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385 Publications visible to you, out of a total of 385
Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression

Abstract

Not specified

Authors: Yaochen Zhang, Don-Kyu Kim, Yan Lu, Yoon Seok Jung, Ji-min Lee, Young-Hoon Kim, Yong Soo Lee, Jina Kim, Bedair Dewidar, Won-IL Jeong, In-Kyu Lee, Sung Jin Cho, Steven Dooley, Chul-Ho Lee, Xiaoying Li, Hueng-Sik Choi

Date Published: 27th Jul 2017

Publication Type: Not specified

4-O'-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice.

Abstract (Expand)

Alcoholic liver disease (ALD) is a leading cause of liver cirrhosis, liver cancer, and related mortality. The endocannabinoid system contributes to the development of chronic liver diseases, where … cannabinoid receptor 2 (CB2) has been shown to have a protecting role. Thus, here, we investigated how CB2 agonism by 4'-O-methylhonokiol (MHK), a biphenyl from Magnolia grandiflora, affects chronic alcohol-induced liver fibrosis and damage in mice. A combination of alcohol (10% vol/vol) and CCl4 (1 ml/kg) was applied to C57BL/6 mice for 5 weeks. MHK (5 mg/kg) was administered daily, and liver damage assessed by serum AST and ALT levels, histology, gene, and protein expression. Endocannabinoids (ECs) and related lipid derivatives were measured by liquid chromatography and mass spectrometry (LC-MS) in liver tissues. In vitro, MHK was studied in TGFbeta1-activated hepatic stellate cells (HSC). MHK treatment alleviated hepatic fibrosis, paralleled by induced expression of matrix metalloproteinases (MMP)-2, -3, -9, and -13, and downregulation of CB1 mRNA. Necrotic lesions and hepatic inflammation were moderately improved, while IL-10 mRNA increased and IFNgamma, Mcl-1, JNK1, and RIPK1 normalized by MHK. Hepatic anandamide (AEA) and related N-acetylethanolamines (NAEs) were elevated in MHK group, whereas fatty acid synthase and diacylglycerol O-acyltransferase 2 expression reduced. In vitro, MHK prevented HSC activation and induced apoptosis via induction of bak1 and bcl-2. To conclude, MHK revealed hepatoprotective effects during alcohol-induced liver damage through the induction of MMPs, AEA, and NAEs and prevention of HSC activation, indicating MHK as a potent therapeutic for liver fibrosis and ALD. KEY MESSAGES: Methylhonokiol improves liver damage and survival. Methylhonokiol reduces hepatic fibrosis and necroinflammation. Methylhonokiol prevents myofibroblast activation and induces apoptosis. Methylhonokiol upregulates endocannabinoids and related N-acylethanolamines. Methylhonokiol contributes to lipid hydrolysis via PPARalpha/gamma.

Authors: E. Patsenker, A. Chicca, V. Petrucci, S. Moghadamrad, A. de Gottardi, J. Hampe, J. Gertsch, N. Semmo, F. Stickel

Date Published: 8th Jul 2017

Publication Type: Not specified

Serum metabolic signatures in patients with overt hepatic encephalopathy.

Abstract

Not specified

Authors: S. Stengel, A. Stallmach, K. Richter, A. Landrock, J. Hampe, T. Bruns

Date Published: 6th Jul 2017

Publication Type: Not specified

Lipidomics of Human Blood Plasma by High-Resolution Shotgun Mass Spectrometry.

Abstract (Expand)

Clinical lipidomics is an emerging biomarker discovery approach that compares lipid profiles under pathologically and physiologically normal conditions. Here we describe a method for the absolute (molar) … quantification of more than 200 molecules from 14 major lipid classes from 5 muL of human blood plasma using high-resolution top-down shotgun mass spectrometry. Because of its technical simplicity and robustness, the protocol lends itself for high-throughput clinical lipidomics screens.

Authors: S. Sales, O. Knittelfelder, A. Shevchenko

Date Published: 4th Jul 2017

Publication Type: Not specified

Computational modelling of Hedgehog signalling in liver regeneration

Abstract (Expand)

Organ regeneration is a very complex process that includes not only the reconstruction of organ mass but also the reorganisation of homeostatic capabilities. This especially applies for the liver, which … performs a variety of metabolic functions. In the last decade, morphogenic pathways such as the Wnt/β-Catenin and Hedgehog signalling pathways have been revealed to orchestrate liver regeneration as well as metabolism. Mathematical models have been successfully applied to liver regeneration, but these have not integrated the Hedgehog signalling pathway. In this review it is tried to compile features of Hh signalling in liver regeneration which can be integrated into liver regeneration modeling.

