A Conscious Porcine Model for Sudden Cardiac Death

No abstract availabl

Triglyceride Blisters in Lipid Bilayers: Implications for Lipid Droplet Biogenesis and the Mobile Lipid Signal in Cancer Cell Membranes

Triglycerides have a limited solubility, around 3%, in phosphatidylcholine lipid bilayers. Using millisecond-scale course grained molecular dynamics simulations, we show that the model lipid bilayer can accommodate a higher concentration of triolein (TO) than earlier anticipated, by sequestering triolein molecules to the bilayer center in the form of a disordered, isotropic, mobile neutral lipid aggregate, at least 17 nm in diameter, which forms spontaneously, and remains stable on at least the microsecond time scale. The results give credence to the hotly debated existence of mobile neutral lipid aggregates of unknown function present in malignant cells, and to the early biogenesis of lipid droplets accommodated between the two leaflets of the endoplasmic reticulum membrane. The TO aggregates give the bilayer a blister-like appearance, and will hinder the formation of multi-lamellar phases in model, and possibly living membranes. The blisters will result in anomalous membrane probe partitioning, which should be accounted for in the interpretation of probe-related measurements

Metabolic Markers of MG-63 Osteosarcoma Cell Line Response to Doxorubicin and Methotrexate Treatment: Comparison to Cisplatin

A high resolution magic angle spinning NMR metabolomics study of the effects of doxorubicin (DOX), methotrexate (MTX) and cisplatin (cDDP) on MG-63 cells is presented and unveils the cellular metabolic adaptations to these drugs, often used together in clinical protocols. Although cDDP-treated cells were confirmed to undergo extensive membrane degradation accompanied by increased neutral lipids, DOX- and MTX-treated cells showed no lipids increase and different phospholipid signatures, which suggests that (i) DOX induces significant membrane degradation, decreased membrane synthesis, and apparent inhibition of de novo lipid synthesis, and (ii) MTX induces decreased membrane synthesis, while no membrane disruption or de novo lipid synthesis seem to occur. Nucleotide signatures were in apparent agreement with the different drug action mechanisms, a link having been found between UDP-GlcNAc and the active pathways of membrane degradation and energy metabolism, for cDDP and DOX, with a relation to oxidative state and DNA degradation, for cDDP. Correlation studies unveiled drug-specific antioxidative signatures, which pinpointed m- and s-inositols, taurine, glutamate/glutamine, and possibly creatine as important in glutathione metabolism. These results illustrate the ability of NMR metabolomics to measure cellular responses to different drugs, a first step toward understanding drug synergism and the definition of new biomarkers of drug efficacy

Potential Markers of Cisplatin Treatment Response Unveiled by NMR Metabolomics of Human Lung Cells

In this work, H-1 high resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy was used to characterize the variations in the metabolome (small metabolites and mobile lipids) of A549 human lung cells in response to exposure to the alkylating drug cisplatin. Multivariate analysis and signal integration of spectral data were carried out to unveil exposure-induced effects and follow their time course. Parallel and strongly correlated increases in lipids (particularly unsaturated triglycerides) and nucleotide sugars (particularly uridine diphosphate N-acetylglucosamine) were found in cisplatin-treated cells, highlighting these compounds as potential biomarkers of treatment response. Other significant changes upon drug exposure comprised an increase in sorbitol and decreases in niacinamide and several amino acids (glutamine, alanine, lysine, methionine, citrulline, phenylalanine and tyrosine). These results show that in vitro NMR metabolomics is a powerful tool for detecting variations in a range of intracellular compounds upon drug exposure, thus offering the possibility of identifying candidate metabolite markers for in vivo monitoring of tumor responsiveness to treatment