Review
Biochemistry & Molecular Biology
Rasheed A. Bailey, Derek L. Beahm, I. Martha Skerrett
Summary: Glycine is an amino acid with unique properties due to its single hydrogen atom side chain. Conserved glycines in proteins often indicate domains involving tight turns or bends. Substitutions at position 12 of certain connexins lead to alterations in function and have been linked to hereditary skin disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Olivia E. Crouthamel, Leping Li, Michael T. Dilluvio, Thomas W. White
Summary: Mutations in the GJA1 gene encoding connexin43 (Cx43) have been linked to various rare genetic disorders, including those affecting the skin. This study investigated the functional consequences of a specific Cx43 mutation (Cx43-G38E) associated with a novel human phenotype. The research showed that the mutation increased the activity of hemichannels, suggesting a potential role in skin and skeletal disorders caused by Cx43 mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Kaat Leroy, Cicero Julio Silva Costa, Alanah Pieters, Bruna dos Santos Rodrigues, Raf Van Campenhout, Axelle Cooreman, Andres Tabernilla, Bruno Cogliati, Mathieu Vinken
Summary: The study investigated changes in connexin expression and gap junction functionality in liver cancer cell lines in vitro, showing enhanced expression of connexin43 and low gap junctional intercellular communication. These findings may benefit future research on anti-cancer drugs and mechanistic investigation in neoplastic hepatocytes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Stefan Dhein, Aida Salameh
Summary: The heart relies on gap junction channels to maintain cell-cell coupling for efficient and rapid electrical conduction. Connexin expression and gap junction localization play crucial roles in modulating cardiac electrical properties, ultimately affecting cardiac stability and function.
Review
Biochemistry & Molecular Biology
Jennifer C. Jones, Thomas M. Bodenstine
Summary: Connexins are important membrane channel proteins that regulate both intercellular communication and cellular metabolism in cancer cells. They have diverse roles in cancer biology, being able to promote or suppress cancer cell function. The relationship between glucose metabolism and connexin function in cancer cells is complex and requires further investigation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Andres Tittarelli
Summary: Connexin-mediated intercellular communication mechanisms play important roles in immune system activities, especially in infections, wounds, cancer, and other inflammatory conditions. Modulating connexin expression and channel activities may be a promising approach for designing therapeutic tools.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Neurosciences
Xinyu Wang, Chuan Jiang, Chunli Lu, Longbing Ma, Yuxin Feng, Shengyu Cui, Qian Li, Kang Li, Xiang Wang, Fengzeng Jian
Summary: In this study, changes in the number and morphology of ependymal cilia in a syringomyelia rat model were investigated. The results showed a decline in cilia during the early stage of the disease, leading to disrupted intercellular communication. In the later stage, cilia were further reduced due to shear stress exposure, causing a potential mechanism of ependymal cilia decline in syringomyelia development.
EXPERIMENTAL NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yuefang Zhou, Thomas M. Bennett, Thomas W. White, Alan Shiels
Summary: CHMP4B is a core sub-unit of the ESCRT-III machinery involved in remodeling and scission processes of biological membranes. It has been found to associate with connexin 46 (Cx46) and connexin 50 (Cx50), and its membrane localization is dependent on Cx50 in lens fiber cells.
Review
Neurosciences
Xiaomin Huang, Yixun Su, Nan Wang, Hui Li, Zhigang Li, Guowei Yin, Hui Chen, Jianqin Niu, Chenju Yi
Summary: Astrocytes play a crucial role in maintaining the normal functions of the Central Nervous System (CNS). During neurodegenerative diseases, alterations in astrocytic connexin expression and function can affect disease progression by impacting neuronal function and survival. Targeting connexins may be a plausible therapeutic strategy for managing these neurodegenerative diseases.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Review
Cell Biology
Andrew M. Boal, Michael L. Risner, Melissa L. Cooper, Lauren K. Wareham, David J. Calkins
Summary: Astrocytes play a crucial role in responding to neurodegenerative stress and are interconnected through gap junctions, primarily composed of connexin-43 (Cx43), forming a broader network. This network contributes to various important processes and is likely to influence the progression of neurodegenerative diseases. Targeting these networks may be critical in the treatment of glaucomatous neurodegeneration and other optic neuropathies.
Article
Cell Biology
Weiqi Zeng, Zhizhao Deng, Yingxin Gao, Guoliang Sun, Xianlong Li, Dongdong Yuan
Summary: Long-term exposure to Ang II significantly enhances the expression and function of Cx43-GJs in HUASMCs, leading to the accumulation of intracellular Ca2+ and the activation of downstream signaling pathways. However, propofol inhibits the function of Cx43-GJs in Ang II-pretreated HUASMCs, resulting in the inhibition of intracellular Ca2+ and its downstream signaling pathways and ultimately excessive relaxation of HUASMCs. This explains why patients with chronic hypertension experience more severe blood pressure fluctuations after propofol induction.
