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Bayesian Gene Set Benchmark Dose Estimation for "omic" responses.
Bioinformatics
January 2025
Division of Intramural Research, Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, North Carolina 27709, United States.
Motivation: Estimating a toxic reference point using tools like the benchmark dose (BMD) is a critical step in setting policy to regulate pollution and ensure safe environments. Toxicity can be measured for different endpoints, including changes in gene expression and histopathology for various tissues, and is typically explored one gene or tissue at a time in a univariate setting that ignores correlation. In this work, we develop a multivariate estimation procedure to estimate the BMD for specified gene sets.
View Article and Find Full Text PDFTAK-994 Mechanistic Investigation into Drug-Induced Liver Injury.
Toxicol Sci
January 2025
Takeda Development Center Americas, Inc, Cambridge, MA, USA.
The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding.
View Article and Find Full Text PDFSynthesis and Application of a Novel Multifunctional Nanoprodrug for Synergistic Chemotherapy and Phototherapy with Hydrogen Sulfide Gas.
J Med Chem
January 2025
Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Rd., Nanchang, Jiangxi 330013, China.
With the dilemma of limited efficacy of individual therapies, it is crucial to develop innovative combination therapy systems to target the complex pathogenesis of cancer. In this study, we designed a nanoprodrug ISL@MIL-101-ADT to facilitate synergistic delivery of hydrogen sulfide (HS) and prodrug ISL for specific eradication of tumor cells with minimal toxicity and maximal efficacy. The nanoprodrug passively targeted tumors through enhanced permeation and retention effects, followed by disintegration and release of IR780, lonidamine (LND), and HS.
View Article and Find Full Text PDFMultilayered Nanocarriers as a New Strategy for Delivering Drugs with Protective and Anti-inflammatory Potential: Studies in Hippocampal Organotypic Cultures Subjected to Experimental Ischemia.
Mol Neurobiol
January 2025
Laboratory of Immunoendocrinology Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland.
Oxidative stress and neuroinflammation play a pivotal role in pathomechanisms of brain ischemia. Our research aimed to formulate a nanotheranostic system for delivering carnosic acid as a neuroprotective agent with anti-oxidative and anti-inflammatory properties to ischemic brain tissue, mimicked by organotypic hippocampal cultures (OHCs) exposed to oxygen-glucose deprivation (OGD). In the first part of this study, the nanocarriers were formulated by encapsulating two types of nanocores (nanoemulsion (AOT) and polymeric (PCL)) containing CA into multilayer shells using the sequential adsorption of charged nanoobjects method.
View Article and Find Full Text PDFDynamics in zebrafish development define transcriptomic specificity after angiogenesis inhibitor exposure.
Arch Toxicol
January 2025
Department of Ecotoxicology, Helmholtz Centre for Environmental Research-UFZ, Permoserstraβe 15, 04318, Leipzig, Germany.
Testing for developmental toxicity is an integral part of chemical regulations. The applied tests are laborious and costly and require a large number of vertebrate test animals. To reduce animal numbers and associated costs, the zebrafish embryo was proposed as an alternative model.
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