Cytotoxicity of Quantum Dots in Receptor-Mediated Endocytic and Pinocytic Pathways in Yeast.

Despite the promising applications of the use of quantum dots (QDs) in the biomedical field, the long-lasting effects of QDs on the cell remain poorly understood. To comprehend the mechanisms underlying the toxic effects of QDs in yeast, we characterized defects associated with receptor-mediated endocytosis (RME) as well as pinocytosis using Saccharomyces cerevisiae as a model in the presence of cadmium selenide/zinc sulfide (CdSe/ZnS) QDs. Our findings revealed that QDs led to an inefficient RME at the early, intermediate, and late stages of endocytic patch maturation at the endocytic site, with the prolonged lifespan of GFP fused yeast fimbrin (Sac6-GFP), a late marker of endocytosis. The transit of FM1-43, a lipophilic dye from the plasma membrane to the vacuole, was severely retarded in the presence of QDs. Finally, QDs caused an accumulation of monomeric red fluorescent protein fused carbamoyl phosphate synthetase 1 (mRFP-Cps1), a vacuolar lumen marker in the vacuole. In summary, the present study provides novel insights into the possible impact of CdSe/ZnS QDs on the endocytic machinery, enabling a deeper comprehension of QD toxicity.

Transcriptomic analysis reveals particulate hexavalent chromium regulates key inflammatory pathways in human lung fibroblasts as a possible mechanism of carcinogenesis.

Hexavalent chromium [Cr(VI)] is considered a major environmental health concern and lung carcinogen. However, the exact mechanism by which Cr(VI) causes lung cancer in humans remains unclear. Since several reports have demonstrated a role for inflammation in Cr(VI) toxicity, the present study aimed to apply transcriptomics to examine the global mRNA expression in human lung fibroblasts after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 µg/cm2 zinc chromate, with a particular emphasis on inflammatory pathways. The results showed Cr(VI) affected the expression of multiple genes and these effects varied according to Cr(VI) concentration and exposure time. Bioinformatic analysis of RNA-Seq data based on the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaCore databases revealed multiple inflammatory pathways were affected by Cr(VI) treatment. qRT-PCR data corroborated RNA-Seq findings. This study showed for the first time that Cr(VI) regulates key inflammatory pathways in human lung fibroblasts, providing novel insights into the mechanisms by which Cr(VI) causes lung cancer.

The Impact of Cadmium Selenide Zinc Sulfide Quantum Dots on the Proteomic Profile of Saccharomyces cerevisiae.

Quantum dots (QDs) have been highly sought after in the past few decades for their potential to be used in many biomedical applications. However, QDs' cytotoxicity is still a major concern that limits the incorporation of QDs into cutting-edge technologies. Thus, it is important to study and understand the mechanism by which QDs exert their toxicity. Although many studies have explored the cytotoxicity of quantum dots through the transcriptomic level and reactive species generation, the impact of quantum dots on the expression of cellular protein remains unclear. Using Saccharomyces cerevisiae as a model organism, we studied the effect of cadmium selenide zinc sulfide quantum dots (CdSe/ZnS QDs) on the proteomic profile of budding yeast cells. We found a total of 280 differentially expressed proteins after 6 h of CdSe/ZnS QDs treatment. Among these, 187 proteins were upregulated, and 93 proteins were downregulated. The majority of upregulated proteins were found to be associated with transcription/RNA processing, intracellular trafficking, and ribosome biogenesis. On the other hand, many of the downregulated proteins are associated with cellular metabolic pathways and mitochondrial components. Through this study, the cytotoxicity of CdSe/ZnS QDs on the proteomic level was revealed, providing a more well-rounded knowledge of QDs' toxicity.

A study on the mechanism of Indium phosphide/zinc sulfide core/shell quantum dots influencing embryo incubation of rare minnow (Gobiocypris rarus).

Quantum dots (QDs) inhibit fish hatching, but the mechanism is still unclear. In this study, the effect of Indium phosphide/zinc sulfide quantum dots (InP/ZnS QDs) on the embryo incubation of rare minnow was investigated. Five experimental concentration groups were set up according to the preliminary experimental results, which were 0, 50, 100, 200 and 400 nM. A direct exposure method was adopted to expose embryos to InP/ZnS QDs solution. The results showed that InP/ZnS QDs significantly inhibited the embryo hatching rate, delayed embryo emergence, affected the expression of genes associated with hatching gland cells and hatching enzymes. InP/ZnS QDs also destroy the structure of the embryo chorion. In addition, QDs can cause oxidative stress in embryos. Transcriptional sequencing analysis showed that InP/ZnS QDs InP/ZnS QDs may have induced the production of a hypoxic environment and triggered induce abnormal cardiac muscle contraction, inflammatory response and apoptosis process in embryos. In conclusion, QDs influences embryo hatchability largely through egg chorion mediation.

Acute oral toxicity of zinc phosphide: an assessment for wild house mice (Mus musculus).

Irregular plagues of house mice, Mus musculus, incur major economic impacts on agricultural production in Australia. The efficacy of zinc phosphide (ZnP), the only registered broadacre control agent for mice, is reported as increasingly variable. Have mice become less sensitive over time or are they taking a sub-lethal dose and developing aversion? In this laboratory study, the sensitivity of mice (wild caught; outbred laboratory strain) was assessed using oral gavage of a range of ZnP concentrations. The estimated LD50 values (72-79 mg ZnP/kg body weight) were similar for each mouse group but are significantly higher than previously reported. The willingness of mice to consume ZnP-coated grains was determined. ZnP-coated grains (50 g ZnP/kg grain) presented in the absence of alternative food were consumed and 94% of wild mice died. Mice provided with alternative food and ZnP-coated wheat grains (either 25 or 50 g ZnP/kg grain) consumed toxic and non-toxic grains, and mortality was lower (33-55%). If a sublethal amount of ZnP-coated grain was consumed, aversion occurred, mostly when alternative food was present. The sensitivity of wild house mice to ZnP in Australia is significantly lower than previously assumed. Under laboratory conditions, ZnP-coated grains coated with a new higher dose (50 g ZnP/kg grain) were readily consumed. Consumption of toxic grain occurred when alternative food was available but was decreased. Our unambiguous findings for house mice indicate a re-assessment of the ZnP loading for baits used for control of many rodents around the world may be warranted.

Differential effects of PEGylated Cd-free CuInS2/ZnS quantum dot (QDs) on substance P and LL-37 induced human mast cell activation.

CuInS2/ZnS-PEG quantum dots (QDs) are among the most widely used near infrared non-cadmium QDs and are favored because of their non-cadmium content and strong tissue penetration. However, with their increasing use, there is great concern about whether exposure to QDs is potentially risky to the environment and humans. Furthermore, toxicological data related to CuInS2/ZnS-PEG QDs are scarce. In the study, we found that CuInS2/ZnS-PEG QDs (0-100 µg/mL) could internalize into human LAD2 mast cells without affecting their survival rate, nor did it cause degranulation or release of IL-8 and TNF-α. However, CuInS2/ZnS-PEG QDs significantly inhibited Substance P (SP) and LL-37-induced degranulation and chemotaxis of LAD2 cells by inhibiting calcium mobilization. Lower concentrations of CuInS2/ZnS-PEG QDs promoted the release of TNF-α and IL-8 stimulated by SP, but higher concentrations of CuInS2/ZnS-PEG QDs significantly inhibited the release of TNF-α and IL-8. On the other hand, CuInS2/ZnS-PEG QDs promoted LL-37-mediated TNF-α release from LAD2 cells in a dose-dependent manner from 6.25 to 100 µg/mL, while release of IL-8 triggered by LL-37 was dose-dependently inhibited within a dose concentration of 12.5-100 µg/mL. Collectively, our data demonstrated that CuInS2/ZnS-PEG QDs differentially mediated human mast cell activation induced by SP and LL-37.

