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Purpose Recent studies have demonstrated that kinetochore-associated protein 1 (KNTC1) plays a significant role in the carcinogenesis of numerous types of cancer. This study aimed to explore the role and possible mechanisms of KNTC1 in the development of pancreatic cancer. Methods and results We analyzed differentially expressed genes by RNA sequencing in three paired pancreatic cancer and para-cancerous tissue samples and found that the expression of KNTC1 was significantly upregulated in pancreatic cancer. A Cancer and Tumor Gene Map pan-analysis showed that high expression of KNTC1 was related to poor prognosis in 9499 tumor samples. With immunohistochemical staining, we found that the high expression of KNTC1 in pancreatic cancer was related to pathological grade and clinical prognosis. Similarly, RT-PCR results indicated that the expression of KNTC1 was higher in three groups of pancreatic cancer cell lines (BxPC-3, PANC-1, and SW1990) than in normal pancreatic ductal cells. We introduced lentivirus-mediated shRNA targeting KNTC1 into PANC-1 and SW1990 cells and found that KNTC1 knockdown significantly decreased cell growth and increased cell apoptosis compared to the control group cells. Bioinformatic analysis of the cell expression profile revealed that differential genes were mainly enriched in the cell cycle, mitosis, and STAT3 signaling pathways, and co-immunoprecipitation confirmed an interaction between KNTC1 and cell division cycle associated 8. Conclusions KNTC1 could be linked to the pathophysiology of pancreatic cancer and may be an early diagnostic marker of cervical precancerous lesions.

碳基荧光纳米探针在生物成像领域展现出诱人的应用前景. 本文通过调节合成方法合成了一种磺酸基修饰的石墨烯量子点(S-GQDs)荧光探针. 该探针呈现出优异的光学和理化性能, 如荧光强度高、 pH稳定、表面带负电等. 研究表明其发光机理主要依赖荧光分子发光机制. 与我们之前报道的氨基化量子点A-GQDs和肿瘤细胞核靶向探针GTTN对比, 该探针具有良好的生物安全性, 可以在相当短的时间内即跨膜进入细胞, 而GTTN在正常的体外培养条件下无法进入细胞. 为此, 我们探究了产生该差异的原因. 结果表明, S-GQDs与A-GQDs截然不同的合成原料导致了他们的毒性差异, 而S-GQDs的不稳定性则是导致其进入细胞、与GTTN明显不同的主要原因.

Zinc oxide nanomaterials have become common food additives in recent years. Casein phosphopeptides (CPP) and vitamin C (VC) are used as functional food additives together with ZnO nanoparticles (ZnO NPs) in many commercial foods. Our previous studies showed that VC can increase the cytotoxicity induced by ZnO NPs both in vitro and in vivo, while CPP can have a cytoprotective effect against oxidative stress induced by ZnO NPs. However, the combined toxic effect of the three additives together in food is unknown. Herein, we have investigated the combined toxicity of ZnO NPs, CPP and VC by altering the sequence of their addition to clarify their toxic mechanisms in the composite systems. When the order of addition of the three materials changes, the cytotoxicity induced by the ZnO NPs changes due to the different concentrations of dissolved Zn ions in the different groups. We have also probed the intestinal absorption of Zn ions with an everted gut sac model. The amount of Zn2+ absorbed in the intestine in different composite systems also responds differently to the sequence of addition of the additives. VC is more powerful at controlling the synergistic toxic effect induced by ZnO NPs compared to the protective role of CPP in the combined systems.

