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34 Publications visible to you, out of a total of 34
Impact of Viscosity on Human Hepatoma Spheroids in Soft Core–Shell Microcapsules

Abstract (Expand)

Abstract The extracellular environment regulates the structures and functions of cells, from the molecular to the tissue level. However, the underlying mechanisms influencing the organization and …ncing the organization and adaptation of cancer in three‐dimensional (3D) environments are not yet fully understood. In this study, the influence of the viscosity of the environment is investigated on the mechanical adaptability of human hepatoma cell (HepG2) spheroids in vitro, using 3D microcapsule reactors formed with droplet‐based microfluidics. To mimic the environment with different mechanical properties, HepG2 cells are encapsulated in alginate core–shell reservoirs (i.e., microcapsules) with different core viscosities tuned by incorporating carboxymethylcellulose. The significant changes in cell and spheroid distribution, proliferation, and cytoskeleton are observed and quantified. Importantly, changes in the expression and distribution of F‐actin and keratin 8 indicate the relation between spheroid stiffness and viscosity of the surrounding medium. The increase of F‐actin levels in the viscous medium can indicate an enhanced ability of tumor cells to traverse dense tissue. These results demonstrate the ability of cancer cells to dynamically adapt to the changes in extracellular viscosity, which is an important physical cue regulating tumor development, and thus of relevance in cancer biology.

Authors: Xuan Peng, Željko Janićijević, Sandy Lemm, Sandra Hauser, Michael Knobel, Jens Pietzsch, Michael Bachmann, Larysa Baraban

Date Published: 25th Jan 2024

Publication Type: Journal

FitMultiCell: simulating and parameterizing computational models of multi-scale and multi-cellular processes.

Abstract (Expand)

MOTIVATION: Biological tissues are dynamic and highly organized. Multi-scale models are helpful tools to analyse and understand the processes determining tissue dynamics. These models usually depend … on parameters that need to be inferred from experimental data to achieve a quantitative understanding, to predict the response to perturbations, and to evaluate competing hypotheses. However, even advanced inference approaches such as approximate Bayesian computation (ABC) are difficult to apply due to the computational complexity of the simulation of multi-scale models. Thus, there is a need for a scalable pipeline for modeling, simulating, and parameterizing multi-scale models of multi-cellular processes. RESULTS: Here, we present FitMultiCell, a computationally efficient and user-friendly open-source pipeline that can handle the full workflow of modeling, simulating, and parameterizing for multi-scale models of multi-cellular processes. The pipeline is modular and integrates the modeling and simulation tool Morpheus and the statistical inference tool pyABC. The easy integration of high-performance infrastructure allows to scale to computationally expensive problems. The introduction of a novel standard for the formulation of parameter inference problems for multi-scale models additionally ensures reproducibility and reusability. By applying the pipeline to multiple biological problems, we demonstrate its broad applicability, which will benefit in particular image-based systems biology. AVAILABILITY AND IMPLEMENTATION: FitMultiCell is available open-source at https://gitlab.com/fitmulticell/fit.

Authors: E. Alamoudi, Y. Schalte, R. Muller, J. Starruss, N. Bundgaard, F. Graw, L. Brusch, J. Hasenauer

Date Published: 1st Nov 2023

Publication Type: Journal

Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging

Abstract (Expand)

Abstract The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular …asts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure‐activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.

Authors: Reik Löser, Manuela Kuchar, Robert Wodtke, Christin Neuber, Birgit Belter, Klaus Kopka, Lakshmi Santhanam, Jens Pietzsch

Date Published: 15th Sep 2023

Publication Type: Journal

Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation—Relevance to Thrombosis

Abstract (Expand)

