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377 Publications visible to you, out of a total of 377

Abstract (Expand)

IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach. Here we present a mathematical model of IL-6-induced JAK1-STAT3 signaling that quantitatively links physiological IL-6 concentrations to the dynamics of IL-6-induced signal transduction and expression of target genes in hepatocytes. The mathematical model consists of coupled ordinary differential equations (ODE) and the model parameters were estimated by a maximum likelihood approach, whereas identifiability of the dynamic model parameters was ensured by the Profile Likelihood. Using model simulations coupled with experimental validation we could optimize the long-term impact of the JAK-inhibitor Ruxolitinib, a therapeutic compound that is quickly metabolized. Model-predicted doses and timing of treatments helps to improve the reduction of inflammatory APP gene expression in primary mouse hepatocytes close to levels observed during regenerative conditions. The concept of improved efficacy of the inhibitor through multiple treatments at optimized time intervals was confirmed in primary human hepatocytes. Thus, combining quantitative data generation with mathematical modeling suggests that repetitive treatment with Ruxolitinib is required to effectively target excessive inflammatory responses without exceeding doses recommended by the clinical guidelines.

Authors: S. Sobotta, A. Raue, X. Huang, J. Vanlier, A. Junger, S. Bohl, U. Albrecht, M. J. Hahnel, S. Wolf, N. S. Mueller, L. A. D'Alessandro, S. Mueller-Bohl, M. E. Boehm, P. Lucarelli, S. Bonefas, G. Damm, D. Seehofer, W. D. Lehmann, S. Rose-John, F. van der Hoeven, N. Gretz, F. J. Theis, C. Ehlting, J. G. Bode, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 9th Oct 2017

Publication Type: Not specified

Abstract

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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

Abstract (Expand)

PURPOSE: To measure normal renal stiffness in adults, taking into account regional variation, hydration, and urinary status. METHODS: Thirty-six healthy volunteers were examined by tomoelastography based on MR elastography at four frequencies, from 40 to 70 Hz and multifrequency shear wave speed recovery. Regional wave speeds were derived for the medulla, cortex (inner cortex and outer cortex), and renal pelvis, and examined for age-related effects. Subgroups were repeatedly examined for reproducibility, amount of prior water drinking, and urinary status. Variations in renal perfusion were simulated ex vivo using a porcine kidney subjected to venous water inflow at different pressures. RESULTS: Shear wave speed (stiffness) of renal parenchyma was 2.46 +/- 0.12 m/s (inner cortex: 2.91 +/- 0.17 m/s; outer cortex: 2.52 +/- 0.11 m/s; medulla: 2.15 +/- 0.08 m/s) without side differences and a tendency toward softening with age (P = 0.028). Corresponding intraclass correlation for reproducibility coefficients were 0.78 (inner cortex: 0.80; outer cortex: 0.81; medulla: 0.80). Water drinking resulted in slightly higher values in inner cortex and lower values in medulla (both P = 0.039), which was consistent with the results in perfused specimens. A full bladder led to higher renal pelvis stiffness (P = 0.004), whereas renal parenchyma remained uninfluenced. Stiffness of the porcine renal cortex increased with venous inflow pressure, whereas medulla stiffness decreased. CONCLUSIONS: Tomoelastography provides full field of view maps of renal stiffness with highly detailed resolution and sensitivity to physiological effects related to age and fluid-solid tissue interactions. These basic data could be used to compare pathological conditions in the future. Magn Reson Med, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine.

Authors: S. R. Marticorena Garcia, M. Grossmann, S. T. Lang, H. Tzschatzsch, F. Dittmann, B. Hamm, J. Braun, J. Guo, I. Sack

Date Published: 30th Aug 2017

Publication Type: Not specified

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

Abstract (Expand)