Nanomaterials have attracted considerable interest owing to their unique physicochemical properties. The wide application of nanomaterials has raised many concerns about their potential risks to human health and the environment. Metal oxide nanoparticles (MONPs), one of the main members of nanomaterials, have been applied in various fields, such as food, medicine, cosmetics, and sensors. This review highlights the bio-toxic effects of widely applied MONPs and their underlying mechanisms. Two main underlying toxicity mechanisms, reactive oxygen species (ROS)- and non-ROS-mediated toxicities, of MONPs have been widely accepted. ROS activates oxidative stress, which leads to lipid peroxidation and cell membrane damage. In addition, ROS can trigger the apoptotic pathway by activating caspase-9 and -3. Non-ROS-mediated toxicity mechanism includes the effect of released ions, excessive accumulation of NPs on the cell surface, and combination of NPs with specific death receptors. Furthermore, the combined toxicity evaluation of some MONPs is also discussed. Toxicity may dramatically change when nanomaterials are used in a combined system because the characteristics of NPs that play a key role in their toxicity such as size, surface properties, and chemical nature in the complex system are different from the pristine NPs.

Nanotechnology has been a rapidly developing field in the past few decades, resulting in the more and more exposure of nanomaterials to human. The increased applications of nanomaterials for industrial, commercial and life purposes, such as fillers, catalysts, semiconductors, paints, cosmetic additives and drug carriers, have caused both obvious and potential impacts on human health and environment. Nanotoxicology is used to study the safety of nanomaterials and has grown at the historic moment. Molecular toxicology is a new subdiscipline to study the interactions and impacts of materials at the molecular level. To better understand the relationship between the molecular toxicology and nanomaterials, this review summarizes the typical techniques and methods in molecular toxicology which are applied when investigating the toxicology of nanomaterials and include six categories: namely; genetic mutation detection, gene expression analysis, DNA damage detection, chromosomal aberration analysis, proteomics, and metabolomics. Each category involves several experimental techniques and methods.

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in photodynamic therapy (PDT) of cancer treatment as excellent regenerative photocatalysts. However, there are some challenges because of their poor dispersity. Transferrin (Tf) was tried to modify the surface of TiO2 NPs to reduce the aggregation, which further affected uptake and excretion on SMMC-7721 human liver cancer cells. Initially, TiO2 NPs modified with Tf (TiO2-Tf NPs) entered into the cells faster than the pure TiO2 NPs which remain attaching on the cell membrane after short-term co-incubation. Tf modification increased the rate and amount of cellular endocytosis. Both TiO2 NPs and TiO2-Tf NPs were observed in lysosomes after long-term co-incubation through clathrin-mediated endocytosis pathway. Expulsion of NPs was then observed and it was found that the exocytosis of TiO2-Tf NPs was fast in the first 24 h, and then slowed down gradually from 24 h to 144 h. Totally, existence of Tf decreased the exocytosis of TiO2 NPs. Furthermore, the differences of cytotoxicity and genotoxicity between TiO2 NPs and TiO2-Tf NPs show that surface-adsorbed Tf components provide some protection from the cytotoxic effect by reducing the production of intracellular ROS. TiO2-Tf NPs obviously affected cell cycle, indicating a significant G2/M phase cell cycle arrest. Our results offer a promising application of easily aggregated TiO2 NPs in the nanomedicine field.

Nanoparticle-based theranostics combines tumor imaging and cancer therapy in one platform, but the synthesis of theranostic agents is impeded by chemical groups on the surface and the size and morphology of the components. Strategies to construct a multifunctional platform for bioimaging and photothermal therapy (PTT) are urgently needed. A new upconversion-magnetic agent (FeCUPs) based on hollow carbon spheres, which is both a photothermal agent and a dual carrier of luminescent and magnetic nanoparticles, provides an effective approach for tumor elimination. Methods: The morphology of FeCUPs was characterized for the construction and size adjustment of the theranostic agent using transmission electron microscopy, high-resolution transmission electron microscopy, energy dispersive spectroscopy and high angle annular dark field scanning transmission electron microscopy. The distribution of FeCUPs was tracked under in-situ upconversion luminescence (UCL) imaging and magnetic resonance imaging (MRI) in vivo. Photothermal therapy was carried out on tumor-bearing mice, after which the toxicity of PTT was evaluated by a blood biochemistry test and histological section analysis. Results: Stable and uniform loading of luminescent nanocomposites on three-dimensional carbon materials is reported for the first time. Based on the mechanism of synthesis, the size of the hybrid particles was adjusted from micrometers to nanometers. External magnetic field-enhanced photothermal therapy with multi-model imaging was accomplished using FeCUPs. Moreover, no cancer recurrence was found during 14 days of recovery without PTT. Conclusions: Hollow carbon spheres, photothermal agents loaded with upconversion nanoparticles inside and magnetic nanoparticles outside were prepared for photothermal therapy. The aggregation of FeCUPs in tumors by the local magnetic field was verified by MRI and UCL imaging, and PTT was enhanced.

