Clays and clay minerals are widely used in many facets of our society. This review addresses the main clays of each phyllosilicate groups, namely, kaolinite, montmorillonite (Mt) and sepiolite, ...placing special emphasis on Mt and kaolinite, which are the clays that are more frequently used in food packaging, one of the applications that are currently exhibiting higher development. The improvements in the composite materials obtained from clays and polymeric matrices are remarkable and well known, but the potential toxicological effects of unmodified or modified clay minerals and derived nanocomposites are currently being investigated with increased interest. In this sense, this work focused on a review of the published reports related to the analysis of the toxicological profile of commercial and novel modified clays and derived nanocomposites. An exhaustive review of the main in vitro and in vivo toxicological studies, antimicrobial activity assessments, and the human and environmental impacts of clays and derived nanocomposites was performed. From the analysis of the scientific literature different conclusions can be derived. Thus, in vitro studies suggest that clays in general induce cytotoxicity (with dependence on the clay, concentration, experimental system, etc.) with different underlying mechanisms such as necrosis/apoptosis, oxidative stress or genotoxicity. However, most of in vivo experiments performed in rodents showed no clear evidences of systemic toxicity even at doses of 5000mg/kg. Regarding to humans, pulmonary exposure is the most frequent, and although clays are usually mixed with other minerals, they have been reported to induce pneumoconiosis per se. Oral exposure is also common both intentionally and unintentionally. Although they do not show a high toxicity through this pathway, toxic effects could be induced due to the increased or reduced exposure to mineral elements. Finally, there are few studies about the effects of clay minerals on wildlife, with laboratory trials showing contradictory outcomes. Clay minerals have different applications in the environment, thus with a strict control of the concentrations used, they can provide beneficial uses.
Despite the extensive number of reports available, there is also a need of systematic in vitro–in vivo extrapolation studies, with still scarce information on toxicity biomarkers such as inmunomodulatory effects or alteration of the genetic expression. In conclusion, a case by case toxicological evaluation is required taking into account that different clays have their own toxicological profiles, their modification can change this profile, and the potential increase of the human/environmental exposure to clay minerals due to their novel applications.
•We compare the effects of four microtubule-targeting drugs on fast axonal transport.•All four drugs inhibit anterograde transport in axoplasm, with varying potencies.•Vincristine and ixabepilone ...also inhibit retrograde transport in axoplasm.•Vincristine and ixabepilone slow the gliding of kinesin-1 driven microtubules.•Axonal transport inhibition may underlie chemotherapy-induced peripheral neuropathy.
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the “dying back” pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections. In this study, we test the hypothesis that microtubule-targeting drugs disrupt fast axonal transport using vesicle motility assays in isolated squid axoplasm and a cell-free microtubule gliding assay with defined components. We compare four clinically-used drugs, eribulin, vincristine, paclitaxel and ixabepilone. Of these, eribulin is associated with a relatively low incidence of severe neuropathy, while vincristine has a relatively high incidence. In vesicle motility assays, we found that all four drugs inhibited anterograde (conventional kinesin-dependent) fast axonal transport, with the potency being vincristine=ixabepilone>paclitaxel=eribulin. Interestingly, eribulin and paclitaxel did not inhibit retrograde (cytoplasmic dynein-dependent) fast axonal transport, in contrast to vincristine and ixabepilone. Similarly, vincristine and ixabepilone both exerted significant inhibitory effects in an in vitro microtubule gliding assay consisting of recombinant kinesin (kinesin-1) and microtubules composed of purified bovine brain tubulin, whereas paclitaxel and eribulin had negligible effects. Our results suggest that (i) inhibition of microtubule-based fast axonal transport may be a significant contributor to neurotoxicity induced by microtubule-targeting drugs, and (ii) that individual microtubule-targeting drugs affect fast axonal transport through different mechanisms.
Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell ...receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.
Gametogenesis is a complex biological process that is particularly sensitive to environmental insults such as chemicals. Many chemicals have a negative impact on the germline, either by directly ...affecting the germ cells, or indirectly through their action on the somatic nursing cells. Ultimately, these effects can inhibit fertility, and they may have negative consequences for the development of the offspring. Recently, nanomaterials such as nanotubes, nanowires, fullerene derivatives (buckyballs), and quantum dots have received enormous national attention in the creation of new types of analytical tools for biotechnology and the life sciences. Despite the wide application of nanomaterials, there is a serious lack of information concerning their impact on human health and the environment. Thus, there are limited studies available on toxicity of nanoparticles for risk assessment of nanomaterials. The purpose of this study was to assess the suitability of a mouse spermatogonial stem cell line as a model to assess nanotoxicity in the male germline in vitro. The effects of different types of nanoparticles on these cells were evaluated by light microscopy, and by cell proliferation and standard cytotoxicity assays. Our results demonstrate a concentration-dependent toxicity for all types of particles tested, whereas the corresponding soluble salts had no significant effect. Silver nanoparticles were the most toxic while molybdenum trioxide (MoO3) nanoparticles were the least toxic. Our results suggest that this cell line provides a valuable model with which to assess the cytotoxicity of nanoparticles in the germ line in vitro.
Copper oxide nanoparticles (CuO NPs) are used extensively in a variety of applications such as antimicrobial agent, photo-catalyst and gas sensors. The expanding production and widespread utilization ...of CuO NPs may pose risks to individual organisms and ecosystem. Comprehensive understanding the CuO NPs-induced adverse effects and their underlying mechanism are of great importance to assess the environmental risk of CuO NPs and to expand their use safely. However, toxic effects of CuO NPs to individual organisms and the mechanism of their action are still deficient and ambiguities. To ensure the safely use of CuO NPs, more attention should be paid on the long-term and chronic effects of CuO NPs at low concentration. Efforts should be devoted to develop techniques to differentiate toxicities induced by CuO NPs or dissolved Cu2+, and to reduce the toxicity of CuO NPs by controlling the particle diameter, modifying surface characteristic, selecting proper exposure route and regulating the release of Cu2+ from CuO NPs. This review provides a brief overview of toxicity of CuO NPs to individual organisms with a broad range of taxa (microorganisms, algae, plants, invertebrates and vertebrates) and to discuss the underlying toxicity mechanisms including oxidative stress, dynamic unbalance and coordination effects.
