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Chemotherapy-induced peripheral neuropathy (CIPN) is widely recognized as a potentially severe toxicity that often leads to dose reduction or discontinuation of cancer treatment. Symptoms may persist despite discontinuation of chemotherapy and quality of life can be severely compromised. The clinical symptoms of CIPN, and the cellular and molecular targets involved in CIPN, are just as diverse as the wide variety of anticancer agents that cause peripheral neurotoxicity. There is an urgent need for extensive molecular and functional investigations aimed at understanding the mechanisms of CIPN. Furthermore, a reliable human cell culture system that recapitulates the diversity of neuronal modalities found in vivo and the pathophysiological changes that underlie CIPN would serve to advance the understanding of the pathogenesis of CIPN. The demonstration of experimental reproducibility in a human peripheral neuronal cell system will increase confidence that such an in vitro model is clinically useful, ultimately resulting in deeper exploration for the prevention and treatment of CIPN. Herein, we review current in vitro models with a focus on key characteristics and attributes desirable for an ideal human cell culture model relevant for CIPN investigations.

This paper introduces a special issue on the ecotoxicology and environmental chemistry of nanoparticles (NPs), and nanomaterials (NMs), in the journal Ecotoxicology. There are many types of NMs and the scientific community is making observations on NP ecotoxicity to inform the wider debate about the risks and benefits of these materials. Natural NPs have existed in the environment since the beginning of Earth’s history, and natural sources can be found in volcanic dust, most natural waters, soils and sediments. Natural NPs are generated by a wide variety of geological and biological processes, and while there is evidence that some natural NPs can be toxic, organisms have also evolved in an environment containing natural NPs. There are concerns that natural nano-scale process could be influenced by the presence of pollution. Manufactured NPs show some complex colloid and aggregation chemistry, which is likely to be affected by particle shape, size, surface area and surface charge, as well as the adsorption properties of the material. Abiotic factors such as pH, ionic strength, water hardness and the presence of organic matter will alter aggregation chemistry; and are expected to influence toxicity. The physico-chemistry is essential to understanding of the fate and behaviour of NPs in the environment, as well as uptake and distribution within organisms, and the interactions of NPs with other pollutants. Data on biological effects show that NPs can be toxic to bacteria, algae, invertebrates and fish species, as well as mammals. However, much of the ecotoxicological data is limited to species used in regulatory testing and freshwater organism. Data on bacteria, terrestrial species, marine species and higher plants is particularly lacking. Detailed investigations of absorption, distribution, metabolism and excretion (ADME) remain to be performed on species from the major phyla, although there are some data on fish. The environmental risk assessment of NMs could be performed using the existing tiered approach and regulatory framework, but with modifications to methodology including chemical characterisation of the materials being used. There are many challenges ahead, and controversies (e.g., reference substances for ecotoxicology), but knowledge transfer from mammalian toxicology, colloid chemistry, as well as material and geological sciences, will enable ecotoxicology studies to move forward in this new multi-disciplinary field.

Gold nanoparticles (Au NPs) are used in many fields, including biomedical applications; however, no conclusive information on their potential cytotoxicity and genotoxicity mechanisms is available. For this reason, experiments in human primary lymphocytes and murine macrophages (Raw264.7) were performed exposing cells to spherical citrate-capped Au NPs with two different nominal diameters (5 nm and 15 nm). The proliferative activity, mitotic, apoptotic, and necrotic markers, as well as chromosomal damage were assessed by the cytokinesis-block micronucleus cytome assay. Fluorescence in situ hybridization with human and murine pancentromeric probes was applied to distinguish between clastogenic and aneuploidogenic effects. Our results indicate that 5 nm and 15 nm Au NPs are able to inhibit cell proliferation by apoptosis and to induce chromosomal damage, in particular chromosome mis-segregation. DNA strand breaks were detected by comet assay, and the modified protocol using endonuclease-III and formamidopyrimidine-DNA glycosylase restriction enzymes showed that pyrimidines and purines were oxidatively damaged by Au NPs. Moreover, we show a size-independent correlation between the cytotoxicity of Au NPs and their tested mass concentration or absolute number, and genotoxic effects which were more severe for Au NP 15 nm compared to Au NP 5 nm. Results indicate that apoptosis, aneuploidy, and DNA oxidation play a pivotal role in the cytotoxicity and genotoxicity exerted by Au NPs in our cell models.

