The toxic mechanisms of cisplatin have been frequently studied in many species and in vitro cell models. The Netherlands Toxicogenomics Centre focuses on developing in vitro alternatives using genomics technologies for animal-based assays on, e.g. genotoxic hazards. Models such as human hepatocellular carcinoma cell line (HepG2) cells, mouse primary hepatocytes (PMH) and mouse embryonic stem cells (mESC) are used. Our aim was to identify possibly robust conserved mechanisms between these models using cisplatin as model genotoxic agent. Transcriptomic data newly generated from HepG2 cells and PMH exposed to 7 µM cisplatin for 12, 24 and 48h and 24 and 48h, respectively, were compared with published data from mESC exposed to 5 µM cisplatin for 2-24h. Due to differences in response time between models and marginal changes after shorter exposure periods, we focused on 24 and 48h. At gene level, 44 conserved differentially expressed genes (DEG), involved in processes such as apoptosis, cell cycle, DNA damage response and DNA repair, were found. Functional analysis shows that limited numbers of pathways are conserved. Transcription factor (TF) network analysis indicates 12 common TF networks responding among all models and time points. Four TF, HNF4-α, SP1, c-MYC and p53, capable of regulating ±50% of all DEG, seem of equal importance in all models and exposure periods. Here we showed that transcriptomic responses across several in vitro cell models following exposure to cisplatin are mainly determined by a conserved complex network of 4 TFs. These conserved responses are hypothesised to provide most relevant information for human toxicity prediction and may form the basis for new in vitro alternatives of risk assessment.
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http://dx.doi.org/10.1093/mutage/get055 | DOI Listing |
Tissue Eng Regen Med
January 2025
Department of Pediatrics, College of Medicine, Ewha Womans University, Seoul, 07804, South Korea.
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January 2025
Department of Pharmacology and Toxicology, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana.
Purpose: Major depressive disorder is one of the most common and burdensome psychiatric disorders worldwide. This study evaluated the anxiolytic- and antidepressant-like activity of three semi-synthetic derivatives of xylopic acid (XA) to identify the most promising derivative based on mechanism(s) of action, in vivo pharmacokinetics and in vitro cytotoxicity.
Methods: The anxiolytic potential and the involvement of GABAergic mechanisms were assessed in the elevated plus-maze and open field tests in mice.
Integr Cancer Ther
January 2025
National Centre for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt.
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January 2025
Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
The intricate link between cholesterol metabolism and host immune responses is well recognized, but the specific mechanisms by which cholesterol biosynthesis influences hepatitis B virus (HBV) replication remain unclear. In this study, we show that SREBP2, a key regulator of cholesterol metabolism, inhibits HBV replication by interacting directly with the HBx protein, thereby preventing its nuclear translocation. We also found that inhibiting the ER-to-Golgi transport of the SCAP-SREBP2 complex or blocking SREBP2 maturation significantly enhances HBV suppression.
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