AIM: To apply an innovative LC-MS/MS method to quantify thiopurine metabolites in human hepatocytes and to associate them to cytotoxicity. METHODS: Immortalized human hepatocytes (IHH cells) were treated for 48 and 96 h, with 1.4 x 10(-4) M azathioprine and 1.1 x 10(-3) M mercaptopurine, concentrations corresponding to the IC50 values calculated after 96 h exposure in previous cytotoxicity analysis. After treatments, cells were collected for LC-MS/MS analysis to quantify 11 thiopurine metabolites with different level of phosphorylation and viable cells were counted by trypan blue exclusion assay to determine thiopurines in vitro effect on cell growth and survival. Statistical significance was determined by analysis of variance (ANOVA). RESULTS: Azathioprine and mercaptopurine had a significant time-dependent cytotoxic effect (p-value ANOVA = 0.012), with a viable cell count compared to controls of 55.5% and 67.5% respectively after 48 h and 23.7% and 36.1% after 96 h; no significant difference could be observed between the two drugs. Quantification of thiopurine metabolites evidenced that the most abundant metabolite was TIMP, representing 57.1% and 40.3% of total metabolites after 48 and 96 h. Total thiopurine metabolites absolute concentrations decreased over time: total mean content decreased from 469.9 pmol/million cells to 83.6 pmol/million cells (p-value ANOVA = 0.0070). However, considering the relative amount of thiopurine metabolites, TGMP content significantly increased from 11.4% cells to 26.4% (p-value ANOVA = 0.017). A significant association between thiopurine effects and viable cell counts could be detected only for MeTIMP: lower MeTIMP concentrations were associated with lower cell survival (p-value ANOVA = 0.011). Moreover, the ratio between MeTIMP and TGMP metabolites directly correlated with cell survival (p-value ANOVA = 0.037). CONCLUSION: Detailed quantification of thiopurine metabolites in a human hepatocytes model provided useful insights on the association between thioguanine and methyl-thioinosine nucleotides with cell viability.

Authors: M. Pelin, E. Genova, L. Fusco, M. Marisat, U. Hofmann, D. Favretto, M. Lucafo, A. Taddio, S. Martelossi, A. Ventura, G. Stocco, M. Schwab, G. Decorti

Date Published: 12th Aug 2017

Publication Type: Not specified

Abstract (Expand)

The liver responds to elevated plasma concentrations of free fatty acids (FFAs) with an enhanced uptake of FFAs and their esterification to triacylglycerol (TAG). On the long term, this may result in massive hepatic TAG accumulation called steatosis hepatitis. In hepatocytes, the poor water-soluble TAG is packed in specialized organelles: Lipid droplets (LDs) serving as transient cellular deposit and lipoproteins (LPs) transporting TAG and cholesterol esters to extra-hepatic tissues. The dynamics of these organelles is controlled by a variety of regulatory surface proteins (RSPs). Assembly and export of VLDLs are mainly regulated by the microsomal transfer protein (MTP) and apoprotein B100. Formation and lipolysis of LDs are regulated by several RSPs. The best studied regulators belong to the PAT (Perilipin/Adipophilin/TIP47) and CIDE families. Knockdown or overexpression of SRPs may significantly affect the total number and size distribution of LDs. Intriguingly, a large cell-to-cell heterogeneity with respect to the number and size of LDs has been found in various cell types including hepatocytes. These findings suggest that the extent of cellular lipid accumulation is determined not only by the imbalance between lipid supply and utilization but also by variations in the expression of RSPs and metabolic enzymes. To better understand the relative regulatory impact of individual processes involved in the cellular TAG turnover, we developed a comprehensive kinetic model encompassing the pathways of the fatty acid and triglyceride metabolism and the main molecular processes governing the dynamics of LDs. The model was parametrized such that a large number of experimental in vitro and in vivo findings are correctly recapitulated. A control analysis of the model revealed that variations in the activity of FFA uptake, diacylglycerol acyltransferase (DGAT) 2, and adipose triglyceride lipase (ATGL) have the strongest influence on the cellular TAG level. We used the model to simulate LD size distributions in human hepatoma cells and hepatocytes exposed to a challenge with FFAs. A random fold change by a factor of about two in the activity of RSPs was sufficient to reproduce the large diversity of droplet size distributions observed in individual cells. Under the premise that the same extent of variability of RSPs holds for the intact organ, our model predicts variations in the TAG content of individual hepatocytes by a factor of about 3-6 depending on the nutritional regime. Taken together, our modeling approach integrates numerous experimental findings on individual processes in the cellular TAG metabolism and LD dynamics metabolism to a consistent state-of-the-art dynamic network model that can be used to study how changes in the external conditions or systemic parameters will affect the TAG content of hepatocytes.

Authors: C. Wallstab, D. Eleftheriadou, T. Schulz, G. Damm, D. Seehofer, J. Borlak, H. G. Holzhutter, N. Berndt

Date Published: 2nd Aug 2017

Publication Type: Not specified

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

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

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

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

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

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

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

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

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

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