Hazard Profiling of Commercially Relevant Quantum Dot Components Revealed Synergistic Interactions between Heavy Metals and Polymers.

Commercially used quantum dots (QDs) exemplify complex nanomaterials with multiple components, though little is known about the type of interactions between these components in determining the overall toxicity of this material. We synthesized and characterized a functional QD (CdSe/ZnS_P&E) that was identical in structure and composition to a patented and commercially applied QD and the combinations of its components (CdSe, CdSe/ZnS, ZnS, CdSe_P&E, ZnS_P&E, and P&E). Cells exposed to incremental concentrations of these materials were investigated for cell viability and cellular perturbations, contributing to a final common pathway of cell death using high-content screening assays in model human intestinal epithelial cells (HIEC-6). The concentrations that resulted in a loss of 20% cell viability (EC20 values) for each tested component were used for estimating the combination index (CI) to evaluate synergistic or antagonistic effects between the components. Complete QD (core/shell-polymer) showed the highest toxic potential due to synergistic interactions between core and surface functional groups. The cationic polymer coating enhanced cellular uptake of the QD, ensuing lysosome acidification and release of heavy metal ions to the intracellular milieu, and caused oxidative stress and cytotoxicity. Overall, this study advances our understanding of the collective contribution of individual components of a functional QD toward its toxic potential and emphasizes the need to study multilayered nanomaterials in their entirety for hazard characterization.

Parental exposure to CdSe/ZnS QDs affects cartilage development in rare minnow (Gobiocypris rarus) offspring.

Cartilage development is a sensitive process that is easily disturbed by environmental toxins. In this study, the toxicity of CdSe/ZnS quantum dots on the skeleton of the next generation (F1) was evaluated using rare minnows (Gobiocypris rarus) as model animals. Four-month-old sexually mature parental rare minnows (F0) were selected and treated with 0, 100, 200, 400 and 800 nmol/L CdSe/ZnS quantum dots for 4 days. Embryos of F1 generation rare minnows were obtained by artificial insemination. The results showed that with increasing maternal quantum dots exposure, the body length of F1 embryos decreased, the overall calcium content decreased, and the deformity and mortality rates increased. Alcian blue staining results showed that the lengths of the craniofacial mandible, mandibular arch length, mandibular width, and CH-CH and CH-PQ angles of larvae of rare minnows increased; histological hematoxylin-eosin staining further indicated that quantum dots affected the development of chondrocytes. Furthermore, high concentrations of CdSe/ZnS quantum dots inhibited the transcript expression of the bmp2b, bmp4, bmp6, runx2b, sox9a, lox1 and col2α1 genes. In conclusion, CdSe/ZnS quantum dots can affect the skeletal development of F1 generation embryos of rare minnows at both the individual and molecular levels, the damage to the craniofacial bone is more obvious, and the toxic effect of high concentrations of quantum dots (400 nmol/L and 800 nmol/L) is more significant.

Particulate hexavalent chromium alters microRNAs in human lung cells that target key carcinogenic pathways.

Hexavalent chromium [Cr(VI)] is a global environmental pollutant and human lung carcinogen. However, the mechanisms of Cr(VI) carcinogenesis are not well defined. Cr(VI)-altered gene expression has been reported in the literature and is implicated in numerous mechanisms of Cr(VI) carcinogenesis. MicroRNAs (miRNAs) play a key role in controlling gene expression and are associated with carcinogenic mechanisms. To date no studies have evaluated global changes in miRNA expression in human cells after Cr(VI) exposure. We used RNA sequencing to evaluate how a particulate Cr(VI) compound (zinc chromate), the most potent form of Cr(VI), alters global miRNA expression after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 µg/cm2 zinc chromate in an immortalized, non-cancerous human lung cell line (WTHBF-6). Particulate Cr(VI) significantly affected expression of miRNAs at all time points and concentrations tested. We also found the number of significantly downregulated miRNAs increased in a time- and concentration-dependent manner and many miRNAs were upregulated after 24 h exposure at the intermediate concentration tested. Pathway analyses of the differentially expressed miRNAs predicted miRNAs target pathways of Cr(VI) carcinogenesis in a time- and concentration-dependent manner. These data are the first to evaluate global changes in miRNA expression in human lung cells after Cr(VI) exposure and indicate miRNAs may play a key role in pathways of Cr(VI) carcinogenesis.