There is still no consensus on the toxicity of nanomaterials Engineered nanomaterials are widely used in consumer products such as cosmetics, paints, fabrics, and electronics. Because of their small size (diameter <100 nm), they often have unusual properties. Once released into the human body or the environment, they are also fiendishly difficult to find again. In 2006, Nel et al. described possible mechanisms by which engineered nanomaterials interact with biological entities and the toxicological responses that may be triggered ( 1 ). Despite much research since then, mechanistic understanding remains limited. Evidence for acute toxicity from nanomaterials at realistic doses is limited; there also is no simple correlation between toxic responses and nanoparticle size or other predictable pattern of toxicity. For answers to emerge, the nanosafety community must embrace recent technical advances and build consensus on testing methodologies.

Gold nanoparticles (AuNPs) are widely used in biomedicine due to their remarkable therapeutic applications. However, little is known about their cytotoxic effects on the ubiquitin proteasome system (UPS). Herein, the cytotoxicity of different sizes of AuNPs (5, 10, and 80 nm) on the UPS was investigated with a particular focus on deubiquitinating enzymes (DUBs) such as ubiquitin-specific proteases (USP) and ubiquitin carboxyl-terminal hydrolases (UCHL-1) in human alveolar epithelial adenocarcinoma (A549). It was found that all sizes of AuNPs reduced the percentage of viable A549 cells and increased lactate dehydrogenase (LDH) release, measured using the MTT and LDH assays, respectively. Furthermore, the 5 nm AuNPs were found to exhibit greater cytotoxicity than the 10 and 80 nm AuNPs. In addition, apoptosis and necrosis were activated through reactive oxygen species (ROS) generation due to AuNPs exposure. The internalisation of AuNPs in A549 cells increased with increasing particle size (80 > 10 > 5 nm). Interestingly, the expression of USP7, USP8, USP10, and UCHL-1 was significantly (p < 0.001) downregulated upon treatment with 5–30 µg/mL of all the AuNPs sizes compared to control cells. Moreover, the inhibition of these proteins triggered mitochondrial-related apoptosis through the upregulation of poly (ADP-ribose) polymerase (PARP), caspase-3, and caspase-9. Collectively, these results indicate that AuNPs suppress the proliferation of A549 cells and can potentially be used as novel inhibitors of the proteasome.

The thermal response of gold and platinum spherical nanoparticles (NPs) upon cooling is studied through atomistic molecular dynamics simulations. The goal is to identify the morphological transformations occurring in the nanomaterials as well as to quantify their dependence on temperature, chemistry, and NP size. For diameters smaller than 3 nm, the transition temperature from a melted/amorphous to a highly crystalline state varies considerably with NP size. For larger NPs, the transition temperature is almost diameter-independent, yet it differs considerably from the transition temperature of the respective bulk materials. The platinum NPs possess a higher level of crystallinity than the gold counterparts under the same conditions because of the stronger cohesive forces that drive the crystallization process. This observation is also supported by the simulated X-ray powder diffraction patterns of the nanomaterials. The larger NPs have a multifaceted crystal surface, and their shape remains almost constant regardless of temperature variations. The smaller NPs have a smoother and more spherical surface, and their shape varies greatly with temperature. By studying the variation of nano-descriptors commonly employed in QSAR models, a qualitative picture of the NPs’ toxicity and reactivity emerges: Small/hot NPs are likely more toxic than their large/cold counterparts. Because of the small size of the NPs considered, the observed structural modifications are challenging to be studied by experimental techniques. The present approach can be readily employed to study other metallic and metal oxide nanomaterials.

Analytical limitations considerably hinder our understanding of the impacts of the physicochemical properties of nanomaterials (NMs) on their biological fate in organisms. Here, using a fit-for-purpose analytical workflow, including dosing and emerging analytical techniques, NMs present in organisms are characterized and quantified across an aquatic food chain. The size and shape of gold (Au)-NMs are shown to control the number of Au-NMs attached to algae that were exposed to an equal initial concentration of 2.9 × 10 11 particles mL −1 . The Au-NMs undergo size/shape-dependent dissolution and agglomeration in the gut of the daphnids, which determines the size distribution of the NMs accumulated in fish. The biodistribution of NMs in fish tissues (intestine, liver, gills, and brain) also depends on NM size and shape, although the highest particle numbers per unit of mass are almost always present in the fish brain. The findings emphasize the importance of physicochemical properties of metallic NMs in their biotransformations and tropic transfers. Biological fate of nanomaterials in organisms is an important topic, however, limitations of analytical techniques has hampered understanding. Here, the authors report on a study into the fate of model, gold nanoparticles in an aquatic food chain using an analytical workflow and range of analytical methods.

