Article
Chemistry, Medicinal
Emiliano Rosatelli, Andrea Carotti, Bruno Cerra, Francesca De Franco, Daniela Passeri, Roberto Pellicciari, Antimo Gioiello
Summary: The activation of TGR5 allows bile acids to modulate nongenomic signaling pathways, leading to physiological actions such as immunosuppression, anti-inflammatory effects, and regulation of glucose metabolism and energy balance. TGR5 agonists have shown promise in drug discovery and preclinical evaluations for the treatment of liver diseases and metabolic syndrome. This study focuses on modifying the chemical structure of bile acids to develop novel chemical tools that can modulate TGR5 in different tissues. The results provide insights into the structure-activity relationships and functional roles of TGR5, uncovering unexpected properties that can be utilized to design selective and potent TGR5 agonists.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Plant Sciences
Muhammad Bello Saidu, Norbert Kusz, Yu-Chi Tsai, Mate Vagvolgyi, Robert Berkecz, David Kokai, Katalin Burian, Judit Hohmann, Dora Redei
Summary: Two previously unknown compounds were isolated from the aerial parts of Euphorbia deightonii Croizat and their structures were determined. Compounds 1, 3, 4, and 7 showed inhibitory effects against herpes simplex virus.
Article
Chemistry, Medicinal
Sylvain Picon, Rajaa Boulahjar, Vanessa Hoguet, Morgane Baron, Isabelle Duplan, Emmanuelle Vallez, Nathalie Hennuyer, Julie Dumont, Veironique Touche, Emilie Dorchies, Manuel Lasalle, Amandine Descat, Catherine Piveteau, Alexandre Biela, Ludovic Chaput, Bruno O. Villoutreix, Emmanuelle Lipka, Emmanuel Sevin, Maxime Culot, Fabien Gosselet, Sophie Lestavel, Pascal Roussel, Rebecca Deprez-Poulain, Florence Leroux, Bart Staels, Benoit Deprez, Anne Tailleux, Julie Charton
Summary: A novel series of potent TGR5 agonists bearing a dihydropyridone scaffold was developed through a high-throughput screening. The synthesis and biological evaluation of 83 analogues led to the identification of the potent nanomolar TGR5 agonist 77A. A three-dimensional quantitative SAR model was also built to guide further development of this dihydropyridone series.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Elkin Escobar-Chaves, Sergio Acin, Diana Lorena Munoz, Maritza Fernandez, Alexandra Echeverri, Fernando Echeverri, Jahir Orozco, Norman Balcazar
Summary: Triterpene-enriched fractions (TFs) from Eucalyptus tereticornis effectively treated obesity-related type 2 diabetes mellitus (T2DM) in mice through intraperitoneal administration, but not orally. To address this, a polymer-based nanoformulation was developed to orally transport TFs in mice and control obesity and T2DM. The nanoformulation exhibited high release of TFs in vitro, leading to weight loss and improved glucose and insulin intolerance in vivo. This study suggests new strategies for using natural products to treat obesity and T2DM.
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
(2023)
Article
Medicine, General & Internal
Xueying Zhu, Dan Cheng, Kaiming Ruan, Meixiao Shen, Yufeng Ye
Summary: This study used Mendelian randomization design to assess the potential causal relationships between type 2 diabetes, glycemic traits, and the risk of keratoconus. The findings suggest that higher fasting glucose levels are associated with a lower risk of keratoconus, while lower proinsulin levels may be linked to a higher risk. Additionally, genetically predicted type 2 diabetes is negatively correlated with keratoconus risk. These associations were supported by sensitivity analyses.
FRONTIERS IN MEDICINE
(2023)
Review
Medicine, General & Internal
Ehtasham Ahmad, Soo Lim, Roberta Lamptey, David R. Webb, Melanie J. Davies
Summary: Type 2 diabetes accounts for nearly 90% of global diabetes cases, with an increasing number of affected individuals, particularly among young people. Early detection and proactive management are crucial for preventing complications and reducing mortality. Technology and precision medicine offer potential improvements to treatment outcomes but face significant barriers.
