Cells utilize calcium ions (Ca) to signal almost all aspects of cellular life, ranging from cell proliferation to cell death, in a spatially and temporally regulated manner. A key aspect of this regulation is the compartmentalization of Ca in various cytoplasmic organelles that act as intracellular Ca stores. Whereas Ca release from the large-volume Ca stores, such as the endoplasmic reticulum (ER) and Golgi apparatus, are preferred for signal transduction, Ca release from the small-volume individual vesicular stores that are dispersed throughout the cell, such as lysosomes, may be more useful in local regulation, such as membrane fusion and individualized vesicular movements. Conceivably, these two types of Ca stores may be established, maintained or refilled via distinct mechanisms. ER stores are refilled through sustained Ca influx at ER-plasma membrane (PM) membrane contact sites (MCSs). In this review, we discuss the release and refilling mechanisms of intracellular small vesicular Ca stores, with a special focus on lysosomes. Recent imaging studies of Ca release and organelle MCSs suggest that Ca exchange may occur between two types of stores, such that the small stores acquire Ca from the large stores via ER-vesicle MCSs. Hence vesicular stores like lysosomes may be viewed as secondary Ca stores in the cell.

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Background Combined chemotherapy is often affected by the different physicochemical properties of chemotherapeutic drugs, which should be improved by the reasonable design of co-loaded preparations. Purpose A kind of simple but practical graphene oxide (GO) wrapped mesoporous silica nanoparticles (MSN) modified with hyaluronic acid (MSN@GO-HA) were developed for the co-delivery of cinnamaldehyde (CA) and doxorubicin (DOX), in order to enhance their combined treatment on tumor cells and reduce their application defects. Methods The MSN CA @GO DOX -HA was constructed by MSN CA (loading CA via physical diffusion) and GO DOX -HA (modified with HA and loading DOX via π–π stacking) through the electrostatic adsorption, followed by the physicochemical characterization, serum stability and in vitro release study. Cytotoxicity on different cells was detected, followed by the tumor cell uptake tests. The intracellular reactive oxygen species (ROS) changes, mitochondrial functions and activities of caspase-3/-9 in MCF-7 cells were also evaluated, respectively. Results The MSN CA @GO DOX -HA nanoparticles kept stable in FBS solution and achieved pH-responsive release behavior, which was beneficial to increase the accumulation of CA and DOX in tumor cells to enhance the treatment. MSN CA @GO DOX -HA exerted higher cytotoxicity to MCF-7 human breast cancer cells than H9c2 cardiac myocyte cells, which were not only attributed to the active targeting to tumor cells by HA, but also related with the activation of intrinsic apoptotic pathway in MCF-7 cells induced by CA, which was mediated by the specific ROS signal amplification and the interference with mitochondrial function. Moreover, the efficacy of DOX was also enhanced by the above process. Conclusion The establishment of the MSN CA @GO DOX -HA nanoparticles played a role in promoting strengths and restricting shortcomings of CA and DOX, thereby exerting their function and achieving efficient treatment against cancer.