Novel Organoid Culture System for Improved Safety Assessment of Nanomaterials.

Over the past few decades, the increased application of nanomaterials has raised questions regarding their safety and possible toxic effects. Organoids have been suggested as promising tools, offering efficient assays for nanomaterial-induced toxicity evaluation. However, organoid systems have some limitations, such as size heterogeneity and poor penetration of nanoparticles because of the extracellular matrix, which is necessary for organoid culture. Here, we developed a novel system for the improved safety assessment of nanomaterials by establishing a 3D floating organoid paradigm. In addition to overcoming the limitations of two-dimensional systems including the lack of in vitro-in vivo cross-talk, our method provides multiple benefits as compared with conventional organoid systems that rely on an extracellular matrix for culture. Organoids cultured using our method exhibited relatively uniform sizing and structural integrity and were more conducive to the internalization of nanoparticles. Our floating culture system will accelerate the research and development of safe nanomaterials.

Development of a bottom-up coarse-grained model for interactions of lipids with TiO 2 nanoparticles.

Understanding interactions of inorganic nanoparticles with biomolecules is important in many biotechnology, nanomedicine, and toxicological research, however, the size of typical nanoparticles makes their direct modeling by atomistic simulations unfeasible. Here, we present a bottom-up coarse-graining approach for modeling titanium dioxide (TiO 2 ) nanomaterials in contact with phospholipids that uses the inverse Monte Carlo method to optimize the effective interactions from the structural data obtained in small-scale all-atom simulations of TiO 2 surfaces with lipids in aqueous solution. The resulting coarse-grained models are able to accurately reproduce the structural details of lipid adsorption on different titania surfaces without the use of an explicit solvent, enabling significant computational resource savings and favorable scaling. Our coarse-grained simulations show that small spherical TiO 2 nanoparticles ( r = 2 nm) can only be partially wrapped by a lipid bilayer with phosphoethanolamine headgroups, however, the lipid adsorption increases with the radius of the nanoparticle. The current approach can be used to study the effect of the size and shape of TiO 2 nanoparticles on their interactions with cell membrane lipids, which can be a determining factor in membrane wrapping as well as the recently discovered phenomenon of nanoquarantining, which involves the formation of layered nanomaterial-lipid structures.

Nanotoxicity of two-dimensional nanomaterials on human skin and the structural evolution of keratin protein.

Two-dimensional (2D) materials have been increasingly widely used in biomedical and cosmetical products nowadays, yet their safe usage in human body and environment necessitates a comprehensive understanding of their nanotoxicity. In this work, the effect of pristine graphene and graphene oxide (GO) on the adsorption and conformational changes of skin keratin using molecular dynamics simulations. It is found that skin keratin can be absorbed through various noncovalent driving forces, such as van der Waals (vdW) and electrostatics. In the case of GO, the oxygen-containing groups prevent tighter contact between skin keratin and the graphene basal plane through steric effects and electrostatic repulsion. On the other hand, electrostatic attraction and hydrogen bonding enhance their binding affinity to positively charged residues such as lysine and arginine. The secondary structure of skin keratin is better preserved in GO system, suggesting that GO has good biocompatibility. The charged groups on GO surface perform as the hydrogen bond acceptors, which is like to the natural receptors of keratin in this physiological environment. This work contributes to a better knowledge of the nanotoxicity of cutting-edge 2D materials on human health, thereby advancing their potential biological applications.

Tailoring metal oxide nanozymes for biomedical applications: trends, limitations, and perceptions.

