Nanotechnology has allowed the construction of various nanostructures for applications, including biomedicine. However, a simple target-specific, economical, and biocompatible drug delivery platform ...with high maximum tolerated doses is still in demand. Here, we report aptamer-tethered DNA nanotrains (aptNTrs) as carriers for targeted drug transport in cancer therapy. Long aptNTrs were self-assembled from only two short DNA upon initiation by modified aptamers, which worked like locomotives guiding nanotrains toward target cancer cells. Meanwhile, tandem “boxcars” served as carriers with high payload capacity of drugs that were transported to target cells and induced selective cytotoxicity. aptNTrs enhanced maximum tolerated dose in nontarget cells. Potent antitumor efficacy and reduced side effects of drugs delivered by biocompatible aptNTrs were demonstrated in a mouse xenograft tumor model. Moreover, fluorophores on nanotrains and drug fluorescence dequenching upon release allowed intracellular signaling of nanotrains and drugs. These results make aptNTrs a promising targeted drug transport platform for cancer theranostics.
The acute liver injury (ALI) and hepatic fibrosis caused by the co-treatment of lipopolysaccharide (LPS)/D-galactosamine (D-GalN) have been extensively studied. However, whether LPS/D-GalN are ...genotoxic has been left unknown. In this study, male mice were divided into eight groups with eight animals in each group. For acute challenge of LPS/D-GalN, the mice in each group received a combination of LPS/D-GalN via intraperitoneal injection at the dose of 25 μg/kg/250 mg/kg, 25 μg/kg/500 mg/kg, or 50 μg/kg/500 mg/kg body weight. An additional group for chronic administration of test compounds was conducted by i.p. injection of LPS/D-GalN (10 μg/kg/100 mg/kg) every other day for 8 weeks. Saline solution (0.9%) and cyclophosphamide (CTX) (50 mg/kg body weight) given by i.p. injection was used as the negative and positive control, respectively. The results of single cell gel electrophoresis (SCGE) assay indicated that acute exposure of the mice to LPS/D-GalN caused severe DNA damage in hepatic cells, but not in the brain, sperm or bone marrow cells, which evidenced the genotoxicity of LPS/D-GalN administrated in combination. Interestingly, the chronic administration of LPS/D-GalN triggered significant genotoxic effects not only in hepatic but also in brain cells, with negative results in sperm and bone marrow cells. Histopathological examination in the liver and brain tissues revealed changes consistent with the SCGE results. The present study indicates genotoxic potential of LPS/D-GalN co-administered in mice, which may serve as an in vivo experimental model for relevant genotoxic study.
Exposure to nanomaterials (NMs) is an emerging threat to human health, and the understanding of their intracellular behavior and related toxic effects is urgently needed. Ferroptosis is a newly ...discovered, iron-mediated cell death that is distinctive from apoptosis or other cell-death pathways. No evidence currently exists for the effect of "iron free" engineered NMs on ferroptosis. We showed by several approaches that (1) zinc oxide nanoparticles (ZnO NPs)-induced cell death involves ferroptosis; (2) ZnO NPs-triggered ferroptosis is associated with elevation of reactive oxygen species (ROS) and lipid peroxidation, along with depletion of glutathione (GSH) and downregulation of glutathione peroxidase 4 (GPx4); (3) ZnO NPs disrupt intracellular iron homeostasis by orchestrating iron uptake, storage and export; (4) p53 largely participates in ZnO NPs-induced ferroptosis; and (5) ZnO particle remnants and dissolved zinc ion both contribute to ferroptosis. In conclusion, our data provide a new mechanistic rationale for ferroptosis as a novel cell-death phenotype induced by engineered NMs.
