Featured
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Article
| Open Access
A generative adversarial network model alternative to animal studies for clinical pathology assessment
Generative AI has the potential to transform the way chemical and drug safety research is conducted. Here the authors show AnimalGAN, a model developed using Generative Adversarial Networks, which simulates virtual animal experiments to generate multidimensional rat clinical pathology measurements.
- Xi Chen
- , Ruth Roberts
- & Weida Tong
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Article
| Open Access
ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.
- Yue Hu
- , Haijun Li
- & Yanhua Ding
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Article
| Open Access
Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics
Untargeted metabolomics enables simultaneous measurement of xenobiotic fate and effects in biological systems. This is demonstrated through discovering extensive biotransformation maps, measuring systemic exposures over time, and directly associating endogenous biochemical responses to internal dose.
- Tara J. Bowen
- , Andrew D. Southam
- & Mark R. Viant
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Article
| Open Access
A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
In vitro secondary pharmacology assays are used to predict the clinical adverse event risks of new drugs. Here, the authors describe a new database, identify the most predictive assays for estimating risk, and propose candidate mechanisms to explain clinically observed risk profiles.
- Jeffrey J. Sutherland
- , Dimitar Yonchev
- & Laszlo Urban
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Article
| Open Access
Regorafenib 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 Access
Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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Article
| Open Access
Differential 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 Access
Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer
Accumulating evidence suggest that chemotherapy could paradoxically promote cancer metastasis. Here the authors report that, in preclinical breast cancer models, adjuvant treatment with doxorubicin induces the formation of an immunosuppressive metastatic niche that promotes relapse but that can be reverted with pharmacological blockade of complement signaling.
- Lea Monteran
- , Nour Ershaid
- & Neta Erez
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Article
| Open Access
Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Propionic acidemia is a serious pediatric inherited disorder with no effective treatments. Here the authors demonstrate that delivering dual mRNAs as an enzyme replacement approach can be used as an effective therapy in a mouse model of propionic acidemia, with potential applicability to chronically administer multiple mRNAs in other genetic disorders.
- Lei Jiang
- , Ji-Sun Park
- & Lin T. Guey
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Article
| Open Access
Predicting the frequencies of drug side effects
Currently, the frequencies of drug side effects are determined in randomised controlled clinical trials. Here the authors develop an interpretable machine learning approach to predict the frequencies of unknown side effects for drugs with a small number of determined side effect frequencies.
- Diego Galeano
- , Shantao Li
- & Alberto Paccanaro
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Article
| Open Access
Edible unclonable functions
Counterfeit medicines are a threat to patient health and public safety. Here, the authors use random patterns formed by fluorescent silk microparticles with various excitation and emission pairs as an edible physical unclonable function that can directly be attached onto the surface of medicines.
- Jung Woo Leem
- , Min Seok Kim
- & Young L. Kim
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Article
| Open Access
Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity
Kinase inhibitors used in chemotherapy are known for their adverse effects on kidney physiology. Here, Calizo et al. show that dasatinib is associated with a higher risk of glomerular toxicity compared to other kinase inhibitors, due to deleterious effects on cytoskeletal biomechanics in podocytes.
- Rhodora C. Calizo
- , Smiti Bhattacharya
- & Evren U. Azeloglu
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Article
| Open Access
Phenotypes associated with genes encoding drug targets are predictive of clinical trial side effects
Safety issues including side effects are one of the major factors causing failure of clinical trials in drug development. Here, the authors leverage information about phenotypes associated with variation in genes encoding drug targets to predict drug-treatment-related side effects.
- Phuong A. Nguyen
- , David A. Born
- & Lucas D. Ward
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Article
| Open Access
Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity
A subset of chemically-modified siRNAs conjugated to trivalent GalNAc may fail during nonclinical development due to rat hepatotoxicity. Here, the authors show that hepatotoxicity may be accounted for by microRNA-like off-target effects of siRNA and can be mitigated by a thermally destabilizing modification in the siRNA seed region.
- Maja M. Janas
- , Mark K. Schlegel
- & Vasant Jadhav
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Article
| Open Access
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.
- Andrea M. Zuhl
- , Charles E. Nolan
- & Douglas S. Johnson
NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease