Unleashing the potential of cell painting assays for compound activities and hazards prediction.

The cell painting (CP) assay has emerged as a potent imaging-based high-throughput phenotypic profiling (HTPP) tool that provides comprehensive input data for in silico prediction of compound activities and potential hazards in drug discovery and toxicology. CP enables the rapid, multiplexed investigation of various molecular mechanisms for thousands of compounds at the single-cell level. The resulting large volumes of image data provide great opportunities but also pose challenges to image and data analysis routines as well as property prediction models. This review addresses the integration of CP-based phenotypic data together with or in substitute of structural information from compounds into machine (ML) and deep learning (DL) models to predict compound activities for various human-relevant disease endpoints and to identify the underlying modes-of-action (MoA) while avoiding unnecessary animal testing. The successful application of CP in combination with powerful ML/DL models promises further advances in understanding compound responses of cells guiding therapeutic development and risk assessment. Therefore, this review highlights the importance of unlocking the potential of CP assays when combined with molecular fingerprints for compound evaluation and discusses the current challenges that are associated with this approach.

The adverse outcome pathway for breast cancer: a knowledge management framework bridging biomedicine and toxicology.

Breast cancer is the most common cancer worldwide, with an estimated 2.3 million new cases diagnosed every year. Effective measures for cancer prevention and cancer therapy require a detailed understanding of the individual key disease mechanisms involved and their interactions at the molecular, cellular, tissue, organ, and organism level. In that regard, the rapid progress of biomedical and toxicological research in recent years now allows the pursuit of new approaches based on non-animal methods that provide greater mechanistic insight than traditional animal models and therefore facilitate the development of Adverse Outcome Pathways (AOPs) for human diseases. We performed a systematic review of the current state of published knowledge with regard to breast cancer to identify relevant key mechanisms for inclusion into breast cancer AOPs, i.e. decreased cell stiffness and decreased cell adhesion, and to concurrently map non-animal methods addressing these key events. We conclude that the broader sharing of expertise and methods between biomedical research and toxicology enabled by the AOP knowledge management framework can help to coordinate global research efforts and accelerate the transition to advanced non-animal methods, which, when combined into powerful method batteries, closely mimic human physiology and disease states without the need for animal testing.

Specific Wheat Fractions Influence Hepatic Fat Metabolism in Diet-Induced Obese Mice.

Low whole grain consumption is a risk factor for the development of non-communicable diseases such as type 2 diabetes. Dietary fiber and phytochemicals are bioactive grain compounds, which could be involved in mediating these beneficial effects. These compounds are not equally distributed in the wheat grain, but are enriched in the bran and aleurone fractions. As little is known on physiological effects of different wheat fractions, the aim of this study was to investigate this aspect in an obesity model. For twelve weeks, C57BL/6J mice were fed high-fat diets (HFD), supplemented with one of four wheat fractions: whole grain flour, refined white flour, bran, or aleurone. The different diets did not affect body weight, however bran and aleurone decreased liver triglyceride content, and increased hepatic n-3 polyunsaturated fatty acid (PUFA) concentrations. Furthermore, lipidomics analysis revealed increased PUFA concentration in the lipid classes of phosphatidylcholine (PC), PC-ether, and phosphatidylinositol in the plasma of mice fed whole grain, bran, and aleurone supplemented diets, compared to refined white flour. Furthermore, bran, aleurone, and whole grain supplemented diets increased microbial α-diversity, but only bran and aleurone increased the cecal concentrations of short-chain fatty acids. The effects on hepatic lipid metabolism might thus at least partially be mediated by microbiota-dependent mechanisms.