In-depth mechanistic analysis including high-throughput RNA sequencing in the prediction of functional and structural cardiotoxicants using hiPSC cardiomyocytes.

Background: Cardiotoxicity remains one of the most reported adverse drug reactions that lead to drug attrition during pre-clinical and clinical drug development. Drug-induced cardiotoxicity may develop as a functional change in cardiac electrophysiology (acute alteration of the mechanical function of the myocardium) and/or as a structural change, resulting in loss of viability and morphological damage to cardiac tissue.

Research Design And Methods: Non-clinical models with better predictive value need to be established to improve cardiac safety pharmacology.

The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development.

Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints.

Chirped pulse amplification in an extreme-ultraviolet free-electron laser.

Chirped pulse amplification in optical lasers is a revolutionary technique, which allows the generation of extremely powerful femtosecond pulses in the infrared and visible spectral ranges. Such pulses are nowadays an indispensable tool for a myriad of applications, both in fundamental and applied research. In recent years, a strong need emerged for light sources producing ultra-short and intense laser-like X-ray pulses, to be used for experiments in a variety of disciplines, ranging from physics and chemistry to biology and material sciences.

An in vitro method to assess toxicity of waterborne metals to fish.

The transcription of metal-responsive genes in the rainbow trout (Oncorhynchus mykiss) gill tissue can be used to detect effects of bioreactive metals in natural waters. Here we take advantage of an in vitro gill epithelium, which can be directly exposed to test water samples. The in vitro gill epithelial model mimics the molecular response of in vivo gill epithelial cells to waterborne contaminants.

Cortisol stimulates the zinc signaling pathway and expression of metallothioneins and ZnT1 in rainbow trout gill epithelial cells.

Intracellular zinc signaling is important in the control of a number of cellular processes. Hormonal factors that regulate cellular zinc influx and initiate zinc signals are poorly understood. The present study investigates the possibility for cross talk between the glucocorticoid and zinc signaling pathways in cultured rainbow trout gill epithelial cells.

Influence of culture conditions on metal-induced responses in a cultured rainbow trout gill epithelium.

A primary culture technique for rainbow trout (Oncorhynchus mykiss) gill cells was optimized to better represent the intact gill in vivo in response to waterborne toxic metals. Modifications in cell seeding density and culture conditions resulted in a gill epithelial cell culture model, which displayed classic in vivo responses to toxic metals. Metallothionein-A (MTA), metallothionein-B (MTB), zinc transporter-1 (ZnT-1), glutathione-S-transferase (GST), and glucose-6-phosphate-dehydrogenase (G6PD) all showed dose-dependent increases in expression at the mRNA level in response to waterborne zinc.

Dietary phenolic antioxidants, caffeic acid and Trolox, protect rainbow trout gill cells from nitric oxide-induced apoptosis.

Caffeic acid (CA) and Trolox are phenolic acids that have beneficial antioxidant effect, but the underlying mechanisms involved are not fully understood. The extent to which CA and Trolox protect against sodium nitroprusside (SNP)-induced oxidative cell injury was investigated in cultured rainbow trout gill cells. The cells exposed to SNP for 24 h displayed a dose-dependent leakage of lactate dehydrogenase (LDH) and decreased cell viability as indicated by the MTT assay (mitochondrial dehydrogenase activity).

ZINC-mediated gene expression offers protection against H2O2-induced cytotoxicity.

The ability of zinc to mobilize defense against reactive oxygen species (ROS) and H2O2-induced apoptosis was studied using a primary culture of rainbow trout gill cells. Gill cells were pretreated for 24 h with 100 microM ZnSO4 followed by 24-h exposure to 100 or 200 microM H2O2, or were subjected to 100 microM ZnSO4 together with 100 or 200 microM H2O2. Metallothionein-A (MTA) and metallothionein-B (MTB) mRNA levels were increased after treatment with zinc or H2O2, separately or in combination.

Nutritive metal uptake in teleost fish.

Transition metals are essential for health, forming integral components of proteins involved in all aspects of biological function. However, in excess these metals are potentially toxic, and to maintain metal homeostasis organisms must tightly coordinate metal acquisition and excretion. The diet is the main source for essential metals, but in aquatic organisms an alternative uptake route is available from the water.