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69 Publications visible to you, out of a total of 69
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

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study

Abstract

Not specified

Authors: Miquel Serra-Burriel, Adrià Juanola, Feliu Serra-Burriel, Maja Thiele, Isabel Graupera, Elisa Pose, Guillem Pera, Ivica Grgurevic, Llorenç Caballeria, Salvatore Piano, Laurens van Kleef, Mathias Reichert, Dominique Roulot, Juan M Pericàs, Jörn M Schattenberg, Emmanuel A Tsochatztis, Indra Neil Guha, Montserrat Garcia-Retortillo, Rosario Hernández, Jordi Hoyo, Matilde Fuentes, Carmen Expósito, Alba Martínez, Patricia Such, Anita Madir, Sönke Detlefsen, Marta Tonon, Andrea Martini, Ann T Ma, Judith Pich, Eva Bonfill, Marta Juan, Anna Soria, Marta Carol, Jordi Gratacós-Ginès, Rosa M Morillas, Pere Toran, J M Navarrete, Antoni Torrejón, Céline Fournier, Anne Llorca, Anita Arslanow, Harry J de Koning, Fernando Cucchietti, Michael Manns, Phillip N Newsome, Rubén Hernáez, Alina Allen, Paolo Angeli, Robert J de Knegt, Tom H Karlsen, Peter Galle, Vincent Wai-Sun Wong, Núria Fabrellas, Laurent Castera, Aleksander Krag, Frank Lammert, Patrick S Kamath, Pere Ginès, Marifé Alvarez, Peter Andersen, Paolo Angeli, Alba Ardèvol, Anita Arslanow, Luca Beggiato, Zahia Ben Abdesselam, Lucy Bennett, Bajiha Boutouria, Alessandra Brocca, M. Teresa Broquetas, Llorenç Caballeria, Valeria Calvino, Judith Camacho, Aura Capdevila, Marta Carol, Laurent Castera, Marta Cervera, Fernando Cucchietti, Anna de Fuentes, Rob de Knegt, Harry J de Koning, Sonke Detlefsen, Alba Diaz, José Diéguez Bande, Vanessa Esnault, Núria Fabrellas, Josep Lluis Falcó, Rosa Fernández, Céline Fournier, Matilde Fuentes, Peter Galle, Edgar García, Montserrat García-Retortillo, Esther Garrido, Pere Ginès, Rosa Gordillo Medina, Jordi Gratacós-Ginès, Isabel Graupera, Ivica Grgurevic, Indra Neil Guha, Eva Guix, Johanne Kragh Hansen, Rebecca Harris, Elena Hernández Boluda, Rosario Hernández-Ibañez, Jordi Hoyo, Arfan Ikram, Simone Incicco, Mads Israelsen, Marta Juan, Adrià Juanola, Ralf Kaiser, Patrick S Kamath, Tom H Karlsen, Maria Kjærgaard, Marko Korenjak, Aleksander Krag, Marcin Krawczyk, Philippe Laboulaye, Irina Lambert, Frank Lammert, Simon Langkjær Sørensen, Cristina Laserna-Jiménez, Sonia Lazaro Pi, Elsa Ledain, Vincent Levy, Katrine Prier Lindvig, Anne Llorca, Vanessa Londoño, Guirec Loyer, Ann T. Ma, Anita Madir, Michael Manns, Denise Marshall, M. Lluïsa Martí, Sara Martínez, Ricard Martínez Sala, Roser Masa-Font, Jane Møller Jensen, Rosa M Morillas, Laura Muñoz, Ruth Nadal, Laura Napoleone, JM Navarrete, Phillip N Newsome, Vibeke Nielsen, Martina Pérez, Juan Manuel Pericás-Pulido, Salvatore Piano, Judit Pich, Elisa Pose, Judit Presas Escobet, Matthias Reichert, Carlota Riba, Dominique Roulot, Ana Belén Rubio, Maria Sánchez-Morata, Jörn Schattenberg, Miquel Serra-Burriel, Feliu Serra-Burriel, Louise Skovborg Just, Milan Sonneveld, Anna Soria, Christiane Stern, Patricia Such, Maja Thiele, Marta Tonon, Pere Toran, Antoni Torrejón, Emmanuel A Tsochatzis, Laurens van Kleef, Paulien van Wijngaarden, Vanessa Velázquez, Ana Viu, Susanne Nicole Weber, Tracey Wildsmith

