Abstract Background: Aggregation-induced emission luminogens (AIEgens) exhibit potent sonosensitivity in nanocarriers compared with conventional organic sonosensitizers owing to the strong fluorescence emission in the aggregated state. However, premature drug leakage and ineffective tumor targeting of current AIE nanosonosensitizers critically restrict their clinical application. Results: Here, an AIEgens-based sonosensitizer (AIE/Biotin-M) with excellent sonosensitivity was developed by assembling salicylaldazine-based amphiphilic polymers (AIE-1) and 4T1 tumor-targeting amphiphilic polymers (DSPE-PEG-Biotin) for the effective delivery of salicylaldazine to 4T1 tumor tissues, aiming to mediate immunogenic SDT. In vitro, AIE/Biotin-M were highly stable and generated plentiful singlet oxygen ( 1 O 2 ) under ultrasound (US) irradiation. After AIE/Biotin-M targeted accumulation in tumor, upon US irradiation, the generation of 1 O 2 not only leaded cancer cells death, but also elicited systemically immune response through causing immunogenic cell death (ICD) of cancer cells. In addition to mediate SDT, AIE/Biotin-M could chelate and reduce Fe 3+ , Cu 2+ and Zn 2+ by salicylaldazine for inhibiting neovascularization in tumor tissues. Ultimately, AIE/Biotin-M systemically inhibited tumor growth and metastasis upon US irradiation. Conclusions: This study presents a facile approach to the development of AIE nanosonosensitizers for cancer SDT.
Fungal basic leucine zipper (bZIP) proteins play a vital role in biological processes such as growth, biotic/abiotic stress responses, nutrient utilization, and invasion. In this study, genome-wide identification of bZIP genes in the fungus Fusarium fujikuroi, the pathogen of bakanae disease, was carried out. Forty-four genes encoding bZIP transcription factors (TFs) from the genome of F. fujikuroi (FfbZIP) were identified and functionally characterized. Structures, domains, and phylogenetic relationships of the sequences were analyzed by bioinformatic approaches. Based on the phylogenetic relationships with the FfbZIP proteins of eight other fungi, the bZIP genes can be divided into six groups (A-F). The additional conserved motifs have been identified and their possible functions were predicted. To analyze functions of the bZIP genes, 11 FfbZIPs were selected according to different motifs they contained and were knocked out by genetic recombination. Results of the characteristic studies revealed that these FfbZIPs were involved in oxygen stress, osmotic stress, cell wall selection pressure, cellulose utilization, cell wall penetration, and pathogenicity. In conclusion, this study enhanced understandings of the evolution and regulatory mechanism of the FfbZIPs in fungal growth, abiotic/biotic stress resistance, and pathogenicity, which could be the reference for other fungal bZIP studies.
Nonviral gene delivery that enables exogenous gene expression in bone mesenchymal stem cells could accelerate clinical application of cell-based gene therapy. This study systematically investigated and compared the potential of polyethylenimine and Lipofectamine 2000 as gene carriers to modify bone mesenchymal stem cells including transfection efficiency, cytotoxicity, intracellular trafficking as well as cell membrane damage and apoptosis/necrosis. Polyethylenimine at its optimal N/P ratio of 10 demonstrated the same toxic effects but lower transfection efficiency (17.1% vs 39.5%) compared to Lipofectamine. Intracellular trafficking resulted in over 80% of bone mesenchymal stem cells that were able to take up polyethylenimine polyplexes, but only 20.69% showed nuclear uptake; however, for Lipofectamine, about half bone mesenchymal stem cells were found to uptake lipoplexes but about 30% displayed nuclear localization. Moreover, the percentages of nuclear localization of both vectors were in close relationship with their transfection efficiency. We concluded that for bone mesenchymal stem cell transfection, polyethylenimine displayed high cellular uptake but Lipofectamine was more effective in delivering genes into the nucleus, which was likely the underlying basis for a more efficient gene expression. Further structure modification of polyethylenimine such as improving its nuclear entry ability will eventually make it a better candidate for bone mesenchymal stem cells’ in vitro gene delivery.
To investigate the mechanisms of taurine (Tau) preventive effect on neurotoxicity induced by manganese (Mn) in rat's prefrontal cortex.SD rats were divided into four groups after one week of observation: normal control:the group animals received daily intraperitoneal (ip.) injections of sterile saline for 3 months; Mn treated group (Mn): rats received ip. injection of MnCl(2).4H(2)O once a day for 3 months; Tau preventive group (Mn + Tau): The Mn level of this group were the same as Mn's, the Tau level 200 mg/kg, three times per week, for 3 months; Tau treated group (Mn-->Tau): After received the daily injection of Mn as Mn group for 3 months, the rats received Tau three times per week for 3 months. The dose of Mn and Tau were the same as above. The experiment lasted 6 months.(1) Mn induced apoptosis of neurons in rat's prefrontal cortex. The ratio of apoptosis of neurons in the Mn treated group [(20.0 +/- 4.3)%] was higher than that of the control group [(1.8 +/- 2.1)%] (P < 0.05) and the ratio of apoptosis in Tau preventive group (Mn + Tau) was lower than that of the Mn treated group (P < 0.05). (2) The production of MDA in Mn treated group was higher than the control group (P < 0.05) and the activity of SOD was lower than that in the control group. In Tau preventive group (Mn + Tau), Tau increased the activity of SOD and decreased the production of the MDA, with the significant difference level compared to the Mn treated group (P < 0.05).Mn induces apoptosis in rat's prefrontal cortex neurons. The main mechanisms of Tau preventing cytotoxicity against Mn is the reduction of the oxidative stress in prefrontal cortex neurons.
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