Author: Madlen Matz-Soja

Date Published: 1st Jul 2017

Publication Type: Not specified

Translational learning from clinical studies predicts drug pharmacokinetics across patient populations.

Abstract (Expand)

Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. … We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level. Taking into account the acquired knowledge describing (patho-)physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies.

Authors: M. Krauss, U. Hofmann, C. Schafmayer, S. Igel, J. Schlender, C. Mueller, M. Brosch, W. von Schoenfels, W. Erhart, A. Schuppert, M. Block, E. Schaeffeler, G. Boehmer, L. Goerlitz, J. Hoecker, J. Lippert, R. Kerb, J. Hampe, L. Kuepfer, M. Schwab

Date Published: 27th Jun 2017

Publication Type: Not specified

Intensity-Independent Noise Filtering in FT MS and FT MS/MS Spectra for Shotgun Lipidomics.

Abstract (Expand)

Shotgun lipidomics relies on the direct infusion of total lipid extracts into a high resolution tandem mass spectrometer. A single shotgun analysis produces several hundred of densely populated FT MS … and FT MS/MS spectra, each of which might comprise thousands of peaks although a very small percentage of those belong to lipids. Eliminating noise by adjusting a minimal peak intensity threshold is biased and inefficient since lipid species and classes vary in their natural abundance and ionization capacity. We developed a method of peak intensity-independent noise filtering in shotgun FT MS and FT MS/MS spectra that capitalizes on a stable composition of the infused analyte leading to consistent time-independent detection of its bona fide components. Repetition rate filtering relies on a single quantitative measure of peaks detection reproducibility irrespectively of their absolute intensities, masses, or assumed elemental compositions. In comparative experiments, it removed more than 95% of signals detectable in shotgun spectra without compromising the accuracy and scope of lipid identification and quantification. It also accelerated spectra processing by 15-fold and increased the number of simultaneously processed spectra by approximately 500-fold hence eliminating the major bottleneck in high-throughput bottom-up shotgun lipidomics.

Authors: K. Schuhmann, H. Thomas, J. M. Ackerman, K. O. Nagornov, Y. O. Tsybin, A. Shevchenko

Date Published: 15th Jun 2017

Publication Type: Not specified

Tomoelastography of the prostate using multifrequency MR elastography and externally placed pressurized-air drivers.

Abstract (Expand)

PURPOSE: To demonstrate the feasibility of in vivo multifrequency magnetic resonance elastography (MRE) of the prostate using externally placed drivers. METHODS: Three pressurized-air drivers were used … to excite shear waves within the prostate at vibration frequencies of 60, 70, and 80 Hz. Full 3D wave fields were acquired by multislice spin-echo echo-planar imaging in conjunction with tomoelastography wave speed recovery for generating full field-of-view stiffness maps. Twelve healthy volunteers were repeatedly scanned to analyze test-retest reproducibility. Five patients with suspected prostate cancer were investigated to demonstrate the clinical feasibility of the method. RESULTS: In healthy volunteers, the shear wave speed of the entire prostate was 2.24 +/- 0.20 m/s with a repeatability coefficient of 0.14 m/s and 88% intraclass correlation coefficient. No significant difference between the peripheral zone (2.27 +/- 0.20 m/s) and the central gland (2.22 +/- 0.23 m/s) was observed. In patients, wave-speed maps displayed stiff regions consistent with the localization of suspicious masses detected by other imaging markers. CONCLUSIONS: The proposed method provides reproducible quantitative maps of tissue stiffness throughout the pelvic region and can easily be integrated into clinical imaging protocols. Clinical stiffness maps display many details of potential interest for cancer diagnosis. Magn Reson Med 79:1325-1333, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine.

Authors: F. Dittmann, R. Reiter, J. Guo, M. Haas, P. Asbach, T. Fischer, J. Braun, I. Sack

Date Published: 6th Jun 2017

Publication Type: Not specified

Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility

Abstract (Expand)

The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer … therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.

Authors: Christiane Rennert, Franziska Eplinius, Ute Hofmann, Janina Johänning, Franziska Rolfs, Wolfgang Schmidt-Heck, Reinhardt Guthke, Rolf Gebhardt, Albert M. Ricken, Madlen Matz-Soja

Date Published: 30th May 2017

Publication Type: Not specified

Large-scale computational models of liver metabolism: How far from the clinics?

