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37 Publications visible to you, out of a total of 37
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

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

Abstract (Expand)

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs …gans responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale.

Authors: Raymond Reif, Ahmed Ghallab, Lynette Beattie, Georgia Günther, Lars Kuepfer, Paul M. Kaye, Jan G. Hengstler

Date Published: 1st Mar 2017

Publication Type: Not specified

The ascending pathophysiology of cholestatic liver disease.

Abstract (Expand)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending … course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).

Authors: P. L. Jansen, A. Ghallab, N. Vartak, R. Reif, F. G. Schaap, J. Hampe, J. G. Hengstler

Date Published: 17th Feb 2017

Publication Type: Not specified

The ascending pathophysiology of cholestatic liver disease

Abstract (Expand)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending … course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).

Authors: Peter L.M. Jansen, Ahmed Ghallab, Nachiket Vartak, Raymond Reif, Frank G. Schaap, Jochen Hampe, Jan G. Hengstler

Date Published: 1st Feb 2017

Publication Type: Not specified

Creation of Three-Dimensional Liver Tissue Models from Experimental Images for Systems Medicine.

Abstract (Expand)

In this chapter, we illustrate how three-dimensional liver tissue models can be created from experimental image modalities by utilizing a well-established processing chain of experiments, microscopic … imaging, image processing, image analysis and model construction. We describe how key features of liver tissue architecture are quantified and translated into model parameterizations, and show how a systematic iteration of experiments and model simulations often leads to a better understanding of biological phenomena in systems biology and systems medicine.

Authors: S. Hoehme, A. Friebel, S. Hammad, D. Drasdo, J. G. Hengstler

Date Published: 11th Nov 2016

Publication Type: Not specified

Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases

Abstract (Expand)

BACKGROUND & AIMS: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher …er ammonia detoxification mechanisms in the liver. METHODS: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time-resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner. RESULTS: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments, the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of cofactors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 μM) to levels close to normal within only 15 min. CONCLUSION: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.

Authors: Ahmed Ghallab, Géraldine Cellière, Sebastian G. Henkel, Dominik Driesch, Stefan Hoehme, Ute Hofmann, Sebastian Zellmer, Patricio Godoy, Agapios Sachinidis, Meinolf Blaszkewicz, Raymond Reif, Rosemarie Marchan, Lars Kuepfer, Dieter Häussinger, Dirk Drasdo, Rolf Gebhardt, Jan G. Hengstler

Date Published: 1st Apr 2016

Publication Type: Not specified

Cholestasis-induced adaptive remodeling of interlobular bile ducts.

Abstract (Expand)

UNLABELLED: Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in … rodents. To determine which changes occur in the three-dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five-fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self-joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five-fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. CONCLUSION: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching.

Authors: N. Vartak, A. Damle-Vartak, B. Richter, O. Dirsch, U. Dahmen, S. Hammad, J. G. Hengstler

Date Published: 27th Nov 2015

Publication Type: Not specified

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