Article
Biochemistry & Molecular Biology
Shizhen Zhao, Xinping Li, Le Wang, Wenjing Peng, Wenling Ye, Weiguo Li, Yan-Dong Wang, Wei-Dong Chen
Summary: The novel 1-benzyl-1H-imidazole-5-carboxamide derivatives 19d and 19e exhibited potent agonistic activities against hTGR5 and significant glucose-lowering effects in vivo, suggesting them as promising candidates for the treatment of diabetes and obesity.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Rachana S. S. Bhimanwar, Kiran Bharat Lokhande, Ashish Shrivastava, Ashutosh Singh, Sohan S. S. Chitlange, Amit Mittal
Summary: Cell surface bile acid receptor TGR5, expressed in various tissues, plays a major role in maintaining blood sugar levels and increasing energy expenditure. It has the potential to be a treatment for type 2 diabetes, obesity, and other metabolic disorders. By using structure-based virtual screening and molecular docking, designed coumarin derivatives were found to have promising activity as TGR5 agonists.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Immunology
Jacob D. Painter, Omid Akbari
Summary: ILC2s, the innate counterparts of Th2 cells, play a critical role in maintaining tissue homeostasis by responding to external stimuli and controlling the inflammation balance in adipose tissue. Their effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile, crucial for tissue homeostasis. The reaction of ILC2s to changes in the metabolic environment is a clear determinant of disease severity, providing a potential avenue for modulation of systemic homeostasis and treatment of T2DM.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Endocrinology & Metabolism
Stefano Balducci, Jonida Haxhi, Massimo Sacchetti, Giorgio Orlando, Patrizia Cardelli, Martina Vitale, Lorenza Mattia, Carla Iacobini, Lucilla Bollanti, Francesco Conti, Silvano Zanuso, Antonio Nicolucci, Giuseppe Pugliese
Summary: The Italian Diabetes and Exercise Study_2 (IDES_2) found that behavioral counseling can increase physical activity and reduce sedentary behavior, leading to improved physical fitness and cardiometabolic risk profile in individuals with type 2 diabetes.
Article
Endocrinology & Metabolism
James D. Johnson
Summary: Hundreds of millions of people are affected by hyperinsulinaemia, insulin resistance, obesity and dysglycaemia that mark a common progression to type 2 diabetes. The relative contributions and order in which these features appear may differ between individuals, but the common clustering and seemingly progressive nature of type 2 diabetes has guided research in this area for decades. The debate surrounding the causal relationships between these features continues, with new data from human trials and controlled animal studies being presented.
Review
Chemistry, Medicinal
Gangliang Huang, Shiyu Huang
Summary: Glucan has gained attention in life science research for its various advantages, but there are still two main issues in pharmacodynamics, including a lack of information on its mechanism of action and slow progress in the study of structure-activity relationships.
PHYTOTHERAPY RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Fang-Yuan Wang, Gui-Lin Wei, Yu-Fan Fan, Dong-Fang Zhao, Ping Wang, Li-Wei Zou, Ling Yang
Summary: In this study, oleanic acid, betulinic acid, and celastrol were identified as potent inhibitors of COMT with the ability to specifically recognize and bind with the enzyme, while reducing the risk of liver toxicity. These findings could lead to the development of new lead compounds and derivatives for further testing.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biology
Wayne Mitchell, Jeffrey D. Tamucci, Emery L. Ng, Shaoyi Liu, Alexander Birk, Hazel H. Szeto, Eric R. May, Andrei T. Alexandrescu, Nathan N. Alder
Summary: Mitochondria play a key role in metabolic homeostasis and their dysfunction is associated with various diseases. This study analyzed the structure-activity relationship of tetrapeptide analogs with different aromatic side chain compositions and sequence registrations. The results showed that these analogs adopt compact reverse turn conformations when bound to membranes and exhibit differences in membrane interactions. The analogs had effects on membrane surface charge and were able to penetrate cells and target mitochondria without strict requirements for side chain composition or sequence register. The analog with tryptophan side chains showed the strongest impact on membrane properties and had the highest efficacy in cell culture studies.
Review
Endocrinology & Metabolism
Chantal Mathieu, Iraj Ahmadzai
Summary: This review examines the use of GLP-1 receptor agonists, specifically in type 1 diabetes, and concludes that they can lower weight and required insulin doses. However, their effects on glucose control and hypoglycemia vary depending on study protocols. Side effects include gastrointestinal complaints. The potential use of GLP-1 receptor agonists in other forms of diabetes is briefly discussed, but current evidence is limited.
Article
Nutrition & Dietetics
Anurag Singh, Davide D'Amico, Penelope A. Andreux, Gillian Dunngalvin, Timo Kern, William Blanco-Bose, Johan Auwerx, Patrick Aebischer, Chris Rinsch
Summary: This study investigates the prevalence of UA producers in a healthy population and the effectiveness of direct UA supplementation in overcoming microbiome variability. Results show that 40% of subjects converted precursor compounds into UA after consuming pomegranate juice. UA producers were characterized by higher gut microbiome diversity and a specific bacteria ratio. Direct supplementation significantly increased plasma UA levels, providing a >6-fold exposure compared to PJ.
