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313 Publications visible to you, out of a total of 313
Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
DEEP-HCC network

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
DEEP-HCC network

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

Hepatocyte apical bulkheads provide a mechanical means to oppose bile pressure
Forschungsnetzwerk LiSyM-Krebs, DEEP-HCC network

Abstract (Expand)

Hepatocytes grow their apical surfaces anisotropically to generate a 3D network of bile canaliculi (BC). BC elongation is ensured by apical bulkheads, membrane extensions that traverse the lumen and … the lumen and connect juxtaposed hepatocytes. We hypothesize that apical bulkheads are mechanical elements that shape the BC lumen in liver development but also counteract elevated biliary pressure. Here, by resolving their structure using STED microscopy, we found that they are sealed by tight junction loops, connected by adherens junctions, and contain contractile actomyosin, characteristics of mechanical function. Apical bulkheads persist at high pressure upon microinjection of fluid into the BC lumen, and laser ablation demonstrated that they are under tension. A mechanical model based on ablation results revealed that apical bulkheads double the pressure BC can hold. Apical bulkhead frequency anticorrelates with BC connectivity during mouse liver development, consistent with predicted changes in biliary pressure. Our findings demonstrate that apical bulkheads are load-bearing mechanical elements that could protect the BC network against elevated pressure.

Authors: Maarten P. Bebelman, Matthew J. Bovyn, Carlotta M. Mayer, Julien Delpierre, Ronald Naumann, Nuno P. Martins, Alf Honigmann, Yannis Kalaidzidis, Pierre A. Haas, Marino Zerial

Date Published: 3rd Apr 2023

Publication Type: Journal

Shell engineering in soft alginate‐based capsules for culturing liver spheroids
DEEP-HCC network

Abstract (Expand)

Functional interaction between cancer cells and the surrounding microenvironment is still not sufficiently understood, which motivates the tremendous interest for the development of numerous in vitro … tumor models. Diverse parameters, for example, transport of nutrients and metabolites, availability of space in the confinement, etc. make an impact on the size, shape, and metabolism of the tumoroids. We demonstrate the fluidics-based low-cost methodology to reproducibly generate the alginate and alginate-chitosan microcapsules and apply it to grow human hepatoma (HepG2) spheroids of different dimensions and geometries. Focusing specifically on the composition and thickness of the hydrogel shell, permeability of the microcapsules was selectively tuned. The diffusion of the selected benchmark molecules through the shell has been systematically investigated using both, experiments and simulations, which is essential to ensure efficient mass transfer and/or filtering of the biochemical species. Metabolic activity of spheroids in microcapsules was confirmed by tracking the turnover of testosterone to androstenedione with chromatography studies in a metabolic assay. Depending on available space, phenotypically different 3D cell assemblies have been observed inside the capsules, varying in the tightness of cell aggregations and their shapes. Conclusively, we believe that our system with the facile tuning of the shell thickness and permeability, represents a promising platform for studying the formation of cancer spheroids and their functional interaction with the surrounding microenvironment.

Authors: Xuan Peng, Željko Janićijević, Sandy Lemm, Markus Laube, Jens Pietzsch, Michael Bachmann, Larysa Baraban

Date Published: 27th Mar 2023

Publication Type: Journal

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors
Forschungsnetzwerk LiSyM-Krebs, DEEP-HCC network

Abstract (Expand)

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, … we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.

