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87 Publications visible to you, out of a total of 87
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

Hepatic Smad7-overexpression causes severe iron overload in the mouse.

Abstract

Not specified

Authors: D. Lai, F. Teng, S. Hammad, J. Werle, T. Maas, A. Teufel, M. U. Muckenthaler, S. Dooley, M. Vujic Spasic

Date Published: 13th Dec 2017

Publication Type: Not specified

A brief history of COMBINE

Abstract (Expand)

Standards for data exchange are critical to the development of any field. They enable researchers and practitioners to transport information reliably, to apply a variety of tools to their problems, and … to reproduce scientific results. Over the past two decades, a range of standards have been developed to facilitate the exchange and reuse of information in the domain of representation and modeling of biological systems. These standards are complementary, so the interactions between their developers increased over time. By the end of the last decade, the community of researchers decided that more interoperability is required between the standards, and that common development is needed to make better use of effort, time, and money devoted to this activity. The COmputational MOdeling in Biology NEtwork (COMBINE) was created to enable the sharing of resources, tools, and other infrastructure. This paper provides a brief history of this endeavor and the challenges that remain.

Authors: Chris J. Myers, Gary Bader, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Nicolas Le Novere, David P. Nickerson, Falk Schreiber, Dagmar Waltemath

Date Published: 1st Dec 2017

Publication Type: Not specified

Modeling approaches for hepatic spatial heterogeneity in pharmacokinetic simulations

Abstract (Expand)

The metabolization and excretion of drugs in the liver are spatially heterogeneous processes. This is due to the spatial variability of physiological processes at different length scales of biological … organization in healthy individuals, while many liver diseases further contribute to the heterogeneity. Classical, well-stirred pharmacokinetic models do not represent this heterogeneity, and various modeling approaches capable of representing heterogeneity have been developed recently. These approaches range from mechanistic and physio-geometrically realistic models focusing on specific spatial scales, via continuum models using homogenized physiological and metabolic properties, to integrative multiscale models. Such models could become essential research tools for simulations involving drugs with notable first-pass effects, fast-acting drugs or tracers, and diseased livers.

Authors: Lars Ole Schwen, Lars Kuepfer, Tobias Preusser

Date Published: 29th Nov 2017

Publication Type: Not specified

The level of caveolin-1 expression determines response to TGF-β as a tumour suppressor in hepatocellular carcinoma cells

Abstract

Not specified

Authors: Joaquim Moreno-Càceres, Daniel Caballero-Díaz, Zeribe Chike Nwosu, Christoph Meyer, Judit López-Luque, Andrea Malfettone, Raquel Lastra, Teresa Serrano, Emilio Ramos, Steven Dooley, Isabel Fabregat

Date Published: 12th Oct 2017

Publication Type: Not specified

Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma

Abstract

Not specified

Authors: Zeribe Chike Nwosu, Dominik Andre Megger, Seddik Hammad, Barbara Sitek, Stephanie Roessler, Matthias Philip Ebert, Christoph Meyer, Steven Dooley

Date Published: 1st Sep 2017

Publication Type: Not specified

A frequent misinterpretation in current research on liver fibrosis: the vessel in the center of CCl4-induced pseudolobules is a portal vein.

Abstract (Expand)

Carbon tetrachloride-induced liver injury is a thoroughly studied model for regeneration and fibrosis in rodents. Nevertheless, its pattern of liver fibrosis is frequently misinterpreted as portal type. … To clarify this, we show that collagen type IV+ "streets" and alpha-SMA+ cells accumulate pericentrally and extend to neighbouring central areas of the liver lobule, forming a 'pseudolobule'. Blood vessels in the center of such pseudolobules are portal veins as indicated by the presence of bile duct cells (CK19+) and the absence of pericentral hepatocytes (glutamine synthetase+). It is critical to correctly describe this pattern of fibrosis, particulary for metabolic zonation studies.

Authors: S. Hammad, A. Braeuning, C. Meyer, F. E. Z. A. Mohamed, J. G. Hengstler, S. Dooley

Date Published: 22nd Aug 2017

Publication Type: Not specified

Genetic determinants of cholangiopathies: Molecular and systems genetics.

Abstract (Expand)

Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid … associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts ("ascending pathophysiology") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage "descending" down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1-6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present "system genetics" as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Authors: M. C. Reichert, R. A. Hall, M. Krawczyk, F. Lammert

Date Published: 2nd Aug 2017

Publication Type: Journal

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