Cancer patients are at a very high risk of serious thrombotic events, often fatal. The causes discussed include the detachment of thrombogenic particles from tumor cells or the adverse effects of …rse effects of chemotherapeutic agents. Cytostatic agents can either act directly on their targets or, in the case of a prodrug approach, require metabolization for their action. Cyclophosphamide (CPA) is a widely used cytostatic drug that requires prodrug activation by cytochrome P450 enzymes (CYP) in the liver. We hypothesize that CPA could induce thrombosis in one of the following ways: (1) damage to endothelial cells (EC) after intra-endothelial metabolization; or (2) direct damage to EC without prior metabolization. In order to investigate this hypothesis, endothelial cells (HUVEC) were treated with CPA in clinically relevant concentrations for up to 8 days. HUVECs were chosen as a model representing the first place of action after intravenous CPA administration. No expression of CYP2B6, CYP3A4, CYP2C9 and CYP2C19 was found in HUVEC, but a weak expression of CYP2C18 was observed. CPA treatment of HUVEC induced DNA damage and a reduced formation of an EC monolayer and caused an increased release of prostacyclin (PGI2) and thromboxane (TXA) associated with a shift of the PGI2/TXA balance to a prothrombotic state. In an in vivo scenario, such processes would promote the risk of thrombus formation.

Authors: Anne Krüger-Genge, Susanne Köhler, Markus Laube, Vanessa Haileka, Sandy Lemm, Karolina Majchrzak, Sarah Kammerer, Christian Schulz, Joachim Storsberg, Jens Pietzsch, Jan-Heiner Küpper, Friedrich Jung

Date Published: 1st Aug 2023

Publication Type: Journal

Myostatin is associated with the presence and development of acute-on-chronic liver failure

Abstract

Not specified

Authors: Astrid Ruiz-Margáin, Alessandra Pohlmann, Silke Lanzerath, Melanie Langheinrich, Alejandro Campos-Murguía, Berenice M. Román-Calleja, Robert Schierwagen, Sabine Klein, Frank Erhard Uschner, Maximilian Joseph Brol, Aldo Torre-Delgadillo, Nayelli C. Flores-García, Michael Praktiknjo, Ricardo U. Macías Rodríguez, Jonel Trebicka

Date Published: 1st Aug 2023

Publication Type: Journal

An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Abstract

Not specified

Authors: Frank Tacke, Tobias Puengel, Rohit Loomba, Scott L. Friedman

Date Published: 1st Aug 2023

Publication Type: Journal

Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

Abstract (Expand)

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic … development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Authors: C. Mayer, S. Nehring, M. Kucken, U. Repnik, S. Seifert, A. Sljukic, J. Delpierre, H. Morales-Navarrete, S. Hinz, M. Brosch, B. Chung, T. Karlsen, M. Huch, Y. Kalaidzidis, L. Brusch, J. Hampe, C. Schafmayer, M. Zerial

Date Published: 31st Jul 2023

Publication Type: Journal

To TIPS or Not to TIPS in High Risk of Variceal Rebleeding and Acute-on-Chronic Liver Failure.

Abstract (Expand)

Variceal bleeding is a consequence of severe portal hypertension in patients with liver cirrhosis. Although the rate of bleeding has decreased over time, variceal bleeding in the presence of acute-on-chronic … liver failure (ACLF) carries a high risk of treatment failure and short-term mortality. Treatment and/or removal of precipitating events (mainly bacterial infection and alcoholic hepatitis) and decrease of portal pressure may improve outcome of patients with acute decompensation or ACLF. Transjugular intrahepatic portosystemic shunts (TIPSs), especially in the preemptive situation, have been found to efficiently control bleeding, prevent rebleeding, and reduce short-term mortality. Therefore, TIPS placement should be considered as an option in the management of ACLF patients with variceal bleeding.

Authors: W. Gu, M. Kimmann, W. Laleman, M. Praktiknjo, J. Trebicka

Date Published: 17th Jul 2023

Publication Type: Journal

Endoscopic Advances in Hepatology.

Abstract (Expand)

Endoscopy is and remains an indispensable tool in diagnosing and managing liver disease and its complications. Due to the progress in advanced endoscopy, endoscopy has become an alternative route for … many surgical, percutaneous, and angiographic interventions, not only as a backup tool when conventional interventions fail but increasingly as a first-line choice. The term endo-hepatology refers to the integration of advanced endoscopy in the practice of hepatology. Endoscopy is key in the diagnosis and management of esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia. Endoscopic ultrasound (EUS) can be used for the evaluation of the liver parenchyma, liver lesions, and surrounding tissues and vessels, including targeted biopsy and complemented with new software functions. Moreover, EUS can guide portal pressure gradient measurement, and assess and help manage complications of portal hypertension. It is crucial that each present-day hepatologist is aware of the (rapidly increasing) full spectrum of diagnostic and therapeutic tools that exist within this field. In this comprehensive review, we would like to discuss the current endo-hepatology spectrum, as well as future directions for endoscopy in hepatology.

