The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate−poly [2-(dimethylamino) ethyl acrylate]−polycaprolactone (PEGMA−PDMAEA−PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolaminepoly(ethylene glycol)-biotin (DSPE−PEG−biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the "proton sponge effect" of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and antimetastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.
Exosomes are vital mediators for intercellular communications in the tumor microenvironment to accelerate colon cancer progression. Leucine-rich repeat-containing 8A (LRRC8A), the core component of the volume-regulated anion channel, is closely associated with acquiring heterogeneity for tumor cells. However, the role of LRRC8A in the exosomes remains largely unknown. Here, we reported that LRRC8A was one of the compositions in the exosomes released from colon cancer HCT116 cells. Downregulation of LRRC8A proteins inhibited ex vivo cell growth and induced apoptosis. Consistently, chloride channel blockers DCPIB and NPPB inhibited cell growth and induced cell apoptosis in a time or concentration-dependent manner. Interestingly, the total amounts and proportions of different diameter exosomes released in 6 hours were not altered by the treatment of DCPIB and NPPB in HCT116 cells. In contrast to the downregulation or inhibition of LRRC8A, overexpression of LRRC8A proteins in HCT116 cells released significantly more distinct populations of exosomes. Importantly, the switches of ratios for exosomes in a hypotonic challenge were eliminated by DCPIB treatment. Collectively, our results uncovered that LRRC8A proteins were responsible for the exosome generation and sorted into exosomes for monitoring the volume regulation.
Introduction: Metabolic disorders are an important health concern that threatens life and burdens society severely. ClC-3 is a member of the chloride voltage-gated channel family, and ClC-3 deletion improved the phenotypes of dysglycemic metabolism and the impairment of insulin sensitivity. However, the effects of a healthy diet on transcriptome and epigenetics in ClC-3−/− mice were not explained in detail.Methods: Here, we performed transcriptome sequencing and Reduced Representation Bisulfite Sequencing for the liver of 3 weeks old WT and ClC-3−/− mice consuming a normal diet to insight into the epigenetic and transcriptomic alterations of ClC-3 deficient mice.Results: In the present study, we found that ClC-3−/− mice that were younger than 8 weeks old had smaller bodies compared to ClC-3+/+ mice with ad libitum self-feeding normal diet, and ClC-3−/− mice that were older than 10 weeks old had a similar body weight. Except for the spleen, lung, and kidney, the average weight of the heart, liver, and brain in ClC-3−/− mice was lower than that in ClC-3+/+ mice. TG, TC, HDL, and LDL in fasting ClC-3−/− mice were not significantly different from those in ClC-3+/+ mice. Fasting blood glucose in ClC-3−/− mice was lower than that in ClC-3+/+ mice; the glucose tolerance test indicated the response to blood glucose increasing for ClC-3−/− mice was torpid, but the efficiency of lowering blood glucose was much higher once started. Transcriptomic sequencing and reduced representation bisulfite sequencing for the liver of unweaned mice indicated that ClC-3 deletion significantly changed transcriptional expression and DNA methylation levels of glucose metabolism-related genes. A total of 92 genes were intersected between DEGs and DMRs-targeted genes, of which Nos3, Pik3r1, Socs1, and Acly were gathered in type II diabetes mellitus, insulin resistance, and metabolic pathways. Moreover, Pik3r1 and Acly expressions were obviously correlated with DNA methylation levels, not Nos3 and Socs1. However, the transcriptional levels of these four genes were not different between ClC-3−/− and ClC-3+/+ mice at the age of 12 weeks.Discussion: ClC-3 influenced the methylated modification to regulate glucose metabolism, of which the gene expressions could be driven to change again by a personalized diet-style intervention.
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