Article
Gastroenterology & Hepatology
Alvaro Rivera-Andrade, Jessica L. Petrick, Christian S. Alvarez, Barry Graubard, Andrea A. Florio, Maria F. Kroker-Lobos, Dominick Parisi, Neal D. Freedman, Mariana Lazo, Eliseo Guallar, John D. Groopman, Manuel Ramirez-Zea, Katherine A. McGlynn
Summary: This study identified a relationship between bile acid levels and non-alcoholic fatty liver disease (NAFLD) at the population level. Individuals with NAFLD had significantly higher levels of certain bile acids, indicating hepatic overproduction of bile acids may be involved in the pathogenesis of NAFLD.
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Biochemistry & Molecular Biology
Annarosa Floreani, Daniela Gabbia, Sara De Martin
Summary: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease with limited treatment options. Ursodeoxycholic acid (UDCA) is the first-line therapy but is ineffective for a significant portion of patients. Obeticholic acid (OCA) is an effective second-line treatment for UDCA-non responders. Future therapies for PBC are promising.
Article
Medicine, Research & Experimental
Shiqi Zhong, Raphael Chevre, David Castano Mayan, Maria Corliano, Blake J. Cochran, Kai Ping Sem, Theo H. van Dijk, Jianhe Peng, Liang Juin Tan, Siddesh V. Hartimath, Boominathan Ramasamy, Peter Cheng, Albert K. Groen, Folkert Kuipers, Julian L. Goggi, Chester Drum, Rob M. van Dam, Ru San Tan, Kerry-Anne Rye, Michael R. Hayden, Ching-Yu Cheng, Shaji Chacko, Jason Flannick, Xueling Sim, Hong Chang Tan, Roshni R. Singaraja
Summary: Reduced CYP8B1 activity is associated with increased insulin sensitivity in humans, possibly due to increased skeletal muscle insulin sensitivity caused by increased circulating CDCA.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Cell Biology
Junliang Kuang, Jieyi Wang, Yitao Li, Mengci Li, Mingliang Zhao, Kun Ge, Dan Zheng, Kenneth C. P. Cheung, Boya Liao, Shouli Wang, Tianlu Chen, Yinan Zhang, Congrong Wang, Guang Ji, Peng Chen, Hongwei Zhou, Cen Xie, Aihua Zhao, Weiping Jia, Xiaojiao Zheng, Wei Jia
Summary: A new treatment for alleviating NAFLD has been discovered, which involves inhibiting intestinal FXR and upregulating hepatic CYP7B1 through a group of gut microbiota-modified bile acids. These bile acids can also increase the abundance of probiotic species and enhance lipid catabolism through the activation of PPARα signaling pathway, leading to an upregulation of hepatic FXR.
Article
Chemistry, Medicinal
Cheng Mo, Xiaoqing Xu, Pan Zhang, Yihong Peng, Xinpeng Zhao, Shijia Chen, Fang Guo, Yating Xiong, Xin-Jie Chu, Xiaodong Xu
Summary: The farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that affects the expressions of genes involved in bile acid metabolism, inflammation, fibrosis, and lipid and glucose homeostasis. Developing FXR agonists for treating NASH and other FXR-related diseases is of great interest. This study describes the design, optimization, and characterization of a series of nonbile acid FXR agonists known as N-methylene-piperazinyl derivatives. Compound 23, or HPG1860, is a potent FXR agonist with high selectivity, favorable pharmacokinetics, and in vivo activity demonstrated in animal models, and it is currently in phase II clinical development for NASH patients.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Engineering, Biomedical
Mengjie Kong, Yan Peng, Liyan Qiu
Summary: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, but there is no FDA-approved drug for its treatment. This study designed oligochitosan-derivated nanovesicles to deliver an FXR agonist and miR-34a antagomir for NAFLD treatment. The nanovesicles effectively reduced lipid deposition in cells and showed promising results in NAFLD mice models. The study also demonstrated the activation of SIRT1 through the FXR/miR-34a/SIRT1 regulatory loop.