With the rapid development of nanotherapy, concerns surrounding the possible use of nanomaterials-mediated immunomodulation are growing. Thus, evaluating the effects of novel materials for potential application in nanotherapy is essential. Herein, we studied the effects of TiO2-nanorods (NRs) on the immune function and their potential application in immunotherapy. TiO2-NRs exerted specific immunomodulatory effects on the main immune cells. Cytokines TNF-α and IL-2, which play a key role in antitumor processes, were upregulated more significantly than other cytokines (IL-4, IL-5, IFN-γ) in the main immune cells. The cells group treated with a high dose of TiO2-NRs (50 mg/L) for 12 h produced a higher TNF-α content of 530.4 pg/mL relative to that (238.2 pg/mL) treated with saline solution only. The TNF-α content increased to 2.2- and 4.9-fold for macrophages and lymphocytes, respectively. Also, we conclude that TiO2-NRs exposure may trigger T cell proliferation and bias toward Th1 immune response and cause a long-lasting activation of lymphocytes involved in adaptive immunity rather than an innate immunity in BALB/c mice. Furthermore, we explored the potential application of TiO2-NRs in immunotherapy. At a given dose of 1 mg/kg, the inhibition rate by TiO2-NRs (26.7%) was much higher than that by DOX (13.3%).

To date, considerable effort has been devoted to determine the potential toxicity of nanoparticles to cells and organisms. However, determining the mechanism of cytotoxicity induced by different types of nanoparticles remains challenging. Herein, typically low toxicity nanomaterials were used as a model to investigate the mechanism of cytotoxicity induced by low toxicity nanomaterials. We studied the effect of nano-TiO2, nano-Al2O3 and nano-SiO2 deposition films on the ion concentration on a cell-free system simulating the cell membrane. The results showed that the ion concentration of K(+), Ca(2+), Na(+), Mg(2+) and SO4(2-) decreased significantly following filtration of the prepared deposition films. More specifically, at a high nano-TiO2 concentration (200 mg L(-1)) and a long nano-TiO2 deposition time (48 h), the concentration of Na(+) decreased from 2958.01 to 2775.72, 2749.86, 2757.36, and 2719.82 mg L(-1), respectively, for the four types of nano-TiO2 studied. Likewise, the concentration of SO4(2-) decreased from 38.83 to 35.00, 35.80, 35.40, and 35.27 mg L(-1), respectively. The other two kinds of typical low toxicity nanomaterials (nano-Al2O3 and nano-SiO2) have a similar impact on the ion concentration change trend. Adsorption of ions on nanoparticles and the hydrated shell around the ions strongly hindered the ions through the nanoparticle films. The endocytosed nanoparticles could be released from the cells without inducing cytotoxicity. Hindering the ion exchange and disrupting the exocytosis process are the main factors that induce cytotoxicity in the presence of excess nano-TiO2 on the cell surface. The current findings may offer a universal principle for understanding the mechanism of cytotoxicity induced by low toxicity nanomaterials.

