Article
Multidisciplinary Sciences
Katalin Mango, Adam Ferenc Kiss, Ferenc Fekete, Reka Erdos, Katalin Monostory
Summary: The CYP2B6 enzyme is a major catalyst for the metabolism of several important drugs, and its function varies greatly among individuals due to both genetic and non-genetic factors. A study found that hepatic CYP2B6 activity is strongly correlated with CYP2B6 mRNA expression, and that both genetic and non-genetic factors can contribute to a mismatch between CYP2B6 genotype and phenotype.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Melissa M. Heintz, Jazmine A. Eccles, Emily M. Olack, Kristal M. Maner-Smith, Eric A. Ortlund, William S. Baldwin
Summary: In addition to over consumption, multiple factors contribute to obesity and non-alcoholic fatty liver disease (NAFLD). CYP2B6, a human detoxification enzyme, has been found to be associated with obesity. It metabolizes PUFAs, with a preference for ALA metabolism and PUFAs at the 9- and 13-positions. Research using transgenic mice showed that CYP2B6 has an anti-obesity effect, but to a lesser extent compared to Cyp2b in mice. The inhibition of CYP2B6 by xenobiotics or dietary fats can worsen obesity and metabolic disease by disrupting PUFA metabolism and producing key lipid metabolites.
Article
Pharmacology & Pharmacy
Han Li, Yu-Guang Wang, Zeng-Chun Ma, Gao Yun-Hang, Song Ling, Chen Teng-Fei, Zhang Guang-Ping, Yue Gao
Summary: The research established stable AhR, CAR, and PXR-responsive HepG2 cell lines for rapid screening of CYP450 enzyme induction and validated their response to different inducers. There was a positive correlation between the induction activities and endogenous CYP mRNA expression.
Article
Genetics & Heredity
Mohammad Bagher Hashemi-Soteh, Elaheh Hosseini, Shokoufeh Fazelnia, Faramarz Ghasemian-Sorbeni, Sara Madahian, Mohammad Reza Shiran
Summary: This study investigated the frequencies of CYP2B6 alleles in the Iranian Mazani ethnic group, showing that the frequencies of CYP2B6*4 and CYP2B6*6 alleles were higher while the frequency of CYP2B6*5 was lower than expected. These results provide insights into ethnic diversity in the Iranian population and offer a basis for rational drug use in this population.
Review
Biochemistry & Molecular Biology
Morgane M. Thibaut, Laure B. Bindels
Summary: This review summarizes the immune-modulatory actions of bile acid-responsive receptors and discusses the contribution of microbiota-derived bile acids to intestinal and hepatic inflammation through these receptors.
TRENDS IN MOLECULAR MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Daniel Rizzolo, Bo Kong, Stephanie Piekos, Liming Chen, Xiaobo Zhong, Jie Lu, Jian Shi, Hao-jie Zhu, Qian Yang, Albert Li, Linhao Li, Hongbing Wang, Anna Siemiatkowska, Celine Park, Leonid Kagan, Grace L. Guo
Summary: Fibroblast growth factors 15 and 19 are important in maintaining bile acid homeostasis, and are currently being tested as potential treatments for certain liver diseases. This study found that long-term elevations of these growth factors can lead to increased expression of drug metabolizing enzymes, affecting drug metabolism and pharmacokinetics. The overexpression of Fgf15 was also found to cause a switch in the expression pattern of these enzymes in male mice, similar to the pattern observed in female mice. This change was associated with differences in growth hormone secretion and STAT5 signaling.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Lena C. Preiss, Ruoqi Liu, Philip Hewitt, David Thompson, Katrin Georgi, Lassina Badolo, Volker M. Lauschke, Carl Petersson
Summary: This study utilized HepaRG cells and PXR, CAR KO cells to investigate the induction mechanisms of CYP3A4 and CYP2B6, revealing that most test compounds induced these enzymes primarily through PXR and to a lesser extent through CAR, while also implicating other non-NHR-driven induction mechanisms.