ACTA BIOMATERIALIA
(2023)
Review
Pharmacology & Pharmacy
Stefano Fiorucci, Michele Biagioli, Monia Baldoni, Patrizia Ricci, Valentina Sepe, Angela Zampella, Eleonora Distrutti
Summary: FXR agonists show potential in treating nonalcoholic fatty liver disease, but side effects such as elevated cholesterol levels and pruritus are common. Studies are underway to evaluate the benefits and safety of combination therapies.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Article
Medicine, Research & Experimental
Arezou Azizsoltani, Behzad Hatami, Mohammad Reza Zali, Vahideh Mahdavi, Kaveh Baghaei, Effat Alizadeh
Summary: This study aimed to deliver obeticholic acid (OCA) to the liver using exosomes, and found that exosome-loaded OCA exerted anti-fibrotic effects in fibrotic mice, leading to improvements in related indicators.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Toxicology
Tianwei Zhang, Shanshan Feng, Jiahuan Li, Zhitao Wu, Qiangqiang Deng, Wei Yang, Jing Li, Guoyu Pan
Summary: This study found that FXR agonists, obeticholic acid (OCA) and Px-102, reduced mitochondrial function in hepatocytes and promoted cell apoptosis. Inhibiting FXR or SHP genes alleviated the cytotoxic effects of OCA and Px-102. The dose-related liver damage caused by OCA and Px-102 was confirmed in a high-fat diet mouse model. OCA or Px-102 led to a decrease in hepatocyte-specific genes and augmenter of liver regeneration in the liver.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jan Heering, Nathalie Jores, Whitney Kilu, Espen Schallmayer, Evelyn Peelen, Andreas Muehler, Hella Kohlhof, Daniel Vitt, Verena Linhard, Santosh L. Gande, Apirat Chaikuad, Sridhar Sreeramulu, Harald Schwalbe, Daniel Merk
Summary: This study elucidates the molecular basis of FXR activation by systematically studying the response of FXR ligands. Different ligands have different effects on FXR activation, which align with structural changes in the ligand binding domain of FXR. The results suggest the potential application of selective modulation of FXR dimerization and co-regulator interactions for FXR ligands.
ACS CHEMICAL BIOLOGY
(2022)
Review
Immunology
Gaber El-Saber Batiha, Hayder M. Al-kuraishy, Ali I. Al-Gareeb, Fadia S. Youssef, Suzy A. El-Sherbeni, Walaa A. Negm
Summary: The causative agent of Covid-19 is a new type of coronavirus called SARS-CoV-2, which severely affects the respiratory tract. Efforts have been made to test different drugs and agents for treatment, but their use has been associated with adverse events. The emergence of SARS-CoV-2 variants has raised the need for effective and safe agents to combat the infection, even in vaccinated individuals. Obeticholic acid (OCA), with its anti-inflammatory effects, may be a potential treatment for Covid-19. This perspective study focuses on the possible medicinal effectiveness of OCA in managing the disease.
INFLAMMOPHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Wen-Cong Li, Su-Xian Zhao, Wei-Guang Ren, Yu-Guo Zhang, Rong-Qi Wang, Ling-Bo Kong, Qing-Shan Zhang, Yue-Min Nan
Summary: The combination of obeticholic acid (OCA) and simvastatin (SIM) showed promising therapeutic effects in a high-fat diet-induced model of non-alcoholic steatohepatitis (NASH), reducing liver inflammation and steatosis, preventing weight gain and fat accumulation.
EXPERIMENTAL AND THERAPEUTIC MEDICINE
(2021)
Review
Oncology
Wenyu Luo, Shiqi Guo, Yang Zhou, Junfeng Zhu, Jingwen Zhao, Mengyao Wang, Lixuan Sang, Bingyuan Wang, Bing Chang
Summary: Bile acids play an important role in cholesterol metabolism and are involved in the development of hepatocellular carcinoma (HCC) by recognizing receptors and mediating downstream pathways. Certain bile acids can delay liver injury and HCC progression. This review introduces the structure, function, metabolism, and enterohepatic circulation of bile acids, summarizes the mechanisms by which they contribute to HCC development, and suggests possible strategies for HCC treatment.