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

Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease (preprint)

Abstract (Expand)

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, Non-alcoholic fatty liver disease (NAFLD) is gaining importance as the … disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Authors: Sebastian Burbano De Lara, Svenja Kemmer, Ina Biermayer, Svenja Feiler, Artyom Vlasov, Lorenza D'Alessandro, Barbara Helm, Yannik Dieter, Ahmed Ghallab, Jan Hengstler, Professor Dr. med. Katrin Hoffmann, Marcel Schilling, Jens Timmer, Ursula Klingmüller

Date Published: 4th 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

Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation

Abstract (Expand)

Abstract The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms …rition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis induced by repeated CCl 4 injections in mice ( n  = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development—initiation, progression, and tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. Public data analysis shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression.

Authors: Seddik Hammad, Christoph Ogris, Amnah Othman, Pia Erdoesi, Wolfgang Schmidt-Heck, Ina Biermayer, Barbara Helm, Yan Gao, Weronika Piorońska, Christian H. Holland, Lorenza A. D’Alessandro, Carolina de la Torre, Carsten Sticht, Sherin Al Aoua, Fabian J. Theis, Heike Bantel, Matthias P. Ebert, Ursula Klingmüller, Jan G. Hengstler, Steven Dooley, Nikola S. Mueller

Date Published: 1st Jul 2023

Publication Type: Journal

Sublethal necroptosis signaling promotes inflammation and liver cancer

Abstract

Not specified

Authors: Mihael Vucur, Ahmed Ghallab, Anne T. Schneider, Arlind Adili, Mingbo Cheng, Mirco Castoldi, Michael T. Singer, Veronika Büttner, Leonie S. Keysberg, Lena Küsgens, Marlene Kohlhepp, Boris Görg, Suchira Gallage, Jose Efren Barragan Avila, Kristian Unger, Claus Kordes, Anne-Laure Leblond, Wiebke Albrecht, Sven H. Loosen, Carolin Lohr, Markus S. Jördens, Anne Babler, Sikander Hayat, David Schumacher, Maria T. Koenen, Olivier Govaere, Mark V. Boekschoten, Simone Jörs, Carlos Villacorta-Martin, Vincenzo Mazzaferro, Josep M. Llovet, Ralf Weiskirchen, Jakob N. Kather, Patrick Starlinger, Michael Trauner, Mark Luedde, Lara R. Heij, Ulf P. Neumann, Verena Keitel, Johannes G. Bode, Rebekka K. Schneider, Frank Tacke, Bodo Levkau, Twan Lammers, Georg Fluegen, Theodore Alexandrov, Amy L. Collins, Glyn Nelson, Fiona Oakley, Derek A. Mann, Christoph Roderburg, Thomas Longerich, Achim Weber, Augusto Villanueva, Andre L. Samson, James M. Murphy, Rafael Kramann, Fabian Geisler, Ivan G. Costa, Jan G. Hengstler, Mathias Heikenwalder, Tom Luedde

Date Published: 1st Jul 2023

Publication Type: Journal

Gene regulatory network inference in the era of single-cell multi-omics.

Abstract (Expand)

The interplay between chromatin, transcription factors and genes generates complex regulatory circuits that can be represented as gene regulatory networks (GRNs). The study of GRNs is useful to understand … how cellular identity is established, maintained and disrupted in disease. GRNs can be inferred from experimental data - historically, bulk omics data - and/or from the literature. The advent of single-cell multi-omics technologies has led to the development of novel computational methods that leverage genomic, transcriptomic and chromatin accessibility information to infer GRNs at an unprecedented resolution. Here, we review the key principles of inferring GRNs that encompass transcription factor-gene interactions from transcriptomics and chromatin accessibility data. We focus on the comparison and classification of methods that use single-cell multimodal data. We highlight challenges in GRN inference, in particular with respect to benchmarking, and potential further developments using additional data modalities.

Authors: P. Badia-I-Mompel, L. Wessels, S. Muller-Dott, R. Trimbour, R. O. Ramirez Flores, R. Argelaguet, J. Saez-Rodriguez

Date Published: 26th Jun 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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