Nanomaterials with enzyme-like properties are known as 'nanozymes'. Nanozymes are preferred over natural enzymes due to their nanoscale characteristics and ease of tailoring of their physicochemical properties such as size, structure, composition, surface chemistry, crystal planes, oxygen vacancy, and surface valence state. Interestingly, nanozymes can be precisely controlled to improve their catalytic ability, stability, and specificity which is unattainable by natural enzymes. Therefore, tailor-made nanozymes are being favored over natural enzymes for a range of potential applications and better prospects. In this context, metal oxide nanoparticles with nanozyme-mimicking characteristics are exclusively being used in biomedical sectors and opening new avenues for future nanomedicine. Realising the importance of this emerging area, here, we discuss the mechanistic actions of metal oxide nanozymes along with their key characteristics which affect their enzymatic actions. Further, in this critical review, the recent progress towards the development of point-of-care (POC) diagnostic devices, cancer therapy, drug delivery, advanced antimicrobials/antibiofilm, dental caries, neurodegenerative diseases, and wound healing potential of metal oxide nanozymes is deliberated. The advantages of employing metal oxide nanozymes, their potential limitations in terms of nanotoxicity, and possible prospects for biomedical applications are also discussed with future recommendations.

The elasticity of silicone-stabilized liposomes has no impact on their in vivo behavior.

BACKGROUND: The elastomechanical properties of nanocarriers have recently been discussed as important for the efficient delivery of various therapeutics. Some data indicate that optimal nanocarriers' elasticity can modulate in vivo nanocarrier stability, interaction with phagocytes, and uptake by target cells. Here, we presented a study to extensively analyze the in vivo behavior of LIP-SS liposomes that were modified by forming the silicone network within the lipid bilayers to improve their elastomechanical properties. We verified liposome pharmacokinetic profiles and biodistribution, including retention in tumors on a mouse model of breast cancer, while biocompatibility was analyzed on healthy mice. RESULTS: We showed that fluorescently labeled LIP-SS and control LIP-CAT liposomes had similar pharmacokinetic profiles, biodistribution, and retention in tumors, indicating that modified elasticity did not improve nanocarrier in vivo performance. Interestingly, biocompatibility studies revealed no changes in blood morphology, liver, spleen, and kidney function but indicated prolonged activation of immune response manifesting in increased concentration of proinflammatory cytokines in sera of animals exposed to all tested liposomes. CONCLUSION: Incorporating the silicone layer into the liposome structure did not change nanocarriers' characteristics in vivo. Further modification of the LIP-SS surface, including decoration with hydrophilic stealth polymers, should be performed to improve their pharmacokinetics and retention in tumors significantly. Activation of the immune response by LIP-SS and LIP-CAT, resulting in elevated inflammatory cytokine production, requires detailed studies to elucidate its mechanism.

Reduced lysosomal activity and increased amyloid beta accumulation in silica-coated magnetic nanoparticles-treated microglia.

Nanoparticles have been used in neurological research in recent years because of their blood-brain barrier penetration activity. However, their potential neuronanotoxicity remains a concern. In particular, microglia, which are resident phagocytic cells, are mainly exposed to nanoparticles in the brain. We investigated the changes in lysosomal function in silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)]-treated BV2 murine microglial cells. In addition, we analyzed amyloid beta (Aß) accumulation and molecular changes through the integration of transcriptomics, proteomics, and metabolomics (triple-omics) analyses. Aß accumulation significantly increased in the 0.1 µg/µl MNPs@SiO2(RITC)-treated BV2 cells compared to the untreated control and 0.01 µg/µl MNPs@SiO2(RITC)-treated BV2 cells. Moreover, the MNPs@SiO2(RITC)-treated BV2 cells showed lysosomal swelling, a dose-dependent reduction in proteolytic activity, and an increase in lysosomal swelling- and autophagy-related protein levels. Moreover, proteasome activity decreased in the MNPs@SiO2(RITC)-treated BV2 cells, followed by a concomitant reduction in intracellular adenosine triphosphate (ATP). By employing triple-omics and a machine learning algorithm, we generated an integrated single molecular network including reactive oxygen species (ROS), autophagy, lysosomal storage disease, and amyloidosis. In silico analysis of the single triple omics network predicted an increase in ROS, suppression of autophagy, and aggravation of lysosomal storage disease and amyloidosis in the MNPs@SiO2(RITC)-treated BV2 cells. Aß accumulation and lysosomal swelling in the cells were alleviated by co-treatment with glutathione (GSH) and citrate. These findings suggest that MNPs@SiO2(RITC)-induced reduction in lysosomal activity and proteasomes can be recovered by GSH and citrate treatment. These results also highlight the relationship between nanotoxicity and Aß accumulation.

