Review
Biochemistry & Molecular Biology
Ji-Won Park, Jung-Hee Kim, Sung-Eun Kim, Jang Han Jung, Myoung-Kuk Jang, Sang-Hoon Park, Myung-Seok Lee, Hyoung-Su Kim, Ki Tae Suk, Dong Joon Kim
Summary: Cholangiopathies are various biliary diseases that affect the biliary epithelium and can lead to cholestasis and liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults, with research focusing on genetic risk, epigenetic changes, dysregulated mucosal immunity, and altered biliary epithelial cell function. Understanding the molecular pathogenesis of these diseases can help clinicians prevent and treat them more effectively.
Article
Medicine, Research & Experimental
Raanan Greenman, Michal Segal-Salto, Neta Barashi, Ophir Hay, Avi Katav, Omer Levi, Ilan Vaknin, Revital Aricha, Sarit Aharoni, Tom Snir, Inbal Mishalian, Devorah Olam, Johnny Amer, Ahmad Salhab, Rifaat Safadi, Yaakov Maor, Palak Trivedi, Christopher J. Weston, Francesca Saffioti, Andrew Hall, Massimo Pinzani, Douglas Thorburn, Amnon Peled, Adi Mor
Summary: CCL24 is involved in fibrosis and inflammation in liver and its inhibition can reduce liver injury. This study found that blocking CCL24 improves inflammation, fibrosis, and cholestasis in PSC, and reduces proliferation and senescence of cholangiocytes.
Article
Gastroenterology & Hepatology
Debashis Haldar, Ashnila Janmohamed, Tim Plant, Matthew Davidson, Hannah Norman, Emily Russell, Olivia Serevina, Kenneth Chung, Kashif Qamar, Bridget Gunson, Bettina Hansen, Alex Richter, Palak J. Trivedi, Gideon M. Hirschfield
Summary: In patients with PBC, the presence of anti-gp210 autoantibodies is associated with adverse clinical manifestations, predicts treatment non-response, and independently predicts decreased transplant-free survival.
LIVER INTERNATIONAL
(2021)
Article
Medicine, Research & Experimental
Nidhi Jalan-Sakrikar, Abid Anwar, Usman Yaqoob, Can Gan, Anthony B. Lagnado, Alexander Q. Wixom, Diana Jurk, Robert C. Huebert
Summary: This study investigated the mechanistic relationship between telomere damage and biliary fibrosis in primary sclerosing cholangitis (PSC). The results showed telomere attrition and reduced telomerase reverse transcriptase (TERT) expression in patients with PSC. Cellular models demonstrated that telomere dysfunction can lead to senescence and fibrosis, which can be rescued by modulating TERT levels.
Review
Biochemistry & Molecular Biology
Burcin Oezdirik, Tobias Mueller, Alexander Wree, Frank Tacke, Michael Sigal
Summary: PSC is an immune-related cholangiopathy associated with high progression rates to end-stage liver disease and risk of various cancers. Emerging evidence suggests a link between gut microbiota and disease pathogenesis, with studies showing differences in the gut microbiome of PSC patients compared to healthy individuals and those with IBD. Further research is needed to understand the role of gut microbiota in PSC and related malignancies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Nutrition & Dietetics
Maryam Ebadi, Elora Rider, Catherine Tsai, Sarah Wang, Ellina Lytvyak, Andrew Mason, Aldo J. Montano-Loza
Summary: This study aimed to investigate the association between severe vitamin D deficiency and disease progression, hepatobiliary malignancies, liver-related mortality, and the need for liver transplantation in primary sclerosing cholangitis (PSC). The results showed that severe vitamin D deficiency was related to an increased risk of hepatobiliary malignancies, and a severe deficiency at diagnosis and persistent deficiencies over time were independently associated with poor clinical liver outcomes.
