The Mechanochemistry of Endocytosis

An integrated theoretical model reveals how the chemical and the mechanical aspects of endocytosis are coordinated coherently in yeast cells, driving progression through the endocytic pathway and ensuring efficient vesicle scission in vivo

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies

Pb(II) Induces Scramblase Activation and Ceramide-Domain Generation in Red Blood Cells

The mechanisms of Pb(II) toxicity have been studied in human red blood cells using confocal microscopy, immunolabeling, fluorescence-activated cell sorting and atomic force microscopy. The process follows a sequence of events, starting with calcium entry, followed by potassium release, morphological change, generation of ceramide, lipid flip-flop and finally cell lysis. Clotrimazole blocks potassium channels and the whole process is inhibited. Immunolabeling reveals the generation of ceramide-enriched domains linked to a cell morphological change, while the use of a neutral sphingomyelinase inhibitor greatly delays the process after the morphological change, and lipid flip-flop is significantly reduced. These facts point to three major checkpoints in the process: first the upstream exchange of calcium and potassium, then ceramide domain formation, and finally the downstream scramblase activation necessary for cell lysis. In addition, partial non-cytotoxic cholesterol depletion of red blood cells accelerates the process as the morphological change occurs faster. Cholesterol could have a role in modulating the properties of the ceramide-enriched domains. This work is relevant in the context of cell death, heavy metal toxicity and sphingolipid signaling.AGA was a predoctoral student supported by the Basque Government and later by the University of the Basque Country (UPV/EHU). This work was also supported in part by grants from the Spanish Government (FEDER/MINECO BFU 2015-66306-P to F.M.G. and A.A.) and the Basque Government (IT849-13 to F.M.G. and IT838-13 to A.A.), and by the Swiss National Science Foundation

Surfactants as microbicides and contraceptive agents: a systematic in vitro study

Background: The urgent need for cheap and easy-to-use protection against both unwanted pregnancies and sexually transmitted diseases has stimulated considerable interest in the use of surfactants as microbicides, anti-viral, and contraceptive agents in recent years. In the present study we report a systematic in vitro evaluation of the microbicidal, anti- viral and contraceptive potential of cationic, anionic, zwitterionic, and non-ionic surfactants. Methodology/Principal Findings: Toxicity was evaluated in mammalian columnar epithelial (MDCK) cells, human sperm cells, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Streptococcus agalactiae and Enterococcus faecalis. The inhibition of adenovirus and lentivirus infection of MDCK cells was also tested. A homologous series of cationic surfactants, alkyl-N,N,N-trimethylammonium bromides (CnTAB), with varying alkyl chains were shown to be bactericidal and fungicidal at doses that were related to the surfactant critical micelle concentrations (CMC), all of them at concentrations significantly below the CMC. In general, bacteria were more susceptible to this surfactant group than C. albicans and this organism, in turn, was more susceptible than MDCK cells. This suggests that the CnTAB may be useful as vaginal disinfectants only in so far as bacterial and fungal infections are concerned. None of the surfactants examined, including those that have been used in pre-clinical studies, showed inhibition of adenovirus or lentivirus infection of MDCK cells or spermicidal activity at doses that were sub-toxic to MDCK cells. Conclusions/Significance: The results of this study lead us to propose that systematic analysis of surfactant toxicity, such as we report in the present work, be made a mandatory pre-condition for the use of these substances in pre-clinical animal and/or human studie