EUROPEAN JOURNAL OF CLINICAL NUTRITION
(2022)
Article
Multidisciplinary Sciences
Jean-David Morel, Lucie Sauzeat, Ludger J. E. Goeminne, Pooja Jha, Evan Williams, Riekelt H. Houtkooper, Ruedi Aebersold, Johan Auwerx, Vincent Balter
Summary: The metallome is often overlooked in mammals, but it plays a crucial role in cell functioning. In this study, the authors analyze the metallome and copper and zinc isotope compositions in aging mice and identify organ-specific, age-dependent, and isotopically-typified networks of interactions that are associated with clinical and molecular traits. The findings shed light on the importance of the metallome as an overlooked omic layer and provide insights into potential manipulation of cellular processes.
NATURE COMMUNICATIONS
(2022)
Review
Multidisciplinary Sciences
Charlotte Sornay, Valentine Vaur, Alain Wagner, Guilhem Chaubet
Summary: The bioconjugation of proteins, a complex process due to their sensitivity and selectivity issues, has been extensively studied. Strategies and reagents have been developed to address chemoselectivity and site-selectivity aspects. This review provides an overview of these strategies, with a focus on utilizing native proteins as substrates.
ROYAL SOCIETY OPEN SCIENCE
(2022)
Article
Multidisciplinary Sciences
Pirkka-Pekka Laurila, Peiling Luan, Martin Wohlwend, Nadege Zanou, Barbara Crisol, Tanes Imamura de Lima, Ludger J. E. Goeminne, Hector Gallart-Ayala, Minho Shong, Julijana Ivanisevic, Nicolas Place, Johan Auwerx
Summary: Inhibition of sphingolipid synthesis, targeting multiple pathogenic pathways, shows promise as a potential treatment for muscular dystrophies.
Article
Chemistry, Multidisciplinary
Thirouard Laura, Holota Helene, Monrose Melusine, Garcia Manon, De Haze Angelique, Damon-Soubeyrand Christelle, Renaud Yoan, Saru Jean-Paul, Perino Alessia, Schoonjans Kristina, Beaudoin Claude, Volle H. David
Summary: This study investigates the impact of the alkylating agent busulfan on spermatogonia homeostasis and the role of the TGR5 pathway. The results show that Tgr5 deficiency facilitates restoration of the spermatogonia homeostasis and accelerates the resurgence of the germ cell lineage after busulfan exposure.
Article
Gastroenterology & Hepatology
Kassem Makki, Harald Brolin, Natalia Petersen, Marcus Henricsson, Dan Ploug Christensen, Muhammad Tanweer Khan, Annika Wahlstrom, Per-Olof Bergh, Valentina Tremaroli, Kristina Schoonjans, Hanns-Ulrich Marschall, Fredrik Backhed
Summary: The study demonstrates that oligofructose, a soluble dietary fiber, improves host metabolism by modulating bacterial transformation of bile acids in mice fed a western-style diet.
Article
Cell Biology
Terytty Yang Li, Arwen W. Gao, Xiaoxu Li, Hao Li, Yasmine J. Liu, Amelia Lalou, Nagammal Neelagandan, Felix Naef, Kristina Schoonjans, Johan Auwerx
Summary: Stressed mitochondria activate the mitochondrial unfolded protein response (UPRmt) to improve organismal health. A study found that increased ATFS-1 translation, mediated by v-ATPase/TORC1, plays an essential role in UPRmt activation and mild mitochondrial stress-induced longevity.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Chemistry, Analytical
Robin Dufossez, Sylvain Ursuegui, Stephanie Baudrey, Ketty Pernod, Safae Mouftakhir, Mustapha Oulad-Abdelghani, Michel Mosser, Guilhem Chaubet, Michael Ryckelynck, Alain Wagner
Summary: Enzyme-linked immunosorbent assay (ELISA) is a widely used method for protein detection in biological science. In this study, a novel droplet-based immunoassay format called D-SIRe was developed, which utilizes the oil/water interface as the capture and detection surface for proteins. This method is fast and sensitive, allowing the detection of analytes at the single bacteria level.