INTERNATIONAL JOURNAL OF ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Danial Efendy Goon, Sharaniza Ab-Rahim, Amir Hakimi Mohd Sakri, Musalmah Mazlan, Jen Kit Tan, Mardiana Abdul Aziz, Norizal Mohd Noor, Effendi Ibrahim, Siti Hamimah Sheikh Abdul Kadir
Summary: The study indicates that the enhanced formulation of TRF ETRF is more effective in promoting fatty acid oxidation, reducing oxidative stress and pro-inflammatory metabolites, and has a better anti-inflammatory effect on NAFLD compared to TRF.
SCIENTIFIC REPORTS
(2021)
Article
Endocrinology & Metabolism
Xianjiao Liu, Jinyan Li, Mengdie Shi, Jun Fu, Yubo Wang, Weili Kang, Jinyan Liu, Fenxia Zhu, Kehe Huang, Xingxiang Chen, Yunhuan Liu
Summary: Melatonin (MT) improves hepatic injury and fibrosis in cholestatic liver disease mice by remodeling gut microbiota and activating intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) axis-mediated inhibition of hepatic bile acid synthesis and promotion of bile acid excretion.
JOURNAL OF PINEAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Ton Schoenmaker, Michal Mokry, Dimitra Micha, Coen Netelenbos, Nathalie Bravenboer, Marjolijn Gilijamse, E. Marelise W. Eekhoff, Teun J. de Vries
Summary: The study revealed that Activin-A exclusively induces differential gene expression in FOP cells compared to control cells, with upregulated genes associated with bone metabolism pathways. This early transcriptomic analysis highlights potential mechanisms underlying ACVR1 R206H-mediated ossifications in FOP patients.
Article
Cardiac & Cardiovascular Systems
Ying Wang, Hua Gao, Fudi Wang, Zhongde Ye, Michal Mokry, Adam W. Turner, Jianqin Ye, Simon Koplev, Lingfeng Luo, Tom Alsaigh, Shaunak S. Adkar, Maria Elishaev, Xiangyu Gao, Lars Maegdefessel, Johan L. M. Bjorkegren, Gerard Pasterkamp, Clint L. Miller, Elsie G. Ross, Nicholas J. Leeper
Summary: This study reveals that vascular smooth muscle cells (SMCs) undergo dedifferentiation and activation of pro-inflammatory pathways during the development of atherosclerosis. ATF3, a transcription factor, is identified as an upstream regulator of this transition. ATF3 represses the transition of SMCs towards a subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 is negatively correlated with complement component C3, and genetic variations that reduce ATF3 expression are associated with an increased risk for atherosclerosis.
CARDIOVASCULAR RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
M. Guy Roukens, Cynthia L. Frederiks, Danielle Seinstra, Luca Braccioli, Antoine A. Khalil, Cornelieke Pals, Simon De Neck, Laura Bornes, Evelyne Beerling, Michal Mokry, Alain de Bruin, Bart Westendorp, Jacco van Rheenen, Paul J. Coffer
Summary: The transcription factor SOX4 plays a crucial role in the development of breast cancer, maintaining tumors in an undifferentiated and proliferative state by regulating stem cell genes. Knockout of SOX4 leads to differentiation of tumor cells, increase in luminal or basal gene expression, decrease in cell cycle gene expression, and impaired primary tumor growth and metastasis. Therapeutic manipulation of SOX4 function could be a promising strategy for cancer differentiation therapy.
Review
Pharmacology & Pharmacy
Michele F. Buono, Lotte Slenders, Marian Wesseling, Robin J. G. Hartman, Claudia Monaco, Hester M. den Ruijter, Gerard Pasterkamp, Michal Mokry
Summary: The pathological definition of the vulnerable plaque has provided valuable insights into the mechanisms of myocardial infarction and stroke. New technologies, such as single-cell transcriptomics, offer opportunities for identifying cell-specific determinants and enhancing the understanding of atherosclerotic diseases. The evolving sequencing technologies have identified candidate genes and molecular mechanisms that may impact the risk of atherosclerotic thrombotic events, posing the challenge of translating these insights into tangible discoveries.