Authors: E. Vanderschueren, J. Trebicka, W. Laleman

Date Published: 17th Jul 2023

Publication Type: Journal

Hepatic inflammatory responses in liver fibrosis.

Abstract (Expand)

Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines … long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.

Authors: L. Hammerich, F. Tacke

Date Published: 3rd Jul 2023

Publication Type: Journal

Acute-On-Chronic Liver Failure: Current Interventional Treatment Options and Future Challenges.

Abstract (Expand)

Acute-on-chronic liver failure (ACLF) is a frequent complication in patients with liver cirrhosis that has high short-term mortality. It is characterized by acute decompensation (AD) of liver cirrhosis, … intra- and extrahepatic organ failure, and severe systemic inflammation (SI). In the recent past, several studies have investigated the management of this group of patients. Identification and treatment of precipitants of decompensation and ACLF play an important role, and management of the respective intra- and extrahepatic organ failures is essential. However, no specific treatment for ACLF has been established to date, and the only curative treatment option currently available for these patients is liver transplantation (LT). It has been shown that ACLF patients are at severe risk of waitlist mortality, and post-LT survival rates are high, making ACLF patients suitable candidates for LT. However, only a limited number of patients are eligible for LT due to related contraindications such as uncontrolled infections. In this case, bridging strategies (e.g., extracorporeal organ support systems) are required. Further therapeutic approaches have recently been developed and evaluated. Thus, this review focuses on current management and potential future treatment options.

Authors: M. Kimmann, J. Trebicka

Date Published: 26th Jun 2023

Publication Type: Journal

Efruxifermin, an investigational treatment for fibrotic or cirrhotic nonalcoholic steatohepatitis (NASH)

Abstract

Not specified

Authors: Tobias Puengel, Frank Tacke

Date Published: 3rd Jun 2023

Publication Type: Journal

Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs

Abstract (Expand)

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic …nd hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.

Authors: Sebastian Braun, Sanja Jelača, Markus Laube, Sven George, Bettina Hofmann, Peter Lönnecke, Dieter Steinhilber, Jens Pietzsch, Sanja Mijatović, Danijela Maksimović-Ivanić, Evamarie Hey-Hawkins

Date Published: 1st Jun 2023

Publication Type: Journal

Isonimesulide and Its Carborane Analogues as Isoform‐Selective COX Inhibitors and Antitumor Agents

Abstract (Expand)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutics against pain, fever, and inflammation; additionally, antitumor properties are reported. NSAIDs reduce the synthesis … of prostaglandins by inhibiting the cyclooxygenase (COX) isoforms COX-1 and COX-2. As nonselective inhibition is associated with off-target effects, strategies to achieve selectivity for the clinically preferred isoform COX-2 are of high interest. The modification of NSAIDs using carborane clusters as phenyl mimetics is reported to alter the selectivity profile through size exclusion. Inspired by these findings, isonimesulide and its carborane derivatives are prepared. The biological screening shows that the carborane containing compounds exhibit a stronger antitumor potential compared to nimesulide and isonimesulide. Furthermore, the replacement of the phenyl ring of isonimesulide with a carborane moiety resulted in a shift of the COX activity from nonactive to COX-active compounds.

Authors: Liridona Useini, Teodora Komazec, Markus Laube, Peter Lönnecke, Jonas Schädlich, Sanja Mijatović, Danijela Maksimović‐Ivanić, Jens Pietzsch, Evamarie Hey‐Hawkins

Date Published: 24th May 2023

Publication Type: Journal

Carborane‐Based Tebufelone Analogs and Their Biological Evaluation In Vitro

Abstract (Expand)

The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory … mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activity in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the observed antiproliferative effect of the para-carborane analogs of tebufelone is enhanced by structural modifications that include chain elongation in combination with introduction of a methylene spacer resulting in higher anticancer activity compared to tebufelone. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.

Authors: Sebastian Braun, Svetlana Paskaš, Markus Laube, Sven George, Bettina Hofmann, Peter Lönnecke, Dieter Steinhilber, Jens Pietzsch, Sanja Mijatović, Danijela Maksimović‐Ivanić, Evamarie Hey‐Hawkins

Date Published: 24th May 2023

Publication Type: Journal

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