Individual and Binary Mixture Toxicity of Five Nanoparticles in Marine Microalga Heterosigma akashiwo.

The investigation of the combined toxic action of different types of nanoparticles (NPs) and their interaction between each other and with aquatic organisms is an important problem of modern ecotoxicology. In this study, we assessed the individual and mixture toxicities of cadmium and zinc sulfides (CdS and ZnS), titanium dioxide (TiO2), and two types of mesoporous silicon dioxide (with no inclusions (SMB3) and with metal inclusions (SMB24)) by a microalga growth inhibition bioassay. The counting and size measurement of microalga cells and NPs were performed by flow cytometry. The biochemical endpoints were measured by a UV-VIS microplate spectrophotometer. The highest toxicity was observed for SMB24 (EC50, 3.6 mg/L) and CdS (EC50, 21.3 mg/L). A combined toxicity bioassay demonstrated that TiO2 and the SMB3 NPs had a synergistic toxic effect in combinations with all the tested samples except SMB24, probably caused by a "Trojan horse effect". Sample SMB24 had antagonistic toxic action with CdS and ZnS, which was probably caused by metal ion scavenging.

Wide visible-range activatable fluorescence ZnSe:Eu3+/Mn2+@ZnS quantum dots: local atomic structure order and application as a nanoprobe for bioimaging.

The development of QDs-based fluorescent bionanoprobe for cellular imaging fundamentally relies upon the precise knowledge of particle-cell interaction, optical properties of QDs inside and outside of the cell, movement of a particle in and out of the cell, and the fate of particle. We reported engineering and physicochemical characterization of water-dispersible Eu3+/Mn2+ co-doped ZnSe@ZnS core/shell QDs and studied their potential as a bionanoprobe for biomedical applications, evaluating their biocompatibility, fluorescence behaviour by CytoViva dual mode fluorescence imaging, time-dependent uptake, endocytosis and exocytosis in RAW 264.7 macrophages. The oxidation state and local atomic structure of the Eu dopant studied by X-ray absorption fine structure (XAFS) analysis manifested that the Eu3+ ions occupied sites in both ZnSe and ZnS lattices for the core/shell QDs. A novel approach was developed to relieve the excitation constraint of wide bandgap ZnSe by co-incorporation of Eu3+/Mn2+ codopants, enabling the QDs to be excited at a wide UV-visible range. The QDs displayed tunable emission colors by a gradual increase in Eu3+ concentration at a fixed amount of Mn2+, systematically enhancing the Mn2+ emission intensity via energy transfer from the Eu3+ to Mn2+ ion. The ZnSe:Eu3+/Mn2+@ZnS QDs presented high cell viability above 85% and induced no cell activation. The detailed analyses of QDs-treated cells by dual mode fluorescence CytoViva microscopy confirmed the systematic color-tunable fluorescence and its intensity enhances as a function of incubation time. The QDs were internalized by the cells predominantly via macropinocytosis and other lipid raft-mediated endocytic pathways, retaining an efficient amount for 24 h. The unique color tunability and consistent high intensity emission make these QDs useful for developing a multiplex fluorescent bionanoprobe, activatable in wide-visible region.

Comparing Transcriptome Profiles of Saccharomyces Cerevisiae Cells Exposed to Cadmium Selenide/Zinc Sulfide and Indium Phosphide/Zinc Sulfide.