Authors: Luisa M. Bachmann, Maria Hanl, Felix Feller, Laura Sinatra, Andrea Schöler, Jens Pietzsch, Markus Laube, Finn K. Hansen

Date Published: 1st Feb 2023

Publication Type: Journal

MSPypeline: a python package for streamlined data analysis of mass spectrometry-based proteomics.
LiSyM network, Forschungsnetzwerk LiSyM-Krebs, SMART-NAFLD, C-TIP-HCC network

Abstract (Expand)

SUMMARY: Mass spectrometry-based proteomics is increasingly employed in biology and medicine. To generate reliable information from large datasets and ensure comparability of results, it is crucial to … implement and standardize the quality control of the raw data, the data processing steps and the statistical analyses. MSPypeline provides a platform for importing MaxQuant output tables, generating quality control reports, data preprocessing including normalization and performing exploratory analyses by statistical inference plots. These standardized steps assess data quality, provide customizable figures and enable the identification of differentially expressed proteins to reach biologically relevant conclusions. AVAILABILITY AND IMPLEMENTATION: The source code is available under the MIT license at https://github.com/siheming/mspypeline with documentation at https://mspypeline.readthedocs.io. Benchmark mass spectrometry data are available on ProteomeXchange (PXD025792). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Advances online.

Authors: S. Heming, P. Hansen, A. Vlasov, F. Schworer, S. Schaumann, P. Frolovaite, W. D. Lehmann, J. Timmer, M. Schilling, B. Helm, U. Klingmuller

Date Published: 26th Jan 2023

Publication Type: Journal

Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-Matrigel matrices.
SMART-NAFLD

Abstract (Expand)

Loss of differentiation of primary human hepatocytes (PHHs) ex vivo is a known problem of in vitro liver models. Culture optimizations using collagen type I and Matrigel reduce the dedifferentiation … process but are not able to prevent it. While neither of these extracellular matrices (ECMs) on their own correspond to the authentic hepatic ECM, a combination of them could more closely resemble the in vivo situation. Our study aimed to systematically analyze the influence of mixed matrices composed of collagen type I and Matrigel on the maintenance and reestablishment of hepatic functions. Therefore, PHHs were cultured on mixed collagen-Matrigel matrices in monolayer and sandwich cultures and viability, metabolic capacity, differentiation markers, cellular arrangement and the cells' ability to repolarize and form functional bile canaliculi were assessed by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), functional assays and immunofluorescence microscopy. Our results show that mixed matrices were superior to pure matrices in maintaining metabolic capacity and hepatic differentiation. In contrast, Matrigel supplementation can impair the development of a proper hepatocytic polarization. Our systematic study helps to compose an optimized ECM to maintain and reestablish hepatic differentiation on cellular and multicellular levels in human liver models.

Authors: L. Seidemann, S. Prinz, J. C. Scherbel, C. Gotz, D. Seehofer, G. Damm

Date Published: 20th Jan 2023

Publication Type: Journal

Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Abstract

Not specified

Authors: Stefan Hoehme, Seddik Hammad, Jan Boettger, Brigitte Begher-Tibbe, Petru Bucur, Eric Vibert, Rolf Gebhardt, Jan G. Hengstler, Dirk Drasdo

Date Published: 2023

Publication Type: Journal

Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Abstract

Not specified

Authors: Le Tao, Guangyue Yang, Tiantian Sun, Jie Tao, Chan Zhu, Huimin Yu, Yalan Cheng, Zongguo Yang, Mingyi Xu, Yuefeng Jiang, Wei Zhang, Zhiyi Wang, Wenting Ma, Liu Wu, Dongying Xue, Dongxue Wang, Wentao Yang, Yongjuan Zhao, Shane Horsefield, Bostjan Kobe, Zhe Zhang, Zongxiang Tang, Qigen Li, Qiwei Zhai, Steven Dooley, Ekihiro Seki, Ping Liu, Jianrong Xu, Hongzhuan Chen, Cheng Liu

Date Published: 2023

Publication Type: Journal

A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM-Krebs Partnering

Abstract

Not specified

Authors: Rilu Feng, Kejia Kan, Carsten Sticht, Yujia Li, Shanshan Wang, Hui Liu, Chen Shao, Stefan Munker, Hanno Niess, Sai Wang, Christoph Meyer, Roman Liebe, Matthias P. Ebert, Steven Dooley, Huiguo Ding, Honglei Weng