Article
Gastroenterology & Hepatology
Kristoffer Kjaergaard, Kim Frisch, Michael Sorensen, Ole Lajord Munk, Alan Frederick Hofmann, Jacob Horsager, Anna Christina Schacht, Mary Erickson, David Shapiro, Susanne Keiding
Summary: The study demonstrated that OCA increased the hepatic transport of conjugated bile acids in PBC patients, reducing the time hepatocytes are exposed to potentially toxic bile acids.
JOURNAL OF HEPATOLOGY
(2021)
Article
Gastroenterology & Hepatology
Qiaoyan Liu, Bo Li, Yikang Li, Yiran Wei, Bingyuan Huang, Jubo Liang, Zhengrui You, You Li, Qiwei Qian, Rui Wang, Jun Zhang, Ruiling Chen, Zhuwan Lyu, Yong Chen, Mingxia Shi, Xiao Xiao, Qixia Wang, Qi Miao, Jing-Yuan Fang, Merrill Eric Gershwin, Min Lian, Xiong Ma, Ruqi Tang
Summary: Comparative analysis of gut microbiome and metabolome in IgG4-SC and PSC patients revealed distinct host-microbe interactions that may contribute to disease pathogenesis, highlighting the uniqueness of IgG4-SC.
Review
Gastroenterology & Hepatology
Frederik Nevens, Michael Trauner, Michael P. Manns
Summary: The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases, particularly in the field of second-line therapies for PBC. These new drugs can target cholestasis, fibrogenesis, immune-mediated action, and symptom relief. Obeticholic acid is currently the only approved second-line therapy for PBC, while other drugs in late-stage clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid, and NADPH oxidase 1/4 inhibitors.
JOURNAL OF HEPATOLOGY
(2023)
Review
Medicine, General & Internal
Claudiu Marinel Ionele, Adina Turcu-Stiolica, Mihaela Simona Subtirelu, Bogdan Silviu Ungureanu, George Ovidiu Cioroianu, Ion Rogoveanu
Summary: The association between primary sclerosing cholangitis (PSC) and metabolic bone disease is still unclear. This meta-analysis found no difference in bone mineral density (BMD-LS) between PSC patients and healthy controls, but lower BMD-LS in PSC patients compared to primary biliary cirrhosis (PBC) patients. The lumbar spine T-score was higher in PSC patients compared with PBC patients. Further well-designed and larger-scale studies are needed to confirm these findings.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Nutrition & Dietetics
Maryam Ebadi, Stephen Ip, Ellina Lytvyak, Somayyeh Asghari, Elora Rider, Andrew Mason, Aldo J. Montano-Loza
Summary: This study aims to investigate the prevalence of vitamin D deficiency in patients with primary biliary cholangitis (PBC) and its impact on treatment response to ursodeoxycholic acid (UDCA), development of cirrhosis, and liver-related events (mortality and liver transplantation).
Article
Gastroenterology & Hepatology
Emmanuel A. Selvaraj, Ahmed Ba-Ssalamah, Sarah Poetter-Lang, Gerard R. Ridgway, J. Michael Brady, Jane Collier, Emma L. Culver, Adam Bailey, Michael Pavlides
Summary: Quantitative biliary analysis using MRCP+ was effective in distinguishing abnormal from normal bile ducts in patients with PSC. Intrahepatic biliary dilatation severity calculated using MRCP+ was elevated in high-risk PSC patients and may be used for risk stratification. This exploratory study laid the groundwork for further investigation of novel quantitative biliary metrics in multicenter studies.
