis. Mechanistic insights were derived from enzyme/pathway inhibition experiments and modulation of oxidative stress levels. To substantiate findings, animal model specimens and human liver tissue cultures were investigated. RESULTS: On its own, ethanol had no effect on hepatocyte apoptosis, whereas TGF-beta increased cell death. Combined treatment led to massive hepatocyte apoptosis, which could also be recapitulated in human HCC liver tissue treated ex vivo. Alcohol boosted the TGF-beta pro-apoptotic gene signature. The underlying mechanism of pathway crosstalk involves SMAD and non-SMAD/AKT signaling. Blunting CYP2E1 and ADH activities did not prevent this effect, implying that it was not a consequence of alcohol metabolism. In line with this, the ethanol metabolite acetaldehyde did not mimic the effect and glutathione supplementation did not prevent the super-induction of cell death. In contrast, blocking GSK-3beta activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-beta. This study provides novel information on the crosstalk between ethanol and TGF-beta. We give evidence that ethanol directly leads to a boost of TGF-beta's pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.

Authors: H. Gaitantzi, C. Meyer, P. Rakoczy, M. Thomas, K. Wahl, F. Wandrer, H. Bantel, H. Alborzinia, S. Wolfl, S. Ehnert, A. Nussler, I. Bergheim, L. Ciuclan, M. Ebert, K. Breitkopf-Heinlein, S. Dooley

Date Published: 21st Jan 2018

Publication Type: Not specified

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