DRUG METABOLISM AND DISPOSITION
(2021)
Article
Biochemical Research Methods
Marta Moreno-Torres, Manoj Kumar, Guillem Garcia-Llorens, Guillermo Quintas, Tine Tricot, Ruben Boon, Laia Tolosa, Burak Toprakhisar, Francois Chesnais, Catherine Verfaillie, Jose Castell
Summary: This article introduces a new strategy to assess the differentiation degree of iPSCs by comparing their cellular metabolome with that of primary human hepatocytes. The analysis of metabolome changes in three different iPSC progenies cultured in different differentiation media validates the feasibility of this approach and identifies the factors that promote metabolome changes.
JOURNAL OF PROTEOME RESEARCH
(2022)
Article
Nutrition & Dietetics
Maria Crespo-Masip, Aurora Perez-Gomez, Alicia Garcia-Carrasco, Ramiro Jover, Carla Guzman, Xavier Dolcet, Merce Ibarz, Cristina Martinez, Auria Eritja, Juan Miguel Diaz-Tocados, Jose Manuel Valdivielso
Summary: This study found that lack of vitamin D signaling increases mortality in a model of overactivation of the insulin receptor by impairing lipid metabolism. These findings highlight the importance of adequate vitamin D levels in patients with type 1 diabetes.
Article
Endocrinology & Metabolism
Maria Crespo-Masip, Aurora Perez-Gomez, Carla Guzman, Sandra Rayego, Nuria Dolade, Alicia Garcia-Carrasco, Ramiro Jover, Jose Manuel Valdivielso
Summary: In this study, we generated PTEN-KO mice to investigate the systemic effect of overactivation of the PI3K/AKT pathway on insulin signaling and glucose homeostasis. Our findings suggest that PTEN deficiency leads to abnormal glucose metabolism and insulin signaling, characterized by low glucose levels and impaired response to glucose and pyruvate administration. We also identified deregulation of glucose transporter expression in the proximal tubule and altered activation of hepatic gluconeogenesis-related genes in PTEN-KO mice. These results indicate that PTEN may play a crucial role in hypoinsulinemic hypoglycemia and could serve as a potential drug target.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ruben Rodriguez-Agudo, Naroa Goikoetxea-Usandizaga, Marina Serrano-Macia, Pablo Fernandez-Tussy, David Fernandez-Ramos, Sofia Lachiondo-Ortega, Irene Gonzalez-Recio, Claudia Gil-Pitarch, Maria Mercado-Gomez, Laura Moran, Maider Bizkarguenaga, Fernando Lopitz-Otsoa, Petar Petrov, Miren Bravo, Sebastiaan Martijn Van Liempd, Juan Manuel Falcon-Perez, Amaia Zabala-Letona, Arkaitz Carracedo, Jose Vicente Castell, Ramiro Jover, Luis Alfonso Martinez-Cruz, Teresa Cardoso Delgado, Francisco Javier Cubero, Maria Isabel Lucena, Raul Jesus Andrade, Jon Mabe, Jorge Simon, Maria Luz Martinez-Chantar
Summary: The study demonstrates that anti-miR-873-5p is effective in combating APAP-induced liver injury by restoring GNMT and the methionine cycle to prevent mitochondrial dysfunction and activate hepatocyte proliferative response.
Article
Nutrition & Dietetics
Marta Moreno-Torres, Carla Guzman, Petar D. Petrov, Ramiro Jover
Summary: In this study, valproic acid (VPA) and natural short-chain fatty acids (SCFAs) were identified as novel transcriptional activators for the human VDR gene. The researchers characterized the responsive elements in the regulatory region of the hVDR gene and found that a short DNA region upstream of the transcription start site is responsible for the increase in transcriptional activity in response to VPA/SCFAs. The results suggest that VPA and SCFAs facilitate the activity of the transcription factor Sp1 in the hVDR gene, promoting VDR upregulation and signaling. These findings may have clinical relevance in epileptic pediatric patients on VPA therapy and suggest a potential role of SCFAs produced by gut microbiota in VDR upregulation.
Review
Biochemistry & Molecular Biology
Marta Moreno-Torres, Guillermo Quintas, Jose Castell
Summary: Metabolomics as a tool holds great potential in DILI biomarker research, although there are limitations and inconsistencies that hinder the translation of research findings into general clinical practice, notable progress has been made in identifying promising novel metabolite biomarkers.