HEPATOLOGY COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Baorong Jiang, Gehui Yuan, Jialin Wu, Qian Wu, Lei Li, Ping Jiang
Summary: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and dysbiosis of gut microbiota. The abundance of Prevotella copri (P. copri) is significantly decreased in PSC patients, suggesting a potential protective effect. In this study, a PSC mouse model was established and intervention with P. copri was found to improve cholestasis and liver fibrosis by enhancing the FXR-related signalling pathway. This suggests that P. copri intervention may be a potential biological treatment for PSC.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2022)
Article
Chemistry, Physical
Ying Liu, Xiaoli Xiang, Bin Wang, Fenying Lu, Ye Dai, Zhicheng Zhang, Wenxuan Xu, Jiangpeng Wang, Cuie Cheng, Tingwang Jiang
Summary: Bio-based surfactants derived from carbohydrates have gained attention due to their environmental friendliness and biodegradability. In this study, a novel class of maltotriose acylhydrazone surfactants was synthesized and their surface activity, emulsifying ability, and potential as drug carriers were investigated.
JOURNAL OF MOLECULAR LIQUIDS
(2023)
Review
Gastroenterology & Hepatology
Michal Prokopic, Ulrich Beuers
Summary: PSC is a rare liver disease characterized by bile duct abnormalities leading to liver fibrosis and potential cholangiocarcinoma. The exact pathogenesis is still unclear, with strong association with inflammatory bowel disease. Current medical treatments have not been proven effective, with liver transplantation remaining the most viable option for late-stage disease.
HEPATOLOGY INTERNATIONAL
(2021)
Article
Gastroenterology & Hepatology
Louise Magherman, Robbe Van Parys, Nele S. Pauwels, Xavier Verhelst, Lindsey Devisscher, Hans Van Vlierberghe, Anja Geerts, Sander Lefere
Summary: This study examined the impact of light-to-moderate alcohol consumption on progressive NAFLD and mortality. It found that moderate alcohol intake increased the risk of advanced fibrosis, liver cirrhosis, and hepatocellular carcinoma. However, light alcohol consumption appeared to protect against all-cause mortality and lower the risk of steatohepatitis. Further research is needed to provide valid recommendations for alcohol consumption in NAFLD patients.
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Pathology
Kevin De Muynck, Bart Vanderborght, Federico F. De Ponti, Eva Gijbels, Sophie Van Welden, Martin Guilliams, Charlotte L. Scott, Alain Beschin, Mathieu Vinken, Sander Lefere, Anja Geerts, Xavier Verhelst, Hans Van Vlierberghe, Lindsey Devisscher
Summary: Primary sclerosing cholangitis (PSC) is a chronic immune-mediated liver disease characterized by bile duct strictures and fibrosis. The role of hepatic macrophages (MFs) in PSC pathogenesis is unclear. This study found that resident Kupffer cells (ResKCs) were depleted during chronic liver injury, while infiltrating monocyte-derived cells (MoKCs) were enriched during the acute phase of PSC. Depletion of KCs did not affect disease outcomes. These findings provide new insights into the heterogeneity of MFs in PSC and suggest that resident and activated KCs do not play a major role in disease progression.