Genotoxic and neurotoxic potential of intracellular nanoplastics: A review.

Plastic waste comprises polymers of different chemicals that disintegrate into nanoplastic particles (NPLs) of 1-100-nm size, thereby littering the environment and posing a threat to wildlife and human health. Research on NPL contamination has up to now focused on the ecotoxicology effects of the pollution rather than the health risks. This review aimed to speculate about the possible properties of carcinogenic and neurotoxic NPL as pollutants. Given their low-dimensional size and high surface size ratio, NPLs can easily penetrate biological membranes to cause functional and structural damage in cells. Once inside the cell, NPLs can interrupt the autophagy flux of cellular debris, alter proteostasis, provoke mitochondrial dysfunctions, and induce endoplasmic reticulum stress. Harmful metabolic and biological processes induced by NPLs include oxidative stress (OS), ROS generation, and pro-inflammatory reactions. Depending on the cell cycle status, NPLs may direct DNA damage, tumorigenesis, and lately carcinogenesis in tissues with high self-renewal capabilities like epithelia. In cells able to live the longest like neurons, NPLs could trigger neurodegeneration by promoting toxic proteinaceous aggregates, OS, and chronic inflammation. NPL genotoxicity and neurotoxicity are discussed based on the gathered evidence, when available, within the context of the intracellular uptake of these newcomer nanoparticles. In summary, this review explains how the risk evaluation of NPL pollution for human health may benefit from accurately monitoring NPL toxicokinetics and toxicodynamics at the intracellular resolution level.

Nanoparticles-mediated entomotoxicology: lessons from biologica.

Nanotechnology has grown in importance in medicine, manufacturing, and consumer products. Nanoparticles (NPs) are also widely used in the field of insect pest management, where they show a variety of toxicological effects on insects. As a result, the primary goal of this review is to compile and evaluate available information on effects of NPs on insects, by use of a timely, bibliometric analysis. We also discussed the manufacturing capacity of NPs from insect tissues and the toxic effects of NPs on insects. To do so, we searched the Web of Science database for literature from 1995 to 2023 and ran bibliometric analyses with CiteSpace© and Bibliometrix©. The analyses covered 614 journals and identified 1763 relevant documents. We found that accumulation of NPs was one of the top trending topics. China, India, and USA had the most published papers. The most overall reported models of insects were those of Aedes aegypti (yellow fever mosquito), Culex quinquefasciatus (southern house mosquito), Bombyx mori (silk moth), and Anopheles stephensi (Asian malaria mosquito). The application and methods of fabrication of NPs using insect tissues, as well as the mechanism of toxicity of NPs on insects, were also reported. A uniform legal framework is required to allow nanotechnology to fully realize its potential while minimizing harm to living organisms and reducing the release of toxic metalloid nanoparticles into the environment.

Nanomaterials in biology and medicine: a new perspective on its toxicity and applications.

Nanotechnology offers excellent prospects for application in biology and medicine. It is used for detecting biological molecules, imaging, and as therapeutic agents. Due to nano-size (1-100 nm) and high surface-to-volume ratio, nanomaterials possess highly specific and distinct characteristics in the biological environment. Recently, the use of nanomaterials as sensors, theranostic, and drug delivery agents has become popular. The safety of these materials is being questioned because of their biological toxicity, such as inflammatory responses, cardiotoxicity, cytotoxicity, inhalation problems, etc., which can have a negative impact on the environment. This review paper focuses primarily on the toxicological effects of nanomaterials along with the mechanisms involved in cell interactions and the generation of reactive oxygen species by nanoparticles, which is the fundamental source of nanotoxicity. We also emphasize the greener synthesis of nanomaterials in biomedicine, as it is non-hazardous, feasible, and economical. The review articles shed light on the complexities of nanotoxicology in biosystems and the environment.

Toxicity assessment of perovskite nanocomposites: In vivo study.