The primary focus of our research was to obtain global gene expression data in baker's yeast exposed to sub-lethal doses of quantum dots (QDs), such as green-emitting CdSe/ZnS and InP/ZnS, to reveal novel insights on their unique mechanisms of toxicity. Despite their promising applications, their toxicity and long-lasting effects on the environment are not well understood. To assess toxicity, we conducted cell viability assays, ROS detection assays, and assessed their effects on the trafficking of Vps10-GFP toward the trans-Golgi network with confocal microscopy. Most notably, we used RNA-sequencing (RNA-seq) to obtain gene expression profiles and gene identities of differentially expressed genes (DEGs) in QD-treated yeast. We found CdSe/ZnS QDs significantly altered genes implicated in carboxylic acid, amino acid, nitrogen compounds, protein metabolic processes, transmembrane transport, cellular homeostasis, cell wall organization, translation, and ribosomal biogenesis. Additionally, we found InP/ZnS QDs to alter genes associated with oxidation-reduction, transmembrane transport, metal ion homeostasis, cellular component organization, translation, and protein and nitrogen compound metabolic processes. Interestingly, we observed an increase in reactive oxygen species (ROS) in CdSe/ZnS-treated cells and a decrease in ROS levels in InP/ZnS-treated cells. Nevertheless, we concluded that both QDs modestly contributed cytotoxic effects on the budding yeast.

Toxic effects of ZnSe/ZnS quantum dots on the reproduction and genotoxiticy of rare minnow (Gobiocypris rarus).

ZnSe/ZnS quantum dots (QDs) have excellent optical properties, but researchers have not clearly determined whether they cause harm to organisms. In the present study, the effect of ZnSe/ZnS QDs on the parents and offspring of rare minnow were evaluated for the first time. Exposure to ZnSe/ZnS QDs altered the testicular structure, caused sperm DNA damage and decreased sperm motility in males. They also suppressed the expression of reproduction-related genes, such as androgen receptor (Ar), DM-related transcription factor 1 (Dmrt1), estrogen receptor (Er), and X-ray repair cross complementing gene 1 (Xrcc1). Continued monitoring of the F1 generation revealed that the embryonic development of the F1 generation was abnormal and the growth index of the F1 generation of adult fish showed hormesis. A comet assay showed that the F1 generation still had DNA damage in the 400 and 800 nmol/L groups at 96 h post-fertilization (hpf). Thus, ZnSe/ZnS QDs damaged the reproductive system of the rare minnow, and this effect continued to the F1 generation.

Systematic evaluation of CdSe/ZnS quantum dots toxicity on the reproduction and offspring health in male BALB/c mice.

Increased applications of quantum dots (QDs) in the biomedical field have aroused attention for their potential toxicological effects. Although numerous studies have been carried out on the toxicity of QDs, their effects on reproductive and development are still unclear. In this study, we systematically evaluated the male reproductive toxicity and developmental toxicity of CdSe/ZnS QDs in BALB/c mice. The male mice were injected intravenously with CdSe/ZnS QDs at the dosage of 2.5 mg/kg BW or 25 mg/kg BW, respectively, and the survival status, biodistribution of QDs in testes, serum sex hormone levels, histopathology, sperm motility and acrosome integrity was measured on Day 1, 7, 14, 28 and 42 after injection. On Day 35 after treatment, male mice were housed with non-exposed female mice, and then offspring number, body weight, organ index and histopathology of major organs, blood routine and biochemical tests of offspring were measured to evaluate the fertility and offspring health. The results showed that CdSe/ZnS QDs could rapidly distribute in the testis, and the fluorescence of QDs could still be detected on Day 42 post-injection. QDs had no adverse effect on the structure of testis and epididymis, but high-dose QDs could induce apoptosis of Leydig cells in testis at an early stage. No significant differences in survival of state, body weight organ index of testis and epididymis, sex hormones levels, sperm quality, sperm acrosome integrity and fertility of male mice were observed in QDs exposed groups. However, the development of offspring was obviously influenced, which was mainly manifested in the slow growth of offspring, changes in organ index of main organs, and the abnormality of liver and kidney function parameters. Our findings revealed that CdSe/ZnS QDs were able to cross the blood-testis barrier (BTB), produce no discernible toxic effects on the male reproductive system, but could affect the healthy growth of future generations to some extent. In view of the broad application prospect of QDs in biomedical fields, our findings might provide insight into the biological safety evaluation of the reproductive health of QDs.