Specific targeting of tumor tissues is essential for tumor imaging and therapeutics but remains challenging. Here, we report an unprecedented method using synthetic sulfonic-graphene quantum dots (sulfonic-GQDs) to exactly target the cancer cell nuclei in vivo without any bio- ligand modification, with no intervention in cells of normal tissues. The key factor for such selectivity is the high interstitial fluid pressure (IFP) in tumor tissues, which allows the penetration of sulfonic-GQDs into the plasma membrane of tumor cells. In vitro, the sulfonic-GQDs are repelled out of the cell membrane because of the repulsive force between negatively charged sulfonic-GQDs and the cell membranes which contributes to the low distribution in normal tissues in vivo. However, the plasma membrane-crossing process can be activated by incubating cells in ultrathin film culture medium because of the attachment of sulfonic-GQDs on cell memebranes. Molecular dynamics simulations demonstrated that, once transported across the plasma membrane, the negatively charged functional groups of these GQDs will leave the membrane with a self-cleaning function retaining a small enough size to achieve penetration through the nuclear membrane into the nucleus. Our study showed that IFP is a previously unrecognized mechanism for specific targeting of tumor cell nuclei and suggested that sulfonic-GQDs may be developed into novel tools for tumor-specific imaging and therapeutics.

Zinc oxide nanoparticles (ZnO NPs) are widely used as food additives, especially in nutritional foods. However, many reports have demonstrated their toxicity in humans and other biological systems. Our study has confirmed that ZnO NPs can induce apoptosis and oxidative damage on human gastric epithelium cells (GES-1). Caseinophosphopeptides (CPP) are also used as functional food additives that sequester prooxidant metals and scavenge free radicals. Herein, we investigate the combined cytotoxicity of ZnO NPs and CPP for the first time. The results show that CPP protects GES-1 cells from oxidative stress induced by ZnO NPs, decreases reactive oxygen species, diminishes the level of malondialdehyde, increases the content of glutathione and improves the activity of superoxide dismutase. Therefore, CPP can protect GES-1 cells against ZnO NP induced injury through the down-regulation of oxidative stress.

Advantages such as strong signal strength, resistance to photobleaching, tunable fluorescence emissions, high sensitivity, and biocompatibility are the driving forces for the application of fluorescent nanoparticles (FNPs) in cancer diagnosis and therapy. In addition, the large surface area and easy modification of FNPs provide a platform for the design of multifunctional nanoparticles (MFNPs) for tumor targeting, diagnosis, and treatment. In order to obtain better targeting and therapeutic effects, it is necessary to understand the properties and targeting mechanisms of FNPs, which are the foundation and play a key role in the targeting design of nanoparticles (NPs). Widely accepted and applied targeting mechanisms such as enhanced permeability and retention (EPR) effect, active targeting, and tumor microenvironment (TME) targeting are summarized here. Additionally, a freshly discovered targeting mechanism is introduced, termed cell membrane permeability targeting (CMPT), which improves the tumorâ targeting rate from less than 5% of the EPR effect to more than 50%. A new design strategy is also summarized, which is promising for future clinical targeting NPs/nanomedicines design. The targeting mechanism and design strategy will inspire new insights and thoughts on targeting design and will speed up precision medicine and contribute to cancer therapy and early diagnosis., J.H., C.L., L.D., and Y.H. contributed equally to this work. This work was been supported by the National Natural Science Foundation of China (Nos. 21371115, 11025526, 21671131, 11875185), the Shanghai University-Universal Medical Imaging Diagnostic Research Foundation (19H00100), the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13078) and the Portuguese Foundation for Science and Technology (IF/00347/2015).