Perovskite solar cells display potential as a renewable energy source because of their high-power conversion efficiency. However, there is limited understanding regarding the potential impact of perovskite on human health and the ecosystem. In this study, two sets of male Wistar albino rats received 35 injections of perovskite composite at a dosage of 0.372 mg/kg body weight. The animals underwent thorough examinations, encompassing morphometric, hematological, biochemical, histological, and behavioral analyses. Liver, kidney, and testis biopsies were processed and examined histologically. Additionally, two groups of mice (perovskite-treated and control mice, each with n = 10) underwent three behavioral tests: the Elevated Zero Maze test, Marble Burying test, and Light-Dark Box test. Perovskite-treated rats displayed a significant increase in levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglycerides, cholesterol, creatinine, blood urea nitrogen, white blood cells, and platelets. However, total bilirubin levels decreased, with no significant alteration in albumin values. Furthermore, exposure to perovskite composite resulted in a slight decrease in lactate dehydrogenase and red blood cell count. Histopathological examination revealed hepatic hydropic degeneration, Kupffer cells hypertrophy and hyperplasia, and renal hydropic degeneration, while testicular tissues remained unaffected. Moreover, behavioral changes were observed in perovskite-treated mice, including depression, anxiety, and compulsive burying activity. These findings suggest that exposure to perovskite can lead to significant hematological and biochemical changes, as well as hepatorenal histopathological alterations and behavioral changes. Additionally, chronic exposure to perovskite materials may induce structural and functional alterations in vital organs.

Iron Oxide Nanoparticles with and without Cobalt Functionalization Provoke Changes in the Transcription Profile via Epigenetic Modulation of Enhancer Activity.

Despite the progress in the field of nanotoxicology, much about the cellular mechanisms that mediate the adverse effects of nanoparticles (NPs) and, in particular, the possible role of epigenetics in nanotoxicity, remains to be clarified. Therefore, we studied the changes occurring in the genome-wide distribution of H3K27ac, H3K4me1, H3K9me2, and H3K27me3 histone modifications and compared them with the transcriptome after exposing NIH3T3 cells to iron-based magnetic NPs (i.e., Fe2O3 and Fe2O3@Co NPs). We found that the transcription response is mainly due to changes in the genomic distribution of H3K27ac that can modulate the activity of enhancers. We propose that alteration of the epigenetic landscape is a key mechanism in defining the gene expression program changes resulting in nanotoxicity. With this approach, it is possible to construct a data set of genomic regions that could be useful for defining toxicity in a manner that is more comprehensive than what is possible with the present toxicology assays.

Lipidomics Analysis Unravels Aberrant Lipid Species and Pathways Induced by Zinc Oxide Nanoparticles in Kidney Cells.

Zinc oxide nanoparticles (ZnO NPs) are widely used in versatile applications, from high technology to household products. While numerous studies have examined the toxic gene profile of ZnO NPs across various tissues, the specific lipid species associated with adverse effects and potential biomarkers remain elusive. In this study, we conducted a liquid chromatography-mass spectrometry based lipidomics analysis to uncover potential lipid biomarkers in human kidney cells following treatment with ZnO NPs. Furthermore, we employed lipid pathway enrichment analysis (LIPEA) to elucidate altered lipid-related signaling pathways. Our results demonstrate that ZnO NPs induce cytotoxicity in renal epithelial cells and modulate lipid species; we identified 64 lipids with a fold change (FC) > 2 and p < 0.01 with corrected p < 0.05 in HK2 cells post-treatment with ZnO NPs. Notably, the altered lipids between control HK2 cells and those treated with ZnO NPs were associated with the sphingolipid, autophagy, and glycerophospholipid pathways. This study unveils novel potential lipid biomarkers of ZnO NP nanotoxicity, representing the first lipidomic profiling of ZnO NPs in human renal epithelial cells.

Melanin for Photoprotection and Hair Coloration in the Emerging Era of Nanocosmetics.

