Gold Nanorods Inhibit Tumor Metastasis by Regulating MMP-9 Activity: Implications for Radiotherapy.

Dysregulation of matrix metalloproteinase (MMP) is strongly implicated in tumor invasion and metastasis. Nanomaterials can interact with proteins and have impacts on protein activity, which provides a potential strategy for inhibiting tumor invasion and metastasis. However, the regulation of MMP activity by nanomaterials has not been fully determined. Herein, we have found that gold nanorods (Au NRs) are able to induce the change of the secondary structure of MMP-9 and thereby inhibit their activity. Interestingly, the inhibition of MMP-9 activity is highly dependent on the aspect ratio of Au NRs, and an aspect ratio of 3.3 shows the maximum inhibition efficiency. Molecular dynamics simulations combined with mathematical statistics algorithm reveal the binding behaviors and interaction modes of MMP-9 with Au NRs in atomic details and disclose the mechanism of aspect ratio-dependent inhibition effect of Au NRs on MMP-9 activity. Au NRs with an aspect ratio of 3.3 successfully suppress the X-ray-activated invasion and metastasis of tumor by inhibiting MMP-9 activity. Our findings provide important guidance for the modulation of MMP-9 activity by tuning key parameters of nanomaterials and demonstrate that gold nanorods could be developed as potential MMP inhibitors.

Transcriptome Analysis Revealed Genes Related to γ-Irradiation Induced Emergence Failure in Third-Instar Larvae of Bactrocera dorsalis.

The oriental fruit fly is a polyphagous and highly invasive economically important pest in the world. We proposed the hypothesis that radiation treatment influence RNA expression in the larvae and leads to emergence failure. Therefore, transcriptome analyses of third-instar larvae of B. dorsalis ionizing, irradiated with 60Co-γ at 116Gy, were conducted and compared with the controls; a total of 608 DEGs were identified, including 348 up-regulated genes and 260 down-regulated ones. In addition, 130 SNPs in 125 unigenes were identified. For the DEGs, the most significantly enriched GO item was hemolymph coagulation, and some of the enriched pathways were involved in digestive processes. The subsequent validation experiment confirmed the differential expression of six genes, including sqd, ENPEP, Jhe, mth, Notch, and Ugt. Additionally, the 3401:G->A SNP in the Notch gene was also successfully validated. According to previous research, this was the first comparative transcriptome study to discover the candidate genes involved in insect molt to pupae. These results not only deepen our understanding of the emerging mechanism of B. dorsalis but also provide new insights into the research of biomarkers for quarantine insect treatment with the appropriate dose of radiation.

Involvement of Mitophagy in Primary Cultured Rat Neurons Treated with Nanoalumina.

The aim of this study was to explore the influence of the neurotoxicity of nanoalumina on primarily cultured neurons. Normal control, particle size control, aluminum, micron-alumina, and nanoalumina at 50-nm and 13-nm particle sizes were included as subjects to evaluate the level of apoptosis, necrosis, and autophagy in primarily cultured neurons and further explore the mitophagy induced by nanoalumina. The results demonstrated that nanoalumina could induce neuronal cell apoptosis, necrosis, and autophagy, among which autophagy was the most notable. When the autophagy inhibitor was added to the nanoalumina-treated group, it significantly downregulated the protein expression levels of Beclin-1 and LC3II/LC3. Observation under a transmission electron microscope and a fluorescence microscope revealed mitophagy characteristics induced by nanoalumina. Additionally, the neurotoxicological effects induced by nanoalumina were more significant than those induced by aluminum and in a particle size-dependent manner.

Effects of soil ingestion on nutrient digestibility and rumen bacterial diversity of Tibetan sheep.