Abstract (Expand)

Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases in general and the metabolism of drugs in particular. This knowledge can be … obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modelling can reveal hidden principles of the system by classification of individual components, analysing their interactions and simulating the effects that are difficult to investigate experimentally. Herein we review the state-of-the-art computational models that describe liver dynamics from the metabolic, gene regulatory and signal transduction perspectives. We focus especially on large-scale liver models described either by genome scale metabolic networks (GSMN) or object-oriented approach. We also discuss the benefits and limitations of each modelling approach and their value for clinical applications in diagnosis, therapy and prevention of liver diseases as well as precision medicine in hepatology. This article is protected by copyright. All rights reserved.

Authors: T. Cvitanovic, M. C. Reichert, M. Moskon, M. Mraz, F. Lammert, D. Rozman

Date Published: 19th May 2017

Publication Type: Not specified

Robust detection and segmentation of cell nuclei in biomedical images based on a computational topology framework

Abstract

Not specified

Authors: Rodrigo Rojas-Moraleda, Wei Xiong, Niels Halama, Katja Breitkopf-Heinlein, Steven Dooley, Luis Salinas, Dieter W. Heermann, Nektarios A. Valous

Date Published: 1st May 2017

Publication Type: Not specified

Quantification of substrate and cellular strains in stretchable 3D cell cultures: an experimental and computational framework

Abstract

Not specified

Authors: P. GONZÁLEZ-AVALOS, M. MÜRNSEER, J. DEEG, A. BACHMANN, J. SPATZ, S. DOOLEY, R. EILS, E. GLADILIN

Date Published: 1st May 2017

Publication Type: Not specified

Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior

Abstract

Not specified

Authors: Wolfgang Schmidt-Heck, Eva C. Wönne, Thomas Hiller, Uwe Menzel, Dirk Koczan, Georg Damm, Daniel Seehofer, Fanny Knöspel, Nora Freyer, Reinhard Guthke, Steven Dooley, Katrin Zeilinger

Date Published: 1st May 2017

Publication Type: Not specified

Ligand-dependent and -independent regulation of human hepatic sphingomyelin phosphodiesterase acid-like 3A expression by pregnane X receptor and crosstalk with liver X receptor.

Abstract (Expand)

Pregnane X receptor (PXR) mainly regulates xenobiotic metabolism and detoxification. Additionally, it exerts pleiotropic effects on liver physiology, which in large parts depend on transrepression of … other liver-enriched transcription factors. Based on the hypothesis that lower expression levels of PXR may reduce the extent of this inhibition, an exploratory genome-wide transcriptomic profiling was performed using HepG2 cell clones with different expression levels of PXR. This screen and confirmatory real-time RT-PCR identified sphingomyelin phosphodiesterase acid-like (SMPDL) 3A, a novel nucleotide phosphodiesterase and phosphoramidase, as being up-regulated by PXR-deficiency. Transient siRNA-mediated knock-down of PXR in HepG2 cells and primary human hepatocytes similarly induced mRNA up-regulation, which translated into increased intracellular and secreted extracellular protein levels. Interestingly, ligand-dependent PXR activation also induced SMPDL3A in HepG2 cells and primary human hepatocytes. Electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated binding of PXR to the previously identified liver X receptor (LXR)-binding DR4 motif as well as to an adjacent ER8 motif in intron 1 of SMPDL3A. Constitutive binding of the unliganded receptor to the intron 1 chromatin indicated ligand-independent repression of SMPDL3A by PXR. Transient transfection and reporter gene analysis confirmed the specific role of these motifs in PXR- and LXR-dependent activation of the SMPDL3A intronic enhancer. PXR inhibited LXR mainly by competition for binding sites. In conclusion, this study describes that a decrease in PXR expression levels and ligand-dependent activation of PXR and LXR increase hepatic SMPDL3A levels, which possibly connects these receptors to hepatic purinergic signaling and phospholipid metabolism and may result in drug-drug interactions with phosphoramidate pro-drugs.

Authors: J. Jeske, A. Bitter, W. E. Thasler, T. S. Weiss, M. Schwab, O. Burk

Date Published: 18th Apr 2017

Publication Type: Not specified

Towards knowledge-driven cross-species extrapolation

Abstract

Not specified

Authors: Christoph Thiel, Ute Hofmann, Ahmed Ghallab, Rolf Gebhardt, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Apr 2017

Publication Type: Not specified

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