CELL COMMUNICATION AND SIGNALING
(2023)
Article
Biochemistry & Molecular Biology
Santipongse Chatchavalvanich, Robert A. Boomsma, Jack M. Tietema, David L. Geenen
Summary: Early coupling between bone marrow-derived mesenchymal stem cells (BM-MSC) and ischemic cardiomyocytes through gap junctions (GJ) may play a crucial role in cell survival and retention in the acute phase of myocardial ischemia.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Avigail Ehrlich, Filippo Molica, Aurelie Hautefort, Brenda R. Kwak
Summary: This review provides an overview of the expression and function of connexins and pannexins in the lymphatic vasculature, focusing on their roles in healthy lymphatic system functions and pathological conditions. The discussion highlights their impact on intercellular communication, immune cell trafficking, and nutrient absorption, as well as their implications in lymphatic disorders and cardiovascular diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Max Zachrisson Totland, Yasufumi Omori, Vigdis Sorensen, Kushtrim Kryeziu, Trond Aasen, Andreas Brech, Edward Leithe
Summary: Gap junctions are clusters of channels in the plasma membrane that enable the diffusion of ions and small molecules between adjacent cells, playing a fundamental role in coordinating tissue functions. The loss of intercellular communication mediated by gap junctions, often observed in cancer pathogenesis, can impact tumor growth and response to treatment. Connexins, integral membrane proteins, not only facilitate cell-cell communication but also modulate signal transduction pathways, cell processes, and the dynamic regulation of gap junction levels. Dysregulation of connexin trafficking in the endocytic system contributes to the loss of gap junctions during carcinogenesis, with potential therapeutic implications in cancer treatment.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Review
Biochemistry & Molecular Biology
Jorge Gonzalez-Casanova, Oliver Schmachtenberg, Agustin D. Martinez, Helmuth A. Sanchez, Paloma A. Harcha, Diana Rojas-Gomez
Summary: Diabetic retinopathy is a major cause of vision loss in the working age population, characterized by progressive deterioration of retinal microvasculature due to long-term metabolic changes. Gap junction channels and connexin hemichannels have been identified as key factors in the pathogenesis of diabetic retinopathy. Understanding the physiological impact of diabetes on these channels and their role in the disease process could lead to the development of novel pharmacological interventions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
Biochemistry & Molecular Biology
Gabriel P. Bacil, Guilherme R. Romualdo, Priscila M. F. D. Piagge, Daniel R. Cardoso, Mathieu Vinken, Bruno Cogliati, Luis F. Barbisan
Summary: This study investigated the hepatic metabolomic profile in a hybrid model of NASH in mice and found that the strain-dependent hepatic metabolomic signature might be linked to the distinct underlying mechanisms of NASH.
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
Nutrition & Dietetics
Zenzi Rosseel, Pieter-Jan Cortoos, Joop Jonckheer, Wilfried Cools, Mathieu Vinken, Hendrik Reynaert, Elisabeth De Waele
Summary: The impact of parenteral nutrition (PN) on liver dysfunction in critically ill patients is largely unknown. This study found that sepsis and acute heart failure (AHF) have the highest influence on liver test disturbances, while PN and hepatotoxic drugs have limited impact. Nutritional adequacy needs improvement.
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
Biotechnology & Applied Microbiology
Raf Van Campenhout, Timo W. M. De Groof, Prashant Kadam, Brenda R. Kwak, Serge Muyldermans, Nick Devoogdt, Mathieu Vinken
Summary: This study successfully developed nanobody-based inhibitors targeting Pannexin1 channels, which showed affinity for both murine and human Pannexin1 proteins. These nanobodies were able to block the release of adenosine triphosphate and display anti-inflammatory effects in vitro, as well as in a relevant mouse model of acute liver disease. The findings suggest that these nanobodies hold promise as therapeutic agents for inflammatory disorders and provide novel tools for further research on the role of Pannexin1 channels in physiological and pathological processes.
JOURNAL OF NANOBIOTECHNOLOGY
(2023)
Review
Cell Biology
Raf Van Campenhout, Anne Caufriez, Andres Tabernilla, Amy Maerten, Sybren De Boever, Julen Sanz-Serrano, Prashant Kadam, Mathieu Vinken
Summary: Pannexin1 proteins form communication channels at the cell membrane surface, facilitating the transfer of molecules and ions. These channels are crucial in cellular processes and can contribute to various diseases. This paper reviews the structure, regulation, and physiological roles of pannexin1 channels, with a focus on their relevance in liver diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(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)