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| Open AccessSulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used but their risks for early neurodevelopment remain controversial. Here, the authors showed in zebrafish larvae that sulindac induces GABAergic neuron apoptosis through autophagy activation that leads to hyperactive behavior.
- Wenwei Sun
- , Meimei Wang
- & Zhibin Huang
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Article
| Open AccessIdentification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity
There is currently no specific antidote for death cap mushroom poisoning treatment. Here, the authors identify STT3B as a druggable target and show that indocyanine green is a STT3B inhibitor that can block α-amanitin toxicity in cell lines, liver organoids and mice.
- Bei Wang
- , Arabella H. Wan
- & Qiao-Ping Wang
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Article
| Open AccessRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis
The mechanism underlying regorafenib’s hepatotoxicity during anticancer therapy remains elusive. Here, the authors show regorafenib inhibits the phosphorylation of EphA2 at Ser897 resulting in the accumulation of p53 and contributes to hepatocytes apoptosis and the formation of hepatotoxicity.
- Hao Yan
- , Wentong Wu
- & Peihua Luo
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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Article
| Open AccessDifferential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors
Patients treated with Aurora kinase inhibitors experience dose-limiting neutropenia while other cytopenias are rare. Here, Chou et al. show that this cell-type specific side effect is partly explained by loss of drug efflux pump expression during neutrophil differentiation.
- David B. Chou
- , Brooke A. Furlong
- & Donald E. Ingber
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Article
| Open AccessLactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
Triclosan is an antimicrobial additive in consumer products that has been detected in human breast milk. Here the authors report that exposure of pregnant mice to triclosan leads to lactational exposure to newborns and the development of liver steatosis.
- André A. Weber
- , Xiaojing Yang
- & Robert H. Tukey
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Article
| Open AccessPrecision digital mapping of endogenous and induced genomic DNA breaks by INDUCE-seq
Understanding how DNA double strand breaks (DSBs) form and are repaired in the genome depends on their accurate measurement. Here the authors describe INDUCE-seq; a DSB-detection method that simultaneously measures physiological and induced breaks throughout the genome.
- Felix M. Dobbs
- , Patrick van Eijk
- & Simon H. Reed
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Article
| Open AccessPortable bioluminescent platform for in vivo monitoring of biological processes in non-transgenic animals
Bioluminescence imaging tends to rely on transgenic luciferase-expressing cells and animals. Here the authors report a portable bioluminescent system to non-invasively measure intra- and extracellular enzymes in vivo in non-transgenic animals which do not express luciferase.
- Aleksey Yevtodiyenko
- , Arkadiy Bazhin
- & Elena A. Goun
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Article
| Open AccessTranscriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity
Cardiotoxic adverse events associated with kinase inhibitors are a growing concern in clinical oncology. Here the authors use cellular transcriptomic responses of human cardiomyocytes treated with protein kinase inhibitors and the associated drug structural signatures to determine an integrated predictive signature of cardiotoxicity.
- J. G. Coen van Hasselt
- , Rayees Rahman
- & Ravi Iyengar
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Perspective
| Open AccessUse cases, best practice and reporting standards for metabolomics in regulatory toxicology
Lack of best practice guidelines currently limits the application of metabolomics in the regulatory sciences. Here, the MEtabolomics standaRds Initiative in Toxicology (MERIT) proposes methods and reporting standards for several important applications of metabolomics in regulatory toxicology.
- Mark R. Viant
- , Timothy M. D. Ebbels
- & Ralf J. M. Weber
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Article
| Open AccessOptimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
- Xinyue Qi
- , Fanlin Li
- & Xuanming Yang
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Article
| Open AccessA novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism
Human liver chimeric mice are increasingly used for drug testing in preclinical development, but express residual murine p450 cytochromes. Here the authors generate mice lacking the Por gene in the liver, and show that human cytochrome metabolism is used following repopulation with human hepatocytes.
- Mercedes Barzi
- , Francis P. Pankowicz
- & Karl-Dimiter Bissig
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Article
| Open AccessFluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice
Bisphenol A is used in the production of many plastic products, but has adverse health effects and is therefore being replaced. Here the authors show that its substitute, fluorene-9-bisphenol, is released from commercial plastic bottles into drinking water, and has anti-oestrogenic effects in mice.
- Zhaobin Zhang
- , Ying Hu
- & Jianying Hu
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Article
| Open AccessReconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions
The rat is a widely-used model for human biology, but we must be aware of metabolic differences. Here, the authors reconstruct the genome-scale metabolic network of the rat, and after reconciling it with an improved human metabolic model, demonstrate the power of the models to integrate toxicogenomics data, providing species-specific biomarker predictions in response to a panel of drugs.
- Edik M. Blais
- , Kristopher D. Rawls
- & Jason A. Papin
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High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening
Current tools to test drug metabolism and toxicity in the liver are mainly based on time-consuming traditional cell culture methods. Here Kwon et al.report a high-throughput system employing cells cultured on micropillars that can be transfected with combinations of drug-metabolizing enzymes.
- Seok Joon Kwon
- , Dong Woo Lee
- & Moo-Yeal Lee