VASCULAR PHARMACOLOGY
(2021)
Article
Biochemical Research Methods
Marcel Kwiatkowski, Madlen Hotze, Julia Schumacher, Abdul R. Asif, Jose Miguel Ramos Pittol, Bertram Brenig, Sanja Ramljak, Hans Zischler, Holger Herlyn
Summary: Multiple spotting in 2-DE/MS can be influenced by protein speciation, amino acid modification, and alternative splicing. The ability to resolve proteomes down to protein species can lead to enrichment of multispotting proteins in 2-DE/MS, and low sensitivity of stains and MS instruments may enhance this effect.
Article
Multidisciplinary Sciences
Xanthe A. M. H. van Dierendonck, Frank Vrieling, Lisa Smeehuijzen, Lei Deng, Joline P. Boogaard, Cresci-Anne Croes, Lieve Temmerman, Suzan Wetzels, Erik Biessen, Sander Kersten, Rinke Stienstra
Summary: In response to inflammatory activation by pathogens, macrophages accumulate triglycerides to suppress lipolysis, thereby attenuating the inflammatory response. This finding is important for understanding the mechanisms of macrophage inflammatory response and the treatment of related diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Endocrinology & Metabolism
Robin van Eenige, Wietse In het Panhuis, Milena Schoenke, Celine Jouffe, Thomas H. Devilee, Ricky Siebeler, Trea C. M. Stree, Hetty C. M. Sips, Amanda C. M. Pronk, Ruben H. P. Vorderman, Hailiang Mei, Jan Bert van Klinken, Michel van Weeghel, Nina H. Uhlenhaut, Sander Kersten, Patrick C. N. Rensen, Sander Kooijman
Summary: This study reveals the mechanisms underlying the diurnal regulation of metabolic activity in brown adipose tissue (BAT). The research findings highlight the role of angiopoietin-like 4 (Angptl4) in mediating lipoprotein lipase (Lpl) activity and triglyceride (TG)-derived fatty acid (FA) uptake in BAT. These results have important implications for improving metabolic health.
MOLECULAR METABOLISM
(2022)
Article
Cardiac & Cardiovascular Systems
Mahmoud Abdellatif, Viktoria Trummer-Herbst, Alexander Martin Heberle, Alina Humnig, Tobias Pendl, Sylvere Durand, Giulia Cerrato, Sebastian J. Hofer, Moydul Islam, Julia Voglhuber, Jose Miguel Ramos Pittol, Oliver Kepp, Gerald Hoefler, Albrecht Schmidt, Peter P. Rainer, Daniel Scherr, Dirk von Lewinski, Egbert Bisping, Julie R. McMullen, Abhinav Diwan, Tobias Eisenberg, Frank Madeo, Kathrin Thedieck, Guido Kroemer, Simon Sedej
Summary: This study suggests a biphasic relationship between insulin-like growth factor 1 receptor (IGF1R) signaling and cardiac health. Higher IGF1R signaling in young mice leads to declining cardiac function and shorter lifespan, while lower IGF1R signaling improves cardiac function and extends lifespan in aging mice.
Article
Biology
Arif Ibrahim Ardisasmita, Imre F. Schene, Indi P. Joore, Gautam Kok, Delilah Hendriks, Benedetta Artegiani, Michal Mokry, Edward E. S. Nieuwenhuis, Sabine A. Fuchs
Summary: A systematic comparison of transcriptomes across different hepatocyte models allows selection of hepatocyte-like cells for specific research questions and can guide improvements in culturing conditions.
