The Lysosome and Intracellular Signalling.

In addition to being the terminal degradative compartment of the cell's endocytic and autophagic pathways, the lysosome is a multifunctional signalling hub integrating the cell's response to nutrient status and growth factor/hormone signalling. The cytosolic surface of the limiting membrane of the lysosome is the site of activation of the multiprotein complex mammalian target of rapamycin complex 1 (mTORC1), which phosphorylates numerous cell growth-related substrates, including transcription factor EB (TFEB). Under conditions in which mTORC1 is inhibited including starvation, TFEB becomes dephosphorylated and translocates to the nucleus where it functions as a master regulator of lysosome biogenesis. The signalling role of lysosomes is not limited to this pathway. They act as an intracellular Ca2+ store, which can release Ca2+ into the cytosol for both local effects on membrane fusion and pleiotropic effects within the cell. The relationship and crosstalk between the lysosomal and endoplasmic reticulum (ER) Ca2+ stores play a role in shaping intracellular Ca2+ signalling. Lysosomes also perform other signalling functions, which are discussed. Current views of the lysosomal compartment recognize its dynamic nature. It includes endolysosomes, autolysosome and storage lysosomes that are constantly engaged in fusion/fission events and lysosome regeneration. How signalling is affected by individual lysosomal organelles being at different stages of these processes and/or at different sites within the cell is poorly understood, but is discussed

Transplacental distribution of chloroquine in sheep

Chloroquine is frequently used during pregnancy in malaria-endemic countries, but no data are available about fetal exposure to the drug. Prophylactic use during labour to obtain effective concentrations in the newborn is also documented. In the present study, the placental transfer of chloroquine was investigated in the pregnant, near-term sheep model. Chronic catheterization allowed blood sampling of maternal and fetal blood. Following a single intramuscular injection or intravenous infusion to the ewe, chloroquine was slowly distributed to the fetus. Peak concentrations in the fetus reached up to +/- 280 ng/ml within 2-4 h after administration while maximal concentrations in the mother reached up to 2,850 ng/ml. The terminal half-life of chloroquine in pregnant sheep was very long, amounting to 65.1 +/- 34.9 h (range 27.4-119 h). Tissue binding was high, as reflected by the extensive volume of distribution (V(area): 19.0 +/- 11.0 l/kg). Total clearance was equal to 3.42 +/- 0.60 ml/min/kg. The transfer rate of chloroquine from the mother to the fetus was low in all animals. So, the placenta is quite an effective barrier for the drug.status: publishe