Date Published: 1st Dec 2022

Publication Type: Journal

Guided interactive image segmentation using machine learning and color-based image set clustering.
LiSyM network, Forschungsnetzwerk LiSyM-Krebs, SMART-NAFLD, C-TIP-HCC network

Abstract (Expand)

MOTIVATION: Over the last decades, image processing and analysis have become one of the key technologies in systems biology and medicine. The quantification of anatomical structures and dynamic processes … in living systems is essential for understanding the complex underlying mechanisms and allows, i.e. the construction of spatio-temporal models that illuminate the interplay between architecture and function. Recently, deep learning significantly improved the performance of traditional image analysis in cases where imaging techniques provide large amounts of data. However, if only a few images are available or qualified annotations are expensive to produce, the applicability of deep learning is still limited. RESULTS: We present a novel approach that combines machine learning-based interactive image segmentation using supervoxels with a clustering method for the automated identification of similarly colored images in large image sets which enables a guided reuse of interactively trained classifiers. Our approach solves the problem of deteriorated segmentation and quantification accuracy when reusing trained classifiers which is due to significant color variability prevalent and often unavoidable in biological and medical images. This increase in efficiency improves the suitability of interactive segmentation for larger image sets, enabling efficient quantification or the rapid generation of training data for deep learning with minimal effort. The presented methods are applicable for almost any image type and represent a useful tool for image analysis tasks in general. AVAILABILITY AND IMPLEMENTATION: The presented methods are implemented in our image processing software TiQuant which is freely available at tiquant.hoehme.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Authors: A. Friebel, T. Johann, D. Drasdo, S. Hoehme

Date Published: 30th Sep 2022

Publication Type: Journal

Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo.
LiSyM network, SMART-NAFLD

Abstract (Expand)

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of … Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Authors: S. Chakraborty, G. Andrieux, P. Kastl, L. Adlung, S. Altamura, M. E. Boehm, L. E. Schwarzmuller, Y. Abdullah, M. C. Wagner, B. Helm, H. J. Grone, W. D. Lehmann, M. Boerries, H. Busch, M. U. Muckenthaler, M. Schilling, U. Klingmuller

Date Published: 20th Sep 2022

Publication Type: Journal

Investigation of Radiotracer Metabolic Stability In Vitro with CYP-Overexpressing Hepatoma Cell Lines.
Forschungsnetzwerk LiSyM-Krebs, DEEP-HCC network

Abstract (Expand)

The characterization of novel radiotracers toward their metabolic stability is an essential part of their development. While in vitro methods such as liver microsome assays or ex vivo blood or tissue … samples provide information on overall stability, little or no information is obtained on cytochrome P450 (CYP) enzyme and isoform-specific contribution to the metabolic fate of individual radiotracers. Herein, we investigated recently established CYP-overexpressing hepatoblastoma cell lines (HepG2) for their suitability to study the metabolic stability of radiotracers in general and to gain insight into CYP isoform specificity. Wildtype HepG2 and CYP1A2-, CYP2C19-, and CYP3A4-overexpressing HepG2 cells were incubated with radiotracers, and metabolic turnover was analyzed. The optimized protocol, covering cell seeding in 96-well plates and analysis of supernatant by radio thin-layer-chromatography for higher throughput, was transferred to the evaluation of three (18)F-labeled celecoxib-derived cyclooxygenase-2 inhibitors (coxibs). These investigations revealed time-dependent degradation of the intact radiotracers, as well as CYP isoform- and substrate-specific differences in their metabolic profiles. HepG2 CYP2C19 proved to be the cell line showing the highest metabolic turnover for each radiotracer studied here. Comparison with human and murine liver microsome assays showed good agreement with the human metabolite profile obtained by the HepG2 cell lines. Therefore, CYP-overexpressing HepG2 cells provide a good complement for assessing the metabolic stability of radiotracers and allow the analysis of the CYP isoform-specific contribution to the overall radiotracer metabolism.