COMMUNICATIONS BIOLOGY
(2022)
Article
Genetics & Heredity
Irena J. J. Muffels, Imre F. Schene, Holger Rehmann, Maarten P. G. Massink, Maria M. van der Wal, Corinna Bauder, Martha Labeur, Natalia G. Armando, Maarten H. Lequin, Michiel L. Houben, Jaques C. Giltay, Saskia Haitjema, Albert Huisman, Fleur Vansenne, Judith Bluvstein, John Pappas, Lala V. Shailee, Yuri A. Zarate, Michal Mokry, Gijs W. van Haaften, Edward E. S. Nieuwenhuis, Damian Refojo, Femke van Wijk, Sabine A. Fuchs, Peter M. van Hasselt
Summary: Variants in NAE1 gene have been found to affect cellular pathways and disease pathophysiology. Decreased NAE1 abundance and overlapping clinical and cellular phenotypes support the pathogenicity of these variants. NAE1 is shown to play a role in protecting against cell death during cellular stress.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Gastroenterology & Hepatology
Koos de Wit, Ulrich Beuers, Anna Mukha, Edwin C. A. Stigter, M. Can Gulersonmez, Jose Ramos M. Pittol, Sabine Middendorp, R. Bart Takkenberg, Saskia W. C. van Mil
Summary: This study investigated the effects of rifaximin on the biotransformation machinery in the small intestine, uncovering its role in promoting ammonia detoxification by increasing glutamine and asparagine concentrations.
LIVER INTERNATIONAL
(2023)
Article
Rheumatology
Janneke G. C. Peeters, Arjan Boltjes, Rianne C. Scholman, Stephin J. Vervoort, Paul J. Coffer, Michal Mokry, Sebastiaan J. Vastert, Femke van Wijk, Jorg van Loosdregt
Summary: This study investigates the epigenetic changes in monocytes derived from inflamed joints of JIA patients and reveals the role of the local inflammatory environment in regulating these changes. The activation phenotype of synovial-derived monocytes is found to be regulated on the epigenetic level, with increased expression and epigenetic alterations in IFN signaling-associated genes. Treatment with the JAK inhibitor ruxolitinib transforms the activated enhancer landscape and reduces disease-associated gene expression, thus inhibiting the inflammatory phenotype.
Article
Veterinary Sciences
Karin Sanders, Hans S. Kooistra, Marieke van den Heuvel, Michal Mokry, Guy C. M. Grinwis, Noortje A. M. van den Dungen, Frank G. van Steenbeek, Sara Galac
Summary: Cushing's syndrome (CS) is more common in dogs and is caused by cortisol-secreting adrenocortical tumours (csACTs) in a significant percentage of cases. By performing RNA sequencing on csACTs and normal adrenal cortices (NACs) of dogs, differentially expressed genes were identified that can improve prognosis and serve as treatment targets. Cytochrome P450 26B1 (CYP26B1) was found to be significantly associated with survival in both canine and human csACTs. Further research could explore the potential use of CYP26B1 inhibitors for inhibiting csACT growth in dogs and humans.
VETERINARY AND COMPARATIVE ONCOLOGY
(2023)
Article
Multidisciplinary Sciences
Maria Stahl Madsen, Marjoleine F. Broekema, Martin Ronn Madsen, Arjen Koppen, Anouska Borgman, Cathrin Grawe, Elisabeth G. K. Thomsen, Denise Westland, Mariette E. G. Kranendonk, Marian Groot Koerkamp, Nicole Hamers, Alexandre M. J. J. Bonvin, Jose M. Ramos Pittol, Kedar Nath Natarajan, Sander Kersten, Frank C. P. Holstege, Houshang Monajemi, Saskia W. C. van Mil, Michiel Vermeulen, Birthe B. Kragelund, David Cassiman, Susanne Mandrup, Eric Kalkhoven
Summary: Mutations in PPAR gamma compromise chromatin remodeling and impair its function, leading to lipodystrophy. By studying two lipodystrophy mutations, the researchers identified the specific interactions that are disrupted and showed how they affect the activation of target genes in adipocytes.
NATURE COMMUNICATIONS
(2022)
Article
Immunology
Arjan Boltjes, Anoushka Ashok Kumar Samat, Maud Plantinga, Michal Mokry, Bas Castelijns, Joost F. Swart, Sebastiaan J. Vastert, Menno Creyghton, Stefan Nierkens, Jorg van Loosdregt, Femke van Wijk
Summary: This study indicates that human dendritic cells (DCs) have specific functional programming in chronic inflammatory conditions. Compared to other cell types, cDC1 remains relatively quiescent and unchanged at the site of inflammation, while cDC2 and monocytes show stronger inflammatory features and T cell activation ability.
FRONTIERS IN IMMUNOLOGY
(2023)