The potential hazard posed by nanomaterials can be significantly influenced by transformations which these materials undergo during their lifecycle, from manufacturing through to disposal. The transformations may depend on the nanomaterials' own physicochemical properties as well as the environment they are exposed to. This study focuses on the mechanisms of transformation of cerium oxide nanoparticles (CeO2 NPs) in laboratory experiments which simulate potential scenarios in which the NPs are exposed to phosphate-bearing media. We have experimented with the transformation of four different kinds of CeO2 NPs, in order to investigate the effects of nanoparticle size, capping agent (three were uncapped and one was PVP capped) and oxidation state (two consisted mostly of Ce4+ and two were a mix of Ce3+/Ce4+). They were exposed to a reaction solution containing KH2PO4, citric acid and ascorbic acid at pH values of 2.3, 5.5 and 12.3, and concentrations of 1mM and 5mM. The transformations were followed by UV-vis, zeta potential and XRD measurements, which were taken after 7 and 21 days, and by transmission electron microscopy after 21 days. X-ray photoelectron spectroscopy was measured at 5mM concentration after 21 days for some samples. Results show that for pH 5 and 5mM phosphate concentration, CePO4 NPs were formed. Nanoparticles that were mostly Ce4+ did not dissolve at 1mM reagent concentration, and did not produce CePO4 NPs. When PVP was present as a capping agent it proved to be an extra reducing agent, and CePO4 was found under all conditions used. This is the first paper where the transformation of CeO2 NPs in the presence of phosphate has been studied for particles with different size, shapes and capping agents, in a range of different conditions and using many different characterisation methods.

Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15–25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.

Background Understanding the impacts of inhaled insoluble nanomaterials as they are encountered in the environment and workplace, in injured lungs remains limited, particularly with respect to their role in the progression or mitigation of lung pathology. While some studies suggest potential protective effects of cerium(IV) oxide nanoparticles (CeO 2 NPs) under certain conditions, their influence during active disease processes is unclear. This study builds on prior work to investigate the effects of CeO 2 NP aerosols on bleomycin-induced pulmonary injury and active disease processes. Method To establish conditions of active pulmonary disease processes, bleomycin was used in both animal and airway epithelium models. Male Sprague-Dawley rats were intratracheally instilled with bleomycin or saline (control) followed by nose-only inhalation exposure to CeO 2 NP aerosols (diameter of ~ 43 nm) or control for 3 h per day for 4 days per week for one or two weeks. At three days postexposure, the animals were sacrificed for analysis of bronchoalveolar lavage (BAL) fluid, lung histopathology and global mRNA expression. Comparative in vitro studies were conducted to investigate biological responses at the cellular level, using 3D human small airway epithelium cultures (SmallAir™) exposed to CeO 2 NP aerosols (with a diameter of ~ 86 nm) at the air-liquid-interface at deposition doses comparable to those received in vivo in the small airway. Results In vivo, bleomycin treatment resulted in an increase in total BAL cells and fibrotic staining, and significant induction of inflammatory and oxidative stress, as shown by mRNA sequencing analysis. One week of exposure to CeO 2 NPs modified these responses by attenuating fibrotic staining and reducing the expression of genes associated with lung function, inflammation and epithelial-mesenchymal transition (EMT). In vitro, CeO 2 NP exposure modulated some bleomycin-induced cellular responses, although these models do not fully capture the complexity of whole body and tissue systems, highlighting limitations and considerations for future in vitro exposure studies. Conclusions In this study, inhaled CeO 2 NPs modulated lung injury responses in the context of active disease, with both potential protective effects and adverse outcomes. These findings demonstrate that the timing of CeO 2 NP exposure relative to disease progression is critical and highlight the need for hazard assessment frameworks to consider context-dependent effects, particularly in the presence of pre-existing lung injury.