Authors: S. Lemm, S. Kohler, R. Wodtke, F. Jung, J. H. Kupper, J. Pietzsch, M. Laube

Date Published: 7th Aug 2022

Publication Type: Journal

Serum Glial Cell Line-Derived Neurotrophic Factor (sGDNF) Is a Novel Biomarker in Predicting Cirrhosis in Patients with Chronic Hepatitis B
LiSyM network

Abstract (Expand)

Objectives. We assessed the potential of glial cell line-derived neurotrophic factor (GDNF) as a useful biomarker to predict cirrhosis in chronic hepatitis B (CHB) patients. Methods. A total of 735 …nts. Methods. A total of 735 patients from two medical centers (385 CHB patients and 350 healthy controls) were included to determine the association of serum and tissue GDNF levels with biopsy-proven cirrhosis. The diagnostic accuracy of serum GDNF (sGDNF) was estimated and compared with other indices of cirrhosis. Results. We showed significantly higher levels of sGDNF in CHB patients with fibrosis (28.4 pg/ml vs. 11.6 pg/ml in patients without) and patients with cirrhosis (33.8 pg/ml vs. 23.5 pg/ml in patients without). The areas under receiver operating curve (AUROCs) of sGDNF were 0.83 (95% confidence interval (CI): 0.80–0.87) for predicting liver fibrosis and 0.84 (95% CI: 0.79–0.89) for cirrhosis. Findings from the serum protein level and hepatic mRNA expression were consistent. Using the best cutoff to predict cirrhosis, we categorized the patients into sGDNF-high and sGDNF-low groups. The sGDNF-high group had significantly larger Masson’s trichrome and reticulin staining-positive area, higher Scheuer score, and METAVIR fibrosis stage (all p < 0.001 ) but not steatosis. On multivariable regression, sGDNF was independently associated with cirrhosis with an odds ratio of 6.98 (95% CI: 1.10–17.94). Finally, we demonstrated that sGDNF outperformed AST to platelet ratio index, FIB-4, fibroscore, forn index, and fibrometer in differentiating F4 vs. F3. Conclusion. Using serum, tissue mRNA, and biopsy data, our study revealed a significant potential of sGDNF as a novel noninvasive biomarker for cirrhosis in CHB patients.

Authors: Guangyue Yang, Liping Zhuang, Tiantian Sun, Yee Hui Yeo, Le Tao, Wei Zhang, Wenting Ma, Liu Wu, Zongguo Yang, Yanqin Yang, Dongying Xue, Jie Zhang, Rilu Feng, Ebert Matthias P., Steven Dooley, Ekihiro Seki, Ping Liu, Cheng Liu

Date Published: 9th Jul 2022

Publication Type: Journal

Deciphering signal transduction networks in the liver by mechanistic mathematical modelling
LiSyM network, SMART-NAFLD

Abstract (Expand)

In health and disease, liver cells are continuously exposed to cytokines and growth factors. While individual signal transduction pathways induced by these factors were studied in great detail, the … cellular responses induced by repeated or combined stimulations are complex and less understood. Growth factor receptors on the cell surface of hepatocytes were shown to be regulated by receptor interactions, receptor trafficking and feedback regulation. Here, we exemplify how mechanistic mathematical modelling based on quantitative data can be employed to disentangle these interactions at the molecular level. Crucial is the analysis at a mechanistic level based on quantitative longitudinal data within a mathematical framework. In such multi-layered information, step-wise mathematical modelling using submodules is of advantage, which is fostered by sharing of standardized experimental data and mathematical models. Integration of signal transduction with metabolic regulation in the liver and mechanistic links to translational approaches promise to provide predictive tools for biology and personalized medicine.

Authors: Lorenza A. D’Alessandro, Ursula Klingmüller, Marcel Schilling

Date Published: 30th Jun 2022

Publication Type: Journal

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