Nanotechnology is revolutionizing fields of high social and economic impact. such as human health preservation, energy conversion and storage, environmental decontamination, and art restoration. However, the possible global-scale application of nanomaterials is raising increasing concerns, mostly related to the possible toxicity of materials at the nanoscale. The possibility of using nanomaterials in cosmetics, and hence in products aimed to be applied directly to the human body, even just externally, is strongly debated. Preoccupation arises especially from the consideration that nanomaterials are mostly of synthetic origin, and hence are often seen as "artificial" and their effects as unpredictable. Melanin, in this framework, is a unique material since in nature it plays important roles that specific cosmetics are aimed to cover, such as photoprotection and hair and skin coloration. Moreover, melanin is mostly present in nature in the form of nanoparticles, as is clearly observable in the ink of some animals, like cuttlefish. Moreover, artificial melanin nanoparticles share the same high biocompatibility of the natural ones and the same unique chemical and photochemical properties. Melanin is hence a natural nanocosmetic agent, but its actual application in cosmetics is still under development, also because of regulatory issues. Here, we critically discuss the most recent examples of the application of natural and biomimetic melanin to cosmetics and highlight the requirements and future steps that would improve melanin-based cosmetics in the view of future applications in the everyday market.

The effects of iron-based nanomaterials (Fe NMs) on plants under stressful environments: Machine learning-assisted meta-analysis.

Mitigating the adverse effects of stressful environments on crops and promoting plant recovery in contaminated sites are critical to agricultural development and environmental remediation. Iron-based nanomaterials (Fe NMs) can be used as environmentally friendly nano-fertilizer and as a means of ecological remediation. A meta-analysis was conducted on 58 independent studies from around the world to evaluate the effects of Fe NMs on plant development and antioxidant defense systems in stressful environments. The application of Fe NMs significantly enhanced plant biomass (mean = 25%, CI = 20%-30%), while promoting antioxidant enzyme activity (mean = 14%, CI = 10%-18%) and increasing antioxidant metabolite content (mean = 10%, CI = 6%-14%), reducing plant oxidative stress (mean = -15%, CI = -20%∼-10%), and alleviating the toxic effects of stressful environments. The observed response was dependent on a number of factors, which were ranked in terms of a Random Forest Importance Analysis. Plant species was the most significant factor, followed by Fe NM particle size, duration of application, dose level, and Fe NM type. The meta-analysis has demonstrated the potential of Fe NMs in achieving sustainable agriculture and the future development of phytoremediation.

Integrative chemical, physiological, and metabolomics analyses reveal nanospecific phytotoxicity of metal nanoparticles.

The increasing application of metal nanoparticles (NPs) via agrochemicals and sewage sludge results in non-negligible phytotoxicological risks. Herein, the potential phytotoxicity of ZnO and CuO NPs on wheat was determined using integrative chemical, physiological, and metabolomics analyses, in comparison to Zn2+ and Cu2+. It was found that ZnO or CuO NPs had a stronger inhibitory effect on wheat growth than Zn2+ or Cu2+. After exposure to ZnO or CuO NPs, wheat seedlings accumulated significantly higher levels of Zn or Cu than the corresponding Zn2+ or Cu2+ treatments, indicating the active uptake of NPs via wheat root. TEM analysis further confirmed the intake of NPs. Moreover, ZnO or CuO NPs exposure altered micronutrients (Fe, Mn, Cu, and Zn) accumulation in the tissues and decreased the activities of antioxidant enzymes. The metabolomics analysis identified 312, 357, 145, and 188 significantly changed metabolites (SCMs) in wheat root exposed to ZnO NPs, CuO NPs, Zn2+, and Cu2+, respectively. Most SCMs were nano-specific to ZnO (80%) and CuO NPs (58%), suggesting greater metabolic reprogramming by NPs than metal ions. Overall, nanospecific toxicity dominated the phytotoxicity of ZnO and CuO NPs, and our results provide a molecular perspective on the phytotoxicity of metal oxide NPs.

Integrating Explicit and Implicit Fullerene Models into UNRES Force Field for Protein Interaction Studies.