Food poisoning and infectious diseases caused by pathogenic bacteria such as Staphylococcus aureus (SA) are serious public health concerns. A method of specific, sensitive, and rapid detection of ...such bacteria is essential and important. This study presents a strategy that combines aptamer and antibiotic-based dual recognition units with magnetic enrichment and fluorescent detection to achieve specific and sensitive quantification of SA in authentic specimens and in the presence of much higher concentrations of other bacteria. Aptamer-coated magnetic beads (Apt-MB) were employed for specific capture of SA. Vancomycin-stabilized fluorescent gold nanoclusters (AuNCs@Van) were prepared by a simple one-step process and used for sensitive quantification of SA in the range of 32–108 cfu/mL with the detection limit of 16 cfu/mL via a fluorescence intensity measurement. And using this strategy, about 70 cfu/mL of SA in complex samples (containing 3 × 108 cfu/mL of other different contaminated bacteria) could be successfully detected. In comparison to prior studies, the developed strategy here not only simplifies the preparation procedure of the fluorescent probes (AuNCs@Van) to a great extent but also could sensitively quantify SA in the presence of much higher concentrations of other bacteria directly with good accuracy. Moreover, the aptamer and antibiotic used in this strategy are much less expensive and widely available compared to common-used antibodies, making it cost-effective. This general aptamer- and antibiotic-based dual recognition strategy, combined with magnetic enrichment and fluorescent detection of trace bacteria, shows great potential application in monitoring bacterial food contamination and infectious diseases.
Polybrominated diphenyl ethers (PBDEs) are aromatic compounds that containing bromine atoms, which possess high efficiency, good thermal stability. However, PBDEs had various known toxic effects and ...were characterized as persistent environmental pollutants. Exposure to a quinone-type metabolite of PBDEs (PBDEQ) is linked with excess production of intracellular reactive oxygen species (ROS) in our previous studies. Here, we observed that PBDEQ exposure led to ROS and mitochondrial dysfunction, which promoted canonical and non-canonical Nod-like receptor protein 3 (NLRP3) inflammasome activation. Further experiments demonstrated that PBDEQ exposure activated Toll-like receptors (TLRs), subsequently regulating nuclear factor kappa B (NF-κB) signaling. Moreover, lysosomal damage and K+ efflux were involved in PBDEQ-driven NLRP3 inflammasome activation. Our in vivo study also illustrated that PBDEQ administration induced liver inflammation in male C57BL/6J mice. Cumulatively, our current finding provided novel insights into PBDEQ-induced pro-inflammatory responses.
Display omitted
•PBDEQ exposure led to ROS and mitochondrial dysfunction.•PBDEQ exposure activate canonical and non-canonical NLRP3 inflammasome.•PBDEQ exposure activate TLRs and NF-κB signal pathways.•PBDEQ exposure causes lysosomal damage and K+ efflux.•PBDEQ administration induced liver inflammation in male C57BL/6J mice.
The current study aimed to identify the radiosensitizing effect of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in combination with radiotherapy in non-small-cell lung cancer (NSCLC) ...cells. The combination of celecoxib potentiated radiation-induced apoptosis; however, no changes in cell cycle distribution and number of phosphorylated histone H2AX foci were detected, indicating a DNA damage-independent mechanism. In an in vivo mouse model, the tumor size was significantly decreased in the group combining celecoxib with radiation compared with the radiation only group. Phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), as well as expression of COX-2 were significantly downregulated in cells treated with the combination of celecoxib and radiation compared with the radiation only group. The result indicated that celecoxib exhibits radiosensitizing effects through COX-2 and Akt/mTOR-dependent mechanisms. Induction the Akt/mTOR signaling pathway promotes radioresistance in various cancers, including NSCLC. Therefore, the current study suggested the therapeutic potential of combination therapy of celecoxib and radiation in the prevention of radioresistance.
In the presence of target S. aureus, the aptamers and teicoplanin bound to S. aureus simultaneously, making the energy donor (aptamer-QDs) and acceptor (Teico-AuNPs) dramatically close to each other ...and turn “on” the FRET.
Display omitted
The detection of bacterial pathogen such as Staphylococcus aureus (S. aureus) is essential for the regulation of food hygiene and disease diagnosis. Herein, we developed a simple one-step fluorescence resonance energy transfer (FRET)-based sensor for specific and sensitive detection of S. aureus in food and serum samples, in which aptamer-modified quantum dots (aptamer-QDs) was employed as the energy donor and antibiotic of teicoplanin functionalized-gold nanoparticles (Teico-AuNPs) was chosen as the energy acceptor. Within 1h, the FRET-based sensor showed a linear range of from 10 cfu/mL to 5×108 cfu/mL, with the low limit of detection (LOD, 2 cfu/mL) for S. aureus in buffer. When further applied to assay S. aureus in real samples, the FRET-based sensor showed good recoveries ranging from 84.5% to 110.0%, with relative standard derivations (RSDs) of 0.01%–0.44% and a LOD of 100 cfu/mL in milk, orange juice and human serum.