ANALYTICAL CHEMISTRY
(2023)
Article
Immunology
Giorgia Benegiamo, Giacomo V. G. von Alvensleben, Sandra Rodriguez-Lopez, Ludger J. E. Goeminne, Alexis M. Bachmann, Jean-David Morel, Ellen Broeckx, Jing Ying Ma, Vinicius Carreira, Sameh A. Youssef, Nabil Azhar, Dermot F. Reilly, Katharine D'Aquino, Shannon Mullican, Maroun Bou-Sleiman, Johan Auwerx
Summary: Mice from different genetic backgrounds have diverse responses to metabolic challenges. PWK/PhJ mice show significant mitochondrial dysfunction and progress to fibrotic NASH similar to human NASH, making them a novel NASH mouse model.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Biology
Ece Yildiz, Gaby El Alam, Alessia Perino, Antoine Jalil, Pierre-Damien Denechaud, Katharina Huber, Lluis Fajas, Johan Auwerx, Giovanni Sorrentino, Kristina Schoonjans
Summary: During severe or chronic hepatic injury, biliary epithelial cells (BECs) can rapidly accumulate lipids and undergo metabolic rewiring, leading to their conversion into reactive progenitor cells. This process, driven by the activation of E2F transcription factors, plays a crucial role in the early stages of non-alcoholic fatty liver disease (NAFLD) and provides insights into the connection between lipid metabolism, stemness, and regeneration.
Article
Nanoscience & Nanotechnology
Robin Dufossez, Marie-Pierre Krafft, Sylvain Ursuegui, Michel Mosser, Safae Mouftakhir, Ketty Pernod, Guilhem Chaubet, Michael Ryckelynck, Alain Wagner
Summary: Droplet-based microfluidics is advancing the development of miniaturized and sensitive enzyme-linked immunosorbent assays (ELISAs). This article investigates the impact of surfactant structure on the efficiency and stability of the antibody grafting process on droplets. It demonstrates that short linkers lead to high functionalization efficiency, while long linkers enhance stability, with an intermediate size required to balance both parameters. The optimal structure is a PEG4 linker connecting a polar di-azide head and a per-fluoropolyether tail.
ACS APPLIED MATERIALS & INTERFACES
(2023)
Article
Cell Biology
Terytty Yang Li, Qi Wang, Arwen W. Gao, Xiaoxu Li, Yu Sun, Adrienne Mottis, Minho Shong, Johan Auwerx
Summary: Lysosomal acidification through v-ATPase is crucial for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). The activation of lysosomes by v-ATPase stimulates mTORC1, which then phosphorylates the transcription factor ATF4, leading to the activation of the UPRmt and mitochondrial function resilience.
Article
Medicine, Research & Experimental
Yu Sun, Hadrien Demagny, Adrien Faure, Francesca Pontanari, Antoine Jalil, Nadia Bresciani, Ece Yildiz, Melanie Korbelius, Alessia Perino, Kristina Schoonjans
Summary: The enzyme asparagine synthetase (ASNS) is responsible for the de novo synthesis of the nonessential amino acid asparagine. The expression of ASNS in pericentral hepatocytes, specialized liver cells in xenobiotic detoxification, is significantly increased in models of acute liver injury. Mice with hepatocyte-specific Asns deletion are more susceptible to pericentral liver damage, which can be reversed by intravenous administration of asparagine. The upregulation of ASNS in response to stress is mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1; NR5A2) through an ATF4-independent, noncanonical pathway.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Chemistry, Analytical
Robin Dufossez, Sylvain Ursuegui, Stephanie Baudrey, Ketty Pernod, Safae Mouftakhir, Mustapha Oulad-Abdelghani, Michel Mosser, Guilhem Chaubet, Michael Ryckelynck, Alain Wagner
Summary: Enzyme-linked immunosorbent assay (ELISA) is an important method for detecting proteins in biological science. By utilizing droplet-based microfluidics, miniaturized, less-consuming, and more sensitive ELISA assays can be developed by encapsulating biological samples and antibody-functionalized particles. This study introduces a new droplet surface immunoassay format that uses the oil/water phase interface as a protein capture and detection surface, eliminating the need for particles. The resulting method, called droplet surface immunoassay by fluorescence relocation (D-SIRe), demonstrates high sensitivity and rapid detection capabilities.
ANALYTICAL CHEMISTRY
(2023)
Article
Endocrinology & Metabolism
Alessia Perino, Kristina Schoonjans
Summary: Bile acids are amphipathic steroid acids that play a crucial role in the regulation of metabolic responses. Their actions through activation of specific receptors control energy homeostasis and alterations in bile acid signaling are associated with metabolic diseases. Modulation of the bile acid pool could be a potential therapeutic approach.