Fullerenes, particularly C60, exhibit unique properties that make them promising candidates for various applications, including drug delivery and nanomedicine. However, their interactions with biomolecules, especially proteins, remain not fully understood. This study implements both explicit and implicit C60 models into the UNRES coarse-grained force field, enabling the investigation of fullerene-protein interactions without the need for restraints to stabilize protein structures. The UNRES force field offers computational efficiency, allowing for longer timescale simulations while maintaining accuracy. Five model proteins were studied: FK506 binding protein, HIV-1 protease, intestinal fatty acid binding protein, PCB-binding protein, and hen egg-white lysozyme. Molecular dynamics simulations were performed with and without C60 to assess protein stability and investigate the impact of fullerene interactions. Analysis of contact probabilities reveals distinct interaction patterns for each protein. FK506 binding protein (1FKF) shows specific binding sites, while intestinal fatty acid binding protein (1ICN) and uteroglobin (1UTR) exhibit more generalized interactions. The explicit C60 model shows good agreement with all-atom simulations in predicting protein flexibility, the position of C60 in the binding pocket, and the estimation of effective binding energies. The integration of explicit and implicit C60 models into the UNRES force field, coupled with recent advances in coarse-grained modeling and multiscale approaches, provides a powerful framework for investigating protein-nanoparticle interactions at biologically relevant scales without the need to use restraints stabilizing the protein, thus allowing for large conformational changes to occur. These computational tools, in synergy with experimental techniques, can aid in understanding the mechanisms and consequences of nanoparticle-biomolecule interactions, guiding the design of nanomaterials for biomedical applications.

Facet-dependent transformation and toxicity of nanoscale zinc oxide in the synthetic saliva.

The nanoscale zinc oxide (n-ZnO) was used in food packages due to its superior antibacterial activity, resulting in potential intake of n-ZnO through the digestive system, wherein n-ZnO interacted with saliva. In recent, facet engineering, a technique for controlling the exposed facets, was applied to n-ZnO, whereas risk of n-ZnO with specific exposed facets in saliva was ignored. ZnO nanoflakes (ZnO-0001) and nanoneedles (ZnO-1010) with the primary exposed facets of {0001} and {1010} respectively were prepared in this study, investigating stability and toxicity of ZnO-0001 and ZnO-1010 in synthetic saliva. Both ZnO-0001 and ZnO-1010 partially transformed into amorphous Zn3(PO4)2 within 1 hr in the saliva even containing orgnaic components, forming a ZnO-Zn3(PO4)2 core-shell structure. Nevertheless, ZnO-1010 relative to ZnO-0001 would likely transform into Zn3(PO4)2, being attributed to superior dissolution of {1010} facet due to its lower vacancy formation energy (1.15 eV) than {0001} facet (3.90 eV). The toxicity of n-ZnO to Caco-2 cells was also dependent on the primary exposed facet; ZnO-0001 caused cell toxicity through oxidative stress, whereas ZnO-1010 resulted in lower cells viability than ZnO-0001 through oxidative stress and membrane damage. Density functional theory calculations illustrated that ·O2- was formed and released on {1010} facet, yet O22- instead of ·O2- was generated on {0001} facet, leading to low oxidative stress from ZnO-0001. All findings demonstrated that stability and toxicity of n-ZnO were dependent on the primary exposed facet, improving our understanding of health risk of nanomaterials.

Current nano-therapeutic approaches ameliorating inflammation in cancer progression.

Cancer is one of the biggest causes of mortality in the world. The advances in cancer research have taken us to distance in understanding the disease, which helps develop therapeutic strategies. Surgery and chemotherapy are the two main chosen routes of combat for cancer. These chemotherapeutic agents are good at targeting cancer, but many lack the specificity to make the distinction between healthy cells. Also, the toxicity of these chemotherapeutic agents is very high. This gap makes it quintessential to either look for better and safe agents or makes it possible for existing agents to meet these needs. Nanotechnology has the potential to deal with these unmet needs. Nanotechnology has been a hot topic recently due to its applications, one of these being nanomedicine. Studies have proven that cancer nanomedicine has a scope of being revolutionary. With the help of nanoparticles, we can make drugs specific for the cancer tissue; it can also help in increasing the bioavailability of the drug. A nanoparticle can be modified as such that it can carry the drug load that is required and deliver it to the specific target. In this review article, we have discussed the advances in nanomedicine and the current clinical status of various nanomedicines. We have extensively explored various strategies used to develop cancer nanomedicine while also discussing their mechanism of action.