Graphene oxide (GO) has been widely used to develop fluorescence resonance energy transfer (FRET) biosensors for tumor markers (e.g., matrix metalloproteinases, MMPs) due to its superior fluorescence ...quenching capacity and unique adsorption characteristics for biomolecules. In this study, fluorescein isothiocyanate-labeled peptide (Pep-FITC) was assembled onto the GO surface through covalent binding to construct a GO-Pep-FITC FRET sensor for sensitive, rapid, and accurate detection of MMP-2 in complex serum samples. Compared to similar GO-based FRET sensors fabricated through physical adsorption, the as prepared ones via covalent binding are significantly more stable under physiological conditions, enabling their detection of MMP-2 with high sensitivity (detection limit: 2.5ng/mL). More importantly, it allows for rapid MMP-2 detection (within 3h) even in complex biological samples with satisfactory accuracy and the relative standard deviation ≤7.03%. Our studies further suggest that such a platform developed here for sensitive, rapid, and accurate detection of biomarkers holds great promise for clinical diagnosis of protease-related diseases.
•A graphene oxide based FRET sensor for MMP-2 was developed by covalent conjugation.•The sensor has better stability to resist the interference from external environment.•A low detection limit for MMP-2 (2.5ng/mL) was obtained by the sensor.•The sensor was used to determine MMP-2 in real serum sample rapidly (within 3h) with good accuracy (RSD≤7.03%).
Tetrachlorobenzoquinone (TCBQ) is a downstream metabolite of pentachlorophenol (PCP). Previously, we demonstrated that TCBQ caused cytotoxicity due to mitochondrial-related apoptosis. Here, we ...confirmed the upregulation of death receptor 5 (DR5) followed by the construction of the death-inducing signaling complex (DISC). We also detected the activation of the caspase cascade, which was correlated with TCBQ-induced apoptotic cell death in PC12 cells. The upregulation of DR5 included transcriptional activation and de novo protein synthesis in response to TCBQ. We also identified the endoplasmic reticulum (ER) as a new target for the TCBQ challenge in PC12 cells. The protein kinase R-like ER kinase/eukaryotic translation initiation factor 2α (PERK/eIF2α)-mediated activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) signaling pathway contributed to the process of TCBQ-induced ER stress. Blocking ATF4, ATF3, or CHOP signaling by gene silencing technology resulted in decreased cell apoptosis after exposure to TCBQ. Finally, NAC ameliorated TCBQ-induced apoptosis and ER stress, which illustrated that TCBQ-induced apoptosis is somehow ROS-dependent. In summary, this study provided important mechanistic insight into how TCBQ utilizes ER stress-related signaling to exhibit pro-apoptotic activity in PC12 cells.
Abstract
Background
With the development of zinc oxide nanoparticles (ZnO NPs) in the field of nanotechnology, their toxicological effects are attracting increasing attention, and the mechanisms for ...ZnO NPs neurotoxicity remain obscure. In an attempt to address concerns regarding neurotoxicity of ZnO NPs, we explored the relationship between free zinc ions, reactive oxygen species (ROS) and neurotoxic mechanisms in ZnO NPs-exposed PC12 cells.
Result
This study demonstrated the requirement of free zinc ions shed by ZnO NPs to over generation of intracellular ROS. Next, we identified autophagic cell death was the major mode of cell death induced by ZnO NPs, and autophagosome accumulation resulted from not only induction of autophagy, but also blockade of autophagy flux. We concluded that autophagic cell death, resulting from zinc ions-ROS-c-Jun N-terminal kinase (JNK)-autophagy positive feedback loop and blockade of autophagosomal-lysosomal fusion, played a major role in the neurotoxicity of ZnO NPs.
Conclusion
Our study contributes to a better understanding of the neurotoxicity of ZnO NPs and might be useful for designing and developing new biosafety nanoparticles in the future.
PDF