AMERICAN JOURNAL OF PATHOLOGY
(2023)
Article
Toxicology
Bruna dos Santos Rodrigues, Kaat Leroy, Milos Mihajlovic, Sybren De Boever, Sarah Vanbellingen, Bruno Cogliati, Joeri L. Aerts, Mathieu Vinken
Summary: Currently, there are no validated in vitro assays for testing the non-genotoxic carcinogenic potential of chemicals. Therefore, the two-year rodent bioassay remains the standard method for identifying these chemicals. Transcriptomic and proteomic analyses have provided a comprehensive understanding of non-genotoxic carcinogenesis, but functional changes at the transcriptional and translational levels have not been addressed. This study tested proposed in vitro biomarkers of non-genotoxic hepatocarcinogenicity using a 3-dimensional model, and found that spheroid cultures of human liver cells may be suitable tools for investigating chemical-induced hepatocarcinogenicity, but the mechanisms and read-outs studied are not eligible biomarkers for detecting non-genotoxic carcinogens.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Oncology
Bart Vanderborght, Kevin De Muynck, Eva Gijbels, Sander Lefere, Charlotte L. Scott, Martin Guilliams, Alain Beschin, Mathieu Vinken, Xavier Verhelst, Anja Geerts, Hans Van Vlierberghe, Lindsey Devisscher
Summary: Due to the rapid progression of the disease and the lack of curative treatments, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. While monocyte-derived tumor-associated macrophages are known to contribute to HCC, the role of Kupffer cells (KCs) remains unclear. This study used a mouse model to investigate the effect of KC depletion on HCC initiation and progression, and found that the temporary ablation of resident KCs did not impact HCC pathogenesis.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Toxicology
Jian Jiang, Jonas van Ertvelde, Goekhan Ertaylan, Ralf Peeters, Danyel Jennen, Theo M. de Kok, Mathieu Vinken
Summary: Drug-induced intrahepatic cholestasis (DIC) is a challenging hepatic toxicity that is difficult to predict in early drug development stages. In vitro toxicogenomics assays using human liver cells have proved to be a practical approach for predicting DIC. This study applied machine learning algorithms to identify transcriptomic signatures of DIC and developed a prediction model with high accuracy and sensitivity. The identified genes provide insights into the mechanisms of DIC and enhance the predictive accuracy of DIC, contributing to the advancement of hazard identification methodologies.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Anne Caufriez, Arthur Lamouroux, Charlotte Martin, Debora Iaculli, Elif Ince Erguc, Rafael Gozalbes, Maria D. Mayan, Brenda R. Kwak, Andres Tabernilla, Mathieu Vinken, Steven Ballet
Summary: Pannexin1 channels play a critical role in paracrine communication, but effective inhibitors for in vivo use are scarce. However, a potential lead candidate, 10Panx1, has shown promise as a Pannexin1 channel inhibitor in both in vitro and in vivo studies. Structural optimization is crucial for clinical application.
BIOORGANIC CHEMISTRY
(2023)
Review
Environmental Sciences
Sebastian Schmeisser, Andrea Miccoli, Martin von Bergen, Elisabet Berggren, Albert Braeuning, Wibke Busch, Christian Desaintes, Anne Gourmelon, Roland Grafstrom, Joshua Harrill, Thomas Hartung, Matthias Herzler, George E. N. Kass, Nicole Kleinstreuer, Marcel Leist, Mirjam Luijten, Philip Marx-Stoelting, Oliver Poetz, Bennard van Ravenzwaay, Rob Roggeband, Vera Rogiers, Adrian Roth, Pascal Sanders, Russell S. Thomas, Anne Marie Vinggaard, Mathieu Vinken, Bob van de Water, Andreas Luch, Tewes Tralau
Summary: The animal-centric approach of chemical safety assessment is under pressure, and there is a growing demand for a paradigm shift due to concerns about overall performance, sustainability, relevance for human health risk assessment, and ethics. New Approach Methodologies (NAMs), including various methods such as QSAR predictions, HTS bioassays, omics applications, cell cultures, organoids, MPS, machine learning models, and AI, have the potential to revolutionize regulatory risk assessment by providing more human-relevant decision-making. However, challenges such as addressing chronic toxicity, stakeholder hesitance, predictivity, reproducibility, and adapting regulatory frameworks need to be overcome for the broader application of NAMs. This conceptual perspective is based on the findings and conclusions of a symposium and workshop held in Berlin in November 2021 and aims to shed light on the gradual integration of NAMs into chemical risk assessment for the protection of human health, leading to an animal-free Next Generation Risk Assessment (NGRA).
ENVIRONMENT INTERNATIONAL
(2023)
Article
Environmental Sciences
Guilherme R. Romualdo, Leticia Cardoso Valente, Ana Carolina Sprocatti dos Santos, Nubia Alves Grandini, Camila Renata Correa Camacho, Mathieu Vinken, Bruno Cogliati, De-Xing Hou, Luis Fernando Barbisan
Summary: We evaluated the promoting effect of glyphosate on western diet-induced non-alcoholic fatty liver disease (NAFLD). The results showed that within the toxicological limits, glyphosate can impair hepatic inflammation and redox dynamics in the NAFLD microenvironment.