Cytotoxicity of quantum dots: Use of quasiSMILES in development of reliable models with index of ideality of correlation and the consensus modelling.

The assessment of cytotoxicity of quantum dots is very essential for environmental and health risk analysis. In the present work we have modelled HeLa cell cytotoxicity of sixty one CdSe quantum dots with ZnS shell as a function of its experimental conditions and molecular construction using quasiSMILES representations. The index of ideality of correlation helps in the building of ten statistically significant models having good fitting ability with value of R2 ranging from 0.8414 to 0.9609 for the training set. The split 5 model is rated as the best model with values of R2, Q2F1, Q2F2 and Q2F3 as 0.8964, 0.8267, 0.8264 and 0.8777 respectively for the calibration set. The extraction of features causing increase and decrease of cytotoxicity of quantum dots indicates importance of neutral surface charge, surface modified with protein, 72 h exposure time, combination of MTT assay with surface protein in decreasing the cytotoxicity. Amphiphilic polymer, polyol ligand with neutral charge, 0.5 - 0.6 nm quantum dot diameter with lipid ligand and unmodified positively charged surface are grouped in toxicity enhancer features. Further, consensus modelling using split 5 and 8 patterns enhances the prediction quality by increasing the R2val to 0.9361 and 0.9656 respectively.

Comparison of developmental toxicity of different surface modified CdSe/ZnS QDs in zebrafish embryos.

Quantum dots (QDs) are new types of nanomaterials. Few studies have focused on the effect of different surface modified QDs on embryonic development. Herein, we compared the in vivo toxicity of CdSe/ZnS QDs with carboxyl (-COOH) and amino (-NH2) modification using zebrafish embryos. After exposure, the two CdSe/ZnS QDs decreased the survival rate, hatching rate, and embryo movement of zebrafish. Moreover, we found QDs attached to the embryo membrane before hatching and the eyes, yolk and heart after hatching. The attached amount of carboxyl QDs was more. Consistently, the Cd content in embryos and larvae was higher in carboxyl QD-treatment. We further observed that the two QDs caused zebrafish pericardial edema and cardiac dysfunction. In line with it, both carboxyl and amino QDs up-regulated the transcription levels of cardiac development-related genes, and the levels were higher in carboxyl QD-treated groups. Furthermore, the chelator of Cd2+ diethylene triamine pentacetate acid could partially rescued the developmental toxicity caused by the two types of QDs suggesting that both the nature of QDs and the release of Cd2+ contribute to the developmental toxicity. In conclusion, the two CdSe/ZnS QDs have developmental toxicity and affect the cardiac development, and the carboxyl QDs is more toxic possibly due to the higher affinity and more release to embryos and larvae. Our study provides new knowledge that the surface functional modification of QDs is critical on the development on aquatic species, which is beneficial to develop and applicate QDs more safely and environment-friendly.

In-vitro and in-vivo evaluation of the molecular mechanisms involved in the toxicity associated to CdSe/ZnS quantum dots exposure.

The use of different types of quantum dots is growing in recent times in both the technology and biomedical industries. Such is the extension of the use of these quantum dots that they have become potential emerging contaminants, which makes it necessary to evaluate their potential toxicity and the impact they may have on both health and the environment. Although studies already exist in this regard, the molecular mechanisms by which CdSe/ZnS quantum dots exert their toxic effects are still unknown. For this reason, in this study, a comprehensive proteomic approach has been designed, applying the SILAC strategy to an in-vitro model (hepatic cells) and the super-SILAC alternative to an in-vivo model, specifically zebrafish larvae. This integral approach, together with additional bioanalytical assays, has made it possible for the identification of proteins, molecular mechanisms and, therefore, biological processes that are altered as a consequence of exposure to CdSe/ZnS quantum dots. It has been demonstrated, on the one hand, that these quantum dots induce hypoxia and ROS generation in hepatic cells, which leads to apoptosis, specifically through the TDP-43 pathway. On the other hand, it has been shown that exposure to CdSe/ZnS quantum dots has a high impact on developing organisms, inducing serious neural and developmental problems in the locomotor system.

Mitigating the toxic effects of CdSe quantum dots towards freshwater alga Scenedesmus obliquus: Role of eco-corona.

The extensive use of semiconducting nanoparticles such as quantum dots in biomedical and industrial products can lead to their inadvertent release into the freshwater system. Natural exudates in the aquatic system comprising extracellular polymeric substance (EPS) and protein-rich metabolites can eventually adsorb onto the quantum dots (QDs) surface and form an eco-corona. The alterations in the physio-chemical and toxicological behavior of CdSe/ZnS QDs under the influence of eco-corona in the freshwater system have not been explored yet. In the present study, lake water medium conditioned with exudate secreted by Scenedesmus obliquus was utilized as an eco-corona forming matrix. The time-based evolution of the eco-corona on the differently charged CdSe/ZnS QDs was analyzed using transmission electron microscopy and dynamic light scattering. Aging of amine-QDs in algal exudate for 72 h showed enhanced aggregation (Mean Hydrodynamic Diameter- 1969 nm) as compared to carboxyl-QDs (1543 nm). Further, eco-coronation tends to impart an overall negative charge to the QDs. The fluorescence intensity of amine-QDs was quenched by 84% due to the accumulation of higher eco-corona. An integrative effect of surface charge and accumulated eco-corona layer influenced the Cd2+ ion leaching from the QDs. An enhancement in the algal cell viability treated with carboxyl - CdSe/ZnS (90%) and amine- CdSe/ZnS QDs (94%) aged for 72 h suggested that eco-corona can effectively mitigate the inherent toxicity of the QDs. The oxidative stress markers in the algal cells (LPO, SOD, and CAT) were in correlation with the cytotoxicity results. The algal photosynthetic efficiency depended on the deposition of eco-coronated QDs on the cell surface. Cellular uptake results indicated low Cd2+ concentration of nearly 13.9 and 11.5% for carboxyl- and amine- CdSe/ZnS QDs respectively. This suggests that eco-coronation directly influences the bioavailability of engineered nanoparticles.

Time-dependent changes in proliferation, DNA damage and clock gene expression in hepatocellular carcinoma and healthy liver of a transgenic mouse model.

Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time-of-day dependent changes of proliferation and DNA damage in HCC. Using transgenic c-myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ-H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev-erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ-H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time-of-day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.

CdSe/ZnS quantum dots exhibited nephrotoxicity through mediating oxidative damage and inflammatory response.

OBJECTIVE: This study aimed to the evaluate the nephrotoxicity of CdSe/ZnS QDs in vitro and vivo, as well as investigate the underlying toxicity mechanisms. RESULTS: In vitro experiments showed that compared with control cells, CdSe/ZnS QDs treatment significantly inhibited cell viability and promoted cell apoptosis in dose-dependent manner in NRK cells. Notably, CdSe/ZnS QDs treatment increased the contents of MDA and ROS, and decreased the activities of SOD, CAT and GSH-Px; however, the co-treatment of NAC and QDs relieved the oxidative damage of NRK cells. Moreover, in vivo experiments also revealed that CdSe/ZnS QDs treatment obviously increased kidney weight coefficient, damaged the kidney function, as well as induced inflammatory response and inhibited the activation of NRF2/Keap1 pathway in kidney tissues of mice. CONCLUSIONS: CdSe/ZnS QDs exhibited obvious nephrotoxicity by mediating oxidative damage and inflammatory response in vitro and in vivo via NRF2/Keap1 pathway. METHODS: The characterization of CdSe/ZnS QDs was analyzed by transmission electron microscope, emission spectrum scanning, and dynamic light scattering. Rat kidney cells (NRK) were exposed to different doses of CdSe/ZnS QDs with or without N-acetylcysteine (NAC, antioxidant). Then, cellular uptake of CdSe/ZnS QDs was detected, and in vitro cytotoxicity was evaluated by MTT assay and TUNEL assay.