Metabolomics of V2O5 nanoparticles and V2O5 nanofibers in human airway epithelial BEAS-2B cells.

Vanadium is a toxic metal listed by the IARC as possibly carcinogenic to humans. Manufactured nanosize vanadium pentoxide (V2O5) materials are used in a wide range of industrial sectors and recently have been developed as nanomedicine for cancer therapeutics, yet limited information is available to evaluate relevant nanotoxicity. In this study we used high-resolution metabolomics to assess effects of two V2O5 nanomaterials, nanoparticles and nanofibers, at exposure levels (0.01, 0.1, and 1 ppm) that did not cause cell death (i.e., non-cytotoxic) in a human airway epithelial cell line, BEAS-2B. As prepared, V2O5 nanofiber exhibited a fibrous morphology, with a width approximately 63 ± 12 nm and length in average 420 ± 70 nm; whereas, V2O5 nanoparticles showed a typical particle morphology with a size 36 ± 2 nm. Both V2O5 nanoparticles and nanofibers had dose-response effects on aminosugar, amino acid, fatty acid, carnitine, niacin and nucleotide metabolism. Differential effects of the particles and fibers included dibasic acid, glycosphingolipid and glycerophospholipid pathway associations with V2O5 nanoparticles, and cholesterol and sialic acid metabolism associations with V2O5 nanofibers. Examination by transmission electron microscopy provided evidence for mitochondrial stress and increased lysosome fusion by both nanomaterials, and these data were supported by effects on mitochondrial membrane potential and lysosomal activity. The results showed that non-cytotoxic exposures to V2O5 nanomaterials impact major metabolic pathways previously associated with human lung diseases and suggest that toxico-metabolomics may be useful to evaluate health risks from V2O5 nanomaterials.

Rare-earth orthovanadate nanoparticles trigger Ca2+-dependent eryptosis.

Introduction. Rare-earth orthovanadate nanoparticles (ReVO4:Eu3+, Re = Gd, Y or La) are promising agents for photodynamic therapy of cancer due to their modifiable redox properties. However, their toxicity limits their application.Objective. The aim of this research was to elucidate pro-eryptotic effects of GdVO4:Eu3+and LaVO4:Eu3+nanoparticles with identification of underlying mechanisms of eryptosis induction and to determine their pharmacological potential in eryptosis-related diseases.Methods. Blood samples (n= 9) were incubated for 24 h with 0-10-20-40-80 mg l-1GdVO4:Eu3+or LaVO4:Eu3+nanoparticles, washed and used to prepare erythrocyte suspensions to analyze the cell membrane scrambling (annexin-V-FITC staining), cell shrinkage (forward scatter signaling), reactive oxygen species (ROS) generation through 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) staining and intracellular Ca2+levels via FLUO4 AM staining by flow cytometry. Internalization of europium-enabled luminescent GdVO4:Eu3+and LaVO4:Eu3+nanoparticles was assessed by confocal laser scanning microscopy.Results.Both nanoparticles triggered eryptosis at concentrations of 80 mg l-1. ROS-mediated mechanisms were not involved in rare-earth orthovanadate nanoparticles-induced eryptosis. Elevated cytosolic Ca2+concentrations were revealed even at subtoxic concentrations of nanoparticles. LaVO4:Eu3+nanoparticles increased intracellular calcium levels in a more pronounced way compared with GdVO4:Eu3+nanoparticles. Our data disclose that the small-sized (15 nm) GdVO4:Eu3+nanoparticles were internalized after a 24 h incubation, while the large-sized (∼30 nm) LaVO4:Eu3+nanoparticles were localized preferentially around erythrocytes.Conclusions.Both internalized GdVO4:Eu3+and non-internalized LaVO4:Eu3+nanoparticles (80 mg l-1) promote eryptosis of erythrocytes after a 24 h exposurein vitrovia Ca2+signaling without involvement of oxidative stress. Eryptosis is a promising model for assessing nanotoxicity.