Article
Health Care Sciences & Services
Guillem Garcia-Llorens, Sergi Lopez-Navarro, Teresa Jaijo, Jose Castell, Roque Bort
Summary: In this study, a novel gene variant was identified, and personalized hepatocyte-like cells were generated using a direct reprogramming strategy, allowing for a clear molecular diagnosis and disease research.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Guillermo Quintas, Florian Caiment, Ivan Rienda, Judith Perez-Rojas, Eugenia Pareja, Jose Castell, Ramiro Jover
Summary: This study investigated the association between miRNAs and liver steatosis, and developed miRNA regression models to predict the percentage of liver fat. The results showed that miRNAs were significantly correlated with liver fat and that a combination of certain miRNAs could accurately predict liver steatosis. These findings highlight the potential use of miRNA as biomarkers for assessing NAFLD in primary healthcare settings.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Maria Mercado-Gomez, Endika Prieto-Fernandez, Naroa Goikoetxea-Usandizaga, Laura Vila-Vecilla, Mikel Azkargorta, Miren Bravo, Marina Serrano-Macia, Leire Egia-Mendikute, Ruben Rodriguez-Agudo, Sofia Lachiondo-Ortega, So Young Lee, Alvaro Eguileor Gine, Claudia Gil-Pitarch, Irene Gonzalez-Recio, Jorge Simon, Petar Petrov, Ramiro Jover, Luis Alfonso Martinez-Cruz, June Ereno-Orbea, Teresa Cardoso Delgado, Felix Elortza, Jesus Jimenez-Barbero, Ruben Nogueiras, Vincent Prevot, Asis Palazon, Maria L. Martinez-Chantar
Summary: SARS-CoV-2 pseudovirus infects human hepatocytes and causes metabolic reprogramming and impaired mitochondrial activity. Patients with fatty liver are more susceptible to infection, but the use of metformin can reduce the risk of infection.
COMMUNICATIONS BIOLOGY
(2022)
Article
Toxicology
Teresa Martinez-Sena, Erika Moro, Marta Moreno-Torres, Guillermo Quintas, Jan Hengstler, Jose V. Castell
Summary: Toxicity studies, especially hepatotoxicity, are crucial in preclinical drug development to minimize undesired toxic effects. In vitro models, particularly cultured hepatocytes, offer a reliable alternative to animal testing for predicting human risk. This study proposes an innovative strategy using mass spectrometry to analyze metabolome changes in HepG2 cells induced by hepatotoxic and non-hepatotoxic compounds. By comparing the alterations and elucidating the mechanisms, specific metabolic patterns were identified, allowing prediction of hepatotoxicity and mechanism-related toxicity.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Nutrition & Dietetics
Alvaro Perez-Rubio, Polina Soluyanova, Erika Moro, Guillermo Quintas, Ivan Rienda, Maria Dolores Perianez, Andres Painel, Jose Vizuete, Judith Perez-Rojas, Jose V. Castell, Ramon Trullenque-Juan, Eugenia Pareja, Ramiro Jover
Summary: Bariatric surgery can resolve non-alcoholic fatty liver disease, but not all patients experience this benefit. This study found that specific changes in gut microbiota and plasma bile acids are associated with resolution of fatty liver after bariatric surgery. The results provide valuable insights for interventions using prebiotics and/or probiotics to promote a gut microbiome that favors fatty liver resolution in bariatric surgery patients.
Article
Chemistry, Analytical
Julia Kuligowski, Alvaro Perez-Rubio, Marta Moreno-Torres, Polina Soluyanova, Judith Perez-Rojas, Ivan Rienda, David Perez-Guaita, Eugenia Pareja, Ramon Trullenque-Juan, Jose Castell, Marcha Verheijen, Florian Caiment, Ramiro Jover, Guillermo Quintas
Summary: This study introduces a novel variable selection approach called cluster PLS (c-PLS) to assess the joint impact of variable groups selected based on biological characteristics on the predictive performance of a multivariate model. The usefulness of c-PLS is shown using miRNomic and metabolomic datasets obtained from the analysis of liver tissue biopsies.
ANALYTICA CHIMICA ACTA
(2024)
Meeting Abstract
Toxicology
P. D. Petrov, P. Soluyanova, S. Sanchez-Campos, J. V. Castell, R. Jover
TOXICOLOGY LETTERS
(2021)