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Computer Science, Interdisciplinary Applications
Jonas van Ertvelde, Anouk Verhoeven, Amy Maerten, Axelle Cooreman, Bruna dos Santos Rodrigues, Julen Sanz-Serrano, Milos Mihajlovic, Ignacio Tripodi, Marc Teunis, Ramiro Jover, Thomas Luechtefeld, Tamara Vanhaecke, Jian Jiang, Mathieu Vinken
Summary: This study introduces a novel approach using artificial intelligence to optimize the adverse outcome pathway (AOP) network of chemical-induced cholestasis. The optimized network was generated through automated data collection and quantitative confidence assessment of molecular initiating events, key events, and key event relationships. The results identified 38 unique key events and 135 key event relationships, with transporter changes being the most frequent key event and having the most confident relationship with the adverse outcome, cholestasis. Other important key events include nuclear receptor changes, intracellular bile acid accumulation, bile acid synthesis changes, oxidative stress, inflammation, and apoptosis.
JOURNAL OF BIOMEDICAL INFORMATICS
(2023)
Article
Chemistry, Medicinal
Arthur Lamouroux, Malaury Tournier, Debora Iaculli, Anne Caufriez, Olga M. Rusiecka, Charlotte Martin, Viviane Bes, Laureano E. Carpio, Yana Girardin, Remy Loris, Andreis Tabernilla, Filippo Molica, Rafael Gozalbes, Maria D. Mayan, Mathieu Vinken, Brenda R. Kwak, Steven Ballet
Summary: A series of macrocyclic peptidomimetics of Pannexin1 channels were developed and synthesized, showing better performance than the linear native peptides. Two compounds, SBL-PX1-42 and SBL-PX1-44, exhibited promising bidirectional inhibitory effects on the channel function. The introduction of triazole-based cross-links in the peptides enhanced helical content and stability. One of the peptides, SBL-PX1-206, efficiently reduced monocyte adhesion to activated endothelial cells, making it a potential candidate for in vivo investigations in animal models of cardiovascular inflammatory disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Gastroenterology & Hepatology
Louis Onghena, Yves Van Nieuwenhove, Laurissa Demeulenaere, Lindsey Devisscher, Xavier Verhelst, Helena Degroote, Sarah Raevens, Hans Van Vlierberghe, Sander Lefere, Anja Geerts
Summary: This study found that patients who had undergone bariatric surgery were more susceptible to alcohol-related liver disease. They were predominantly younger women with lower alcohol consumption compared to those without prior surgery. Bariatric surgery and older age at diagnosis were both associated with poorer survival outcomes.
LIVER INTERNATIONAL
(2023)
Article
Biochemistry & Molecular Biology
Eva Gijbels, Kevin De Muynck, Bart Vanderborght, Tim Meese, Filip Van Nieuwerburgh, Aude Vanlander, Frederik Berrevoet, Bart Hendrikx, Anne Hoorens, Hans Van Vlierberghe, Mathieu Vinken, Lindsey Devisscher
Article
Chemistry, Medicinal
Arthur Lamouroux, Malaury Tournier, Debora Iaculli, Anne Caufriez, Olga M. Rusiecka, Charlotte Martin, Viviane Bes, Laureano E. Carpio, Yana Girardin, Remy Loris, Andreis Tabernilla, Filippo Molica, Rafael Gozalbes, Maria D. Mayan, Mathieu Vinken, Brenda R. Kwak, Steven Ballet
Summary: A series of macrocyclic (stapled) peptidomimetics of 10Panx1 were developed and synthesized, which showed promising potential in inhibiting Panx1 channels and reducing cell adhesion in in vitro experiments.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
