Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH
dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH
was much lower and exocytosis of PAMAM-NH
was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH
from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH
aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH
in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH
in MCF-7/ADR cells and provided a guide of using PAMAM-NH
as a drug and gene vector in resistant cells.
There are abundant glycyrrhetinic acid (GA) receptors on the cellular membrane of hepatocytes and hepatocellular carcinoma (HCC) cells. The receptor binding effect might be related to the structure of the guiding molecule. GA exists in two stereoisomers with C3-hydroxyl and C11-carbonyl active groups.
The objective of this study was to investigate the relationship between the HCC-targeted effect and the configurations and groups of GA.
Methods and results
Different GA derivatives (18β-GA, 18α-GA, 3-acetyl-18β-GA [3-Ace-GA] and 11-deoxy-18β-GA [11-Deo-GA]) were used to investigate the targeting effect of GA’s configurations and groups on HCC cells. The EC
values of competition to binding sites and the ratio of specific binding in HepG2 cells showed that 18β-GA and 3-Ace-GA demonstrated significant competitive effect with fluorescein isothiocyanate (FITC)-labeled GA. Then, the GA derivatives were distearoyl-phosphatidylethanolamine (DSPE)-PEGylated. 18β-GA-, 18α-GA-, 3-Ace-GA-and 11-Deo-GA-modified liposomes were prepared and characterized by size, zeta potential, encapsulation efficiency, loading capacity, leakage and membrane stability. Evaluation on the cellular location in vitro and tumor targeting in vivo was carried out. Compared to common long-circulation liposome (PEG-Lip), more 18β-GA- and 3-Ace-GA-modified liposomes aggregated around HepG2 cells in vitro in short time and transferred into HCC tumors in vivo for a longer time.
The β-configuration hydrogen atom on C18 position of GA played the most important role on the targeting effect. C11-carbonyl and C3-hydroxy groups of GA have certain and little influence on targeting action to HCC, respectively. In general, GA might be a promising targeting molecule for the research on liver diseases and hepatoma therapy.
C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2–STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and CXCL12, which trigger the epithelial–mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor–stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.
Scorpion toxins can kill other animals by inducing paralysis and arrhythmia, which limits the potential applications of these agents in the clinical management of diseases. Antitumor-analgesic peptide (AGAP), purified from Karsch, has been proved to possess analgesic and antitumor activities. Trp, a conserved aromatic residue of AGAP, might play an important role in mediating AGAP activities according to the sequence and homology-modeling analyses. Therefore, an AGAP mutant, W38G, was generated, and effects of both AGAP and the mutant W38G were examined by whole-cell patch clamp techniques on the sodium channels hNa1.4 and hNa1.5, which were closely associated with the biotoxicity of skeletal and cardiac muscles, respectively. The data showed that both W38G and AGAP inhibited the peak currents of hNa1.4 and hNa1.5; however, W38G induced a much weaker inhibition of both channels than AGAP. Accordingly, W38G exhibited much less toxic effect on both skeletal and cardiac muscles than AGAP The analgesic activity of W38G and AGAP were verified as well, and W38G retained analgesic activity similar to AGAP. Inhibition to both Na1.7 and Na1.8 was involved in the analgesic mechanism of AGAP and W38G. These findings indicated that Trp was a key amino acid involved in the biotoxicity of AGAP, and the AGAP mutant W38G might be a safer alternative for clinical application because it retains the analgesic efficacy with less toxicity to skeletal and cardiac muscles.
This paper proposes a bi-level model for traffic network signal control, which is formulated as a dynamic Stackelberg game and solved as a mathematical program with equilibrium constraints (MPEC). The lower-level problem is a dynamic user equilibrium (DUE) with embedded dynamic network loading (DNL) sub-problem based on the LWR model (Lighthill and Whitham, 1955;Richards, 1956). The upper-level decision variables are (time-varying) signal green splits with the objective of minimizing network-wide travel cost. Unlike most existing literature which mainly use an on-and-off (binary) representation of the signal controls, we employ a continuum signal model recently proposed and analyzed in , which aims at describing and predicting the aggregate behavior that exists at signalized intersections without relying on distinct signal phases. Advantages of this continuum signal model include fewer integer variables, less restrictive constraints on the time steps, and higher decision resolution. It simplifies the modeling representation of large-scale urban traffic networks with the benefit of improved computational efficiency in simulation or optimization. We present, for the LWR-based DNL model that explicitly captures vehicle spillback, an in-depth study on the implementation of the continuum signal model, as its approximation accuracy depends on a number of factors and may deteriorate greatly under certain conditions. The proposed MPEC is solved on two test networks with three metaheuristic methods. Parallel computing is employed to significantly accelerate the solution procedure.
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