TiO(2) nanotubes (TiO(2)-NTs) are currently attracting a high interest because the intrinsic properties of TiO(2) provide the basis for many outstanding functional features. Herein, we focus on the cytotoxicity and sublocation of TiO(2)-NTs in neural stem cells (NSCs). The cytotoxicity of TiO(2)-NTs is investigated using the methyl tetrazolium cytotoxicity and reactive oxygen species assay, the apoptosis assay by flow cytometry. Cell viability assay shows that TiO(2)-NTs inside cells are nontoxic at the low concentration. A time-dependent relationship is observed, while a dose-dependent relationship is seen only at the concentration higher than 150 μg/ml. The uptake happens shortly after incubation with cells. TiO(2)-NTs can easily pass through the cell membrane and enter into the cells. The uptake amount is increased with prolonging incubation time and reach to maximum at 48 h. Transmission electron microscopy and confocal is used to study subcellular location of TiO(2)-NTs. It is found that TiO(2)-NTs traversed cell membrane and localized in many vesicles (endosomes and lysosomes) and cytoplasm. TiO(2)-NTs in NSCs firstly disperse or metabolism by lysosomal enzymes and then exocytosis from NSCs.

Application of nanotechnology and nanomaterials in cancer therapeutics has attracted much attention in recent years. Nano titanium dioxide is one of the most important inorganic functional materials. Cellular toxicity of pH-controlled antitumor drug release system of titanium dioxide nanotubes (TiO2-NTs) in pancreatic cancer cells (SW1990) was evaluated in this paper. The anticancer drug, doxorubicin (DOX) was easily loaded on TiO2-NTs through adsorption forces because of its high specific surface area and perfect surface activity. The drug release from the nanotubes was pH dependent. The toxicological effects were studied after co-incubation of SW1990 with TiO2-NTs-DOX, TiO2-NTs and DOX, respectively. The cellular effect of DOX released from the TiO2-NTs-DOX was same as when DOX was used alone, indicating that the synthesized TiO2-NTs are well qualified as drug carriers in antitumor drug controlled-release system.

At present, safety evaluation standards for nanofood additives are made based on the toxic effects of a single additive. Since the size, surface properties and chemical nature influence the toxicity of nanomaterials, the toxicity may have dramatically changed when nanomaterials are used as food additives in a complex system. Herein, we investigated the combined toxicity of zinc oxide nanoparticles (ZnO NPs) and vitamin C (Vc, ascorbic acid). The results showed that Vc increased the cytotoxicity significantly compared with that of the ZnO only NPs. When the cells were exposed to ZnO NPs at a concentration less than 15 mg L(-1), or to Vc at a concentration less than 300 mg L(-1), there was no significant cytotoxicity, both in the case of gastric epithelial cell line (GES-1) and neural stem cells (NSCs). However, when 15 mg L(-1) of ZnO NPs and 300 mg L(-1) of Vc were introduced to cells together, the cell viability decreased sharply indicating significant cytotoxicity. Moreover, the significant increase in toxicity was also shown in the in vivo experiments. The dose of the ZnO NPs and Vc used in the in vivo study was calculated according to the state of food and nutrition enhancer standard. After repeated oral exposure to ZnO NPs plus Vc, the injury of the liver and kidneys in mice has been indicated by the change of these indices. These findings demonstrate that the synergistic toxicity presented in a complex system is essential for the toxicological evaluation and safety assessment of nanofood.

Graphene quantum dots (GQDs) have various alluring properties and potential applications, but their large-scale applications are limited by current synthetic methods that commonly produce GQDs in small amounts. Moreover, GQDs usually exhibit polycrystalline or highly defective structures and thus poor optical properties. Here we report the gram-scale synthesis of single-crystalline GQDs by a facile molecular fusion route under mild and green hydrothermal conditions. The synthesis involves the nitration of pyrene followed by hydrothermal treatment in alkaline aqueous solutions, where alkaline species play a crucial role in tuning their size, functionalization and optical properties. The single-crystalline GQDs are bestowed with excellent optical properties such as bright excitonic fluorescence, strong excitonic absorption bands extending to the visible region, large molar extinction coefficients and long-term photostability. These high-quality GQDs can find a large array of novel applications in bioimaging, biosensing, light emitting diodes, solar cells, hydrogen production, fuel cells and supercapacitors.