Tibetan sheep (Ovis aries) are the most numerous livestock in Tibet Plateau pasture ecosystem and have strong ecological adaptability. In the natural grazing system, soil as a natural nutrient carrier and involuntarily or intentionally ingested by Tibetan sheep contribute as an important feed approach. However, quantifying the dosages of soil ingestion for the Tibetan sheep still needs to be clarified. This study aims to characterize nutrient digestibility and rumen bacterial communities by Tibetan sheep in response to different levels of soil ingestion. Thirty sheep were selected and divided into five treatments with soil ingestion (0%, 5%, 10%, 15%, and 20%). The conclusion demonstrated that soil ingestion improved the dry matter digestibility (59.3-62.97%), ether extract (59.79-67.87%) and crude protein (59.81-66.47%) digestibility, particularly 10% soil ingestion has highest nutrient digestibility. The rumen fermentation environment adjusted after soil ingestion by improvement of pH, ammonia nitrogen and volatile fatty acids. Appropriate soil ingestion reduced the bacterial diversity ranged from 946 to 1000 OUTs as compared control (1012), and the rumen bacterial community dominant by typical fiber digestion associated Firmicutes (47.48-53.56%), Bacteroidetes (34.93-40.02%) and Fibrobacteres (4.36-9.27%). Especially, the highest digestible feed capacity and stronger environment adaptability present in 10% soil ingestion Tibetan sheep. Overall, soil ingestion stimulates rumen metabolism by creating a favorable environment for microbial fermentation, improved bacterial community abundance associated with cellulose and saccharide degradation, contribute nutrient digestibility and growth performance of Tibetan sheep.

Postchronic Single-Walled Carbon Nanotube Exposure Causes Irreversible Malignant Transformation of Human Bronchial Epithelial Cells through DNA Methylation Changes.

As environmental pollutants and possible carcinogens, carbon nanotubes (CNTs) have recently been found to induce carcinogenesis and tumor metastasis after long-term pulmonary exposure. However, whether CNT-induced carcinogenesis can be inherited and last for generations remains unclear. Herein, postchronic single-walled carbon nanotubes (SWCNTs) exposed human lung cell model (BEAS-2B cells) are established to investigate SWCNT-induced carcinogenesis. At a tolerated sublethal dose level, postchronic SWCNT exposure significantly increases the migration and invasion abilities of BEAS-2B cells, leading to malignant cell transformation. Notably, the malignant transformation of BEAS-2B cells is irreversible within a 60 day recovery period after SWCNT exposure, and the malignant transformation activities of cells gradually increase during the recovery period. Moreover, these transformed cells promote carcinogenesis in vivo, accompanied by a raised level of biomarkers of lung adenocarcinoma. Further mechanism analyses reveal that postchronic exposure to SWCNTs causes substantial DNA methylation and transcriptome dysregulation of BEAS-2B cells. Subsequent enrichment and clinical database analyses reveal that differentially expressed/methylated genes of BEAS-2B cells are enriched in cancer-related biological pathways. These results not only demonstrate that postchronic SWCNT-exposure-induced carcinogenesis is heritable but also uncover a mechanism from the perspective of DNA methylation.

Matrix metalloproteinase inhibitors (MMPIs) as attractive therapeutic targets: Recent progress and current challenges.

Matrix metalloproteinase (MMP) plays an essential role in many physiological and pathological processes. An increase in MMP activity contributes to excessive degradation and remodeling of the extracellular matrix (ECM), which has been correlated with invasion and metastasis of tumors. Matrix metalloproteinase inhibitor (MMPI) has been developed as an attractive therapeutic target for decades, suggesting inspiring therapeutic effects in preclinical studies. However, achieving specificity remains an important challenge in the development of MMPIs, limiting their clinical application and bringing about the risk of biosafety. Nanomaterials can be used as alternative candidates for MMPI design, providing a new strategy for this problem. This report reviewed the research about MMPIs, summarized their MMPs activity regulation mechanisms, and discussed their failures in clinical trials. Furthermore, we outlined several schemes of MMPIs screening and design. Finally, we reviewed the therapeutic application prospects of MMPIs and discussed the remaining challenges and solutions, which may offer new insights for the development of MMPIs studies.

Pharmacological Ascorbate Promotes the Tumor Radiosensitization of Au@Pd Nanoparticles with Simultaneous Protection of Normal Tissues.

Nanoradiosensitizers containing high-Z elements hold great potential in radiotherapy owing to the increasing energy deposition effect on X-ray irradiation. However, their potential clinical application is limited by the irradiation damage in nontarget tissues surrounding the tumor site, as well as the safety concerns for nanomaterials. Our findings demonstrate that pharmacological ascorbate displays a synergistic radiosensitizing effect in combination with nanoradiosensitizers. By engineering the Au@Pd core-shell nanostructures and precisely regulating their shell thickness, the obtained Au@Pd nanomaterials exhibit excellent ascorbate oxidase-like activity. Along with the accelerating generation of H2O2, pharmacological ascorbate significantly enhances the radiosensitizing effect of Au@Pd-PEG nanoparticles on both cancer cells and solid tumor. Interestingly, pharmacological ascorbate effectively protects normal tissues from X-ray-induced injury. The present work demonstrates that pharmacological ascorbate is an ideal agent for selectively improving the radiosensitizing effect of nanomaterials, providing a promising strategy to facilitate the clinical translation of nanoradiosensitizers.

Understanding the Nano-Bio Interactions and the Corresponding Biological Responses.

Due to the increasing amount of work being put into the development of nanotechnology, the field of nanomaterials holds great promise for revolutionizing biomedicine. However, insufficient understanding of nanomaterial-biological microenvironment (nano-bio) interactions hinders the clinical translation of nanomedicine. Therefore, a systematic understanding of nano-bio interaction is needed for the intelligent design of safe and effective nanomaterials for biomedical applications. In this review, we summarize the latest experimental and theoretical developments in the fields of nano-bio interfaces and corresponding biological outcomes from the perspective of corona and redox reactions. We also show that nano-bio interaction can offer a variety of multifunctional platforms with a broad range of applications in the field of biomedicine. The potential challenges and opportunities in the study of nano-bio interfaces are also provided.

Antimicrobial Peptide-Templated Silver Nanoclusters with Membrane Activity for Enhanced Bacterial Killing.

We aimed to develop antimicrobial agents that satisfy biosafety considerations while exhibiting efficient antimicrobial activity. Peptide-capped silver nanoclusters (peptide@AgNCs) were designed. In addition, the antimicrobial activity and mechanism of peptide@AgNCs were studied. The hemolysis and cytotoxicity tests on mammalian cells were used to confirm the biocompatibility of peptide@ AgNCs. KLA@AgNCs exhibited dramatic antimicrobial activity without inducing significant cytotoxicity in mammalian cells. The KLA@AgNCs destroyed the integrity of the bacterial membrane and induced ROS accumulation, causing oxidative damage to biomolecules. The malfunction of the respiratory chain complexes I and V completely suppresses the energy production, ultimately accelerating the death of the bacteria. Our findings may advance the development of Ag-based nanomaterials with enhanced bactericidal activity and improved biocompatibility.

Optimization of Antibacterial Efficacy of Noble-Metal-Based Core-Shell Nanostructures and Effect of Natural Organic Matter.

Noble-metal-based nanomaterials made of less toxic metals have been utilized as potential antibacterial agents due to their distinctive oxidase-like activity. In this study, we fabricated core-shell structured Pd@Ir bimetallic nanomaterials with an ultrathin shell. Pd@Ir nanostructures show morphology-dependent bactericidal activity, in which Pd@Ir octahedra possessing higher oxidase-like activity exert bactericidal activity stronger than that of Pd@Ir cubes. Furthermore, our results reveal that the presence of natural organic matter influences the antibacterial behaviors of nanomaterials. Upon interaction with humic acid (HA), the Pd@Ir nanostructures induce an elevated level of reactive oxygen species, resulting in significantly enhanced bactericidal activity of the nanostructures. Mechanism analysis shows that the presence of HA efficiently enhances the oxidase-like activity of nanomaterials and promotes the cellular internalization of nanomaterials. We believe that the present study will not only demonstrate an effective strategy for improving the bactericidal activity of noble-metal-based nanomaterials but also provide an understanding of the antibacterial behavior of nanomaterials in the natural environment.

Lanosterol Disrupts the Aggregation of Amyloid-ß Peptides.

Lanosterol, an amphipathic molecule, was discovered only very recently to effectively hinder the aggregation of lens proteins and dissolve the extremely stable fibrillar aggregates in cataracts. Here, we combined computational and experimental approaches to study how lanosterol disrupts the aggregation of another important peptide, amyloid-ß (Aß) peptide, associated with the Alzheimer's Disease (AD). Molecular dynamics simulations using the core amyloidogenic segment (KLVFFA) of Aß peptide revealed that lanosterol exhibits at least two types of inhibition mechanism on the self-assembly of Aß peptides. First, lanosterol entangles with peptides and forms a hydrophobic core with residues Phe-19 and Phe-20 in particular. Second, it interferes with the steric zipper interaction at the ß-sheet-ß-sheet interface. These simulation data suggest that lanosterol induces the unfolding of the Aß peptide and the separation of the ß-sheet layers. This predicted inhibition effect of lanosterol was then confirmed by an in vitro ThT fluorescence assay and AFM imaging. The cell toxicity assay also showed that the treatment of lanosterol indeed mitigates the cytotoxicity of the Aß peptide in PC-12 cells. Moreover, lanosterol shows a stronger suppression effect on Aß peptides' aggregation than cholesterol because of its higher hydrophobicity. This result establishes a foundation for the development of lanosterol-based potential therapies for AD and other protein conformational diseases.

Facet-regulated adhesion of double-stranded DNA on palladium surfaces.

A better understanding of interactions between metal-nanomaterial surfaces and biomolecules such as DNAs is critical for their biomedical applications. Here we investigated double-stranded DNA (dsDNA) adhering to palladium (Pd) nanosheets with two different exposed facets, {100} and {111}, using a combined computational and experimental approach. Different dsDNA binding modes on the two surfaces were observed, with a surprising "upright" conformation on Pd(100) and a "flat" conformation on Pd(111). Molecular dynamics simulations showed a stronger binding of the dsDNA on Pd(111) than Pd(100), which resulted in significant conformational changes and hydrogen bond breakage in the dsDNA on Pd(111). Further analyses revealed that the different binding strengths were caused by the number and arrangement of water molecules in the first solvation shell (FSS) of the two Pd surfaces. The water hydrogen bond network in the FSS of Pd(100) is compact and resists the embedding of dsDNA, while it is less compact on Pd(111), which allows penetration of dsDNA and its direct contact with Pd(111) surface atoms, thereby exhibiting stronger binding. Further free energy calculations with umbrella sampling supported these observations. Finally, these computational predictions on the adsorption capacity of dsDNA on Pd surfaces were confirmed by gel electrophoresis experiments.

Photogenerated Charge Carriers in Molybdenum Disulfide Quantum Dots with Enhanced Antibacterial Activity.

Molybdenum disulfide (MoS2) nanosheets have received considerable interest due to their superior physicochemical performances to graphene nanosheets. As the lateral size and layer thickness decrease, the formed MoS2 quantum dots (QDs) show more promise as photocatalysts, endowing them with potential antimicrobial properties under environmental conditions. However, studies on the antibacterial photodynamic therapy of MoS2 QDs have rarely been reported. Here, we show that MoS2 QDs more effectively promote the creation and separation of electron-hole pair than MoS2 nanosheets, resulting in the formation of multiple reactive oxygen species (ROS) under simulated solar light irradiation. As a result, photoexcited MoS2 QDs show remarkably enhanced antibacterial activity, and the ROS-mediated oxidative stress plays a dominant role in the antibacterial mechanism. The in vivo experiments showed that MoS2 QDs are efficacious in wound healing under simulated solar light irradiation and exert protective effects on normal tissues, suggesting good biocompatibility properties. Our findings provide a full description of the photochemical behavior of MoS2 QDs and the resulting antibacterial activity, which might advance the development of MoS2-based nanomaterials as photodynamic antibacterial agents under environmental conditions.

Palladium concave nanocrystals with high-index facets accelerate ascorbate oxidation in cancer treatment.

Intravenous pharmacological dose of ascorbate has been proposed as a potential antitumor therapy; however, its therapeutic efficacy is limited due to the slow autoxidation. Here, we report that palladium (Pd) nanocrystals, which possess intrinsic oxidase-like activity, accelerate the autoxidation of ascorbate, leading to the enhancement of its antitumor efficacy. The oxidase-like activity of Pd nanocrystals was facet-dependent, with the concave nanostructure enclosed by high-index facets catalyzing ascorbate autoxidation more efficiently than the planar nanostructure enclosed by low-index facets. Our first-principles calculations provide the underlying molecular mechanisms for the facet-dependent activation of O2 molecule and subsequent ascorbate oxidation. Further in vitro and in vivo assays demonstrate the enhancement of the antitumor efficacy of ascorbate with these Pd concave nanocubes. Our animal experiments also indicate the combined approach with both ascorbate and Pd concave nanocubes displays an even better efficacy than currently available clinical medicines, with no obvious cytotoxicity to normal cells.

Fabrication of PEGylated Fe@Bi2S3 nanocomposites for dual-mode imaging and synergistic thermoradiotherapy.

Nanocomposites for integrating imaging and therapy have attracted tremendous attention for biomedical applications. Herein, Fe@Bi2S3 nanocomposites modified with polyethylene glycol (PEG) molecules are fabricated for synergistic thermoradiotherapy. For such nanocomposites, Bi2S3 exhibits a strong absorbance in the near-infrared (NIR) region, which allows Bi2S3 to convert energy from light into heat for effective photothermal therapy (PTT), whereas Bi can also significantly enhance radio-mediated cell death induction as a radiotherapy sensitizer due to its high atomic number (high-Z). Most importantly, it is found that the combination of PTT and radiation therapy (RT), using PEGylated Fe@Bi2S3 nanocomposites, can bring a strong synergistic effect for the tumor treatment in in vitro and in vivo experiments. Besides, the magnetic Fe core and the Bi2S3 shell components endow this nanocomposite with an ability to serve as both a magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent. Therefore, our work presents a new type of multifunctional nanocomposite with the potential for synergistic thermoradiotherapy and simultaneously MRI/CT imaging.

Comparison of the life-history parameters and competition outcome with Moina macrocopa between two morphs of Brachionus forficula.

In rotifers, the costs of morphological defenses, especially the development of long spines, have been investigated for several decades. However, the obtained results were inconsistent and the underlying reasons were complicated. Investigations on more species might be helpful to find out the reasons. In the present study, Brachionus forficula was selected as the model organism. The differences in developmental durations, life-table demography, starvation resistant time and the competitive ability with Moina macrocopa were compared between B. forficula with long (LPS) and short (SPS) posterior spines. The results showed that LPS showed relatively longer durations of juvenile stage at 1.0 × 106, 2.0 × 106 and 4.0 × 106 cells/ml Scenedesmus obliquus, and longer embryo stage at 2.0 × 106 cells/ml S. obliquus than SPS. The intrinsic rate of population increase and net reproduction rate were lower in LPS than SPS, suggesting the energy input to reproduction decreased. The starvation resistant time was also reduced in LPS, in comparison to SPS, further supporting that LPS consumed more energy, which might be directed to the development of long spines. All these results revealed that LPS spent more energy for individual growth than SPS, which might be used to develop long spines. Moreover, the maximum population density and population growth rate of LPS were always lower than those of SPS, suggesting that LPS might have a weaker competition ability with M. macrocope than SPS.

Evaluation of the structure-activity relationship of carbon nanomaterials as antioxidants.

AIM: To develop the potential application of carbon nanomaterials as antioxidants calls for better understanding of how the specific structure affects their antioxidant activity. MATERIALS & METHODS: Several typical carbon nanomaterials, including graphene quantum dots and fullerene derivatives were characterized and their radical scavenging activities were evaluated; in addition, the in vitro and in vivo radioprotection experiments were performed. RESULTS: These carbon nanomaterials can efficiently scavenge free radicals in a structure-dependent manner. In vitro assays demonstrate that administration of these carbon nanomaterials markedly increases the surviving fraction of cells exposed to ionizing radiation. Moreover, in vivo experiments confirm that their administration can also increase the survival rates of mice exposed to radiation. CONCLUSION: All results confirm that large, buckyball-shaped fullerenes show the strongest antioxidant properties and the best radioprotective efficiency. Our work will be useful in guiding the design and optimization of nanomaterials for potential antioxidant and radioprotection bio-applications.

Bactericidal Effects of Silver Nanoparticles on Lactobacilli and the Underlying Mechanism.

While the antibacterial properties of silver nanoparticles (AgNPs) have been demonstrated across a spectrum of bacterial pathogens, the effects of AgNPs on the beneficial bacteria are less clear. To address this issue, we compared the antibacterial activity of AgNPs against two beneficial lactobacilli ( Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus casei) and two common opportunistic pathogens ( Escherichia coli and Staphylococcus aureus). Our results demonstrate that those lactobacilli are highly susceptible to AgNPs, while the opportunistic pathogens are not. Acidic environment caused by the lactobacilli is associated with the bactericidal effects of AgNPs. Our mechanistic study suggests that the acidic growth environment of lactobacilli promotes AgNP dissolution and hydroxyl radical (•OH) overproduction. Furthermore, increases in silver ions (Ag+) and •OH deplete the glutathione pool inside the cell, which is associated with the increase in cellular reactive oxygen species (ROS). High levels of ROS may further induce DNA damage and lead to cell death. When E. coli and S. aureus are placed in a similar acidic environment, they also become more susceptible to AgNPs. This study provides a mechanistic description of a pH-Ag+-•OH bactericidal pathway and will contribute to the responsible development of products containing AgNPs.

Differential Pd-nanocrystal facets demonstrate distinct antibacterial activity against Gram-positive and Gram-negative bacteria.

Noble metal-based nanomaterials have shown promise as potential enzyme mimetics, but the facet effect and underlying molecular mechanisms are largely unknown. Herein, with a combined experimental and theoretical approach, we unveil that palladium (Pd) nanocrystals exhibit facet-dependent oxidase and peroxidase-like activities that endow them with excellent antibacterial properties via generation of reactive oxygen species. The antibacterial efficiency of Pd nanocrystals against Gram-positive bacteria is consistent with the extent of their enzyme-like activity, that is {100}-faceted Pd cubes with higher activities kill bacteria more effectively than {111}-faceted Pd octahedrons. Surprisingly, a reverse trend of antibacterial activity is observed against Gram-negative bacteria, with Pd octahedrons displaying stronger penetration into bacterial membranes than Pd nanocubes, thereby exerting higher antibacterial activity than the latter. Our findings provide a deeper understanding of facet-dependent enzyme-like activities and might advance the development of noble metal-based nanomaterials with both enhanced and targeted antibacterial activities.

Inhibition of the proteasome activity by graphene oxide contributes to its cytotoxicity.

Due to its hydrophobicity and other unique physicochemical properties, graphene oxide (GO) has been extensively utilized in various biological applications. However, introducing nanomaterials into the biological environment may raise serious risk in terms of nanotoxicity, leading to some unintended changes to the structure and the function of other biomolecules. This study investigates the interaction of GO with the ubiquitin-proteasome system, one of the essential machineries in the cellular metabolism, using a combination of experimental and computational approaches. The experimental results show that GO could adsorb the 20S proteasome, causing a dose-dependent suppression of the proteolytic activity of proteasome. This adverse effect eventually disturbed other important cellular activities relevant to cell cycle and survival. Meanwhile, the molecular dynamics simulations revealed that when 20S proteasome was adsorbed onto the graphene surface, the central gate in the outer ring (α-subunit) for the entry and the exit of the peptide ligand to the protease active site was effectively blocked. These findings of GO induced functional disturbance of 20S proteasome provides a novel perspective to understand the molecular mechanism of GO's cytotoxicity, which might further promote applications of GO in potential therapies for various cancers due to the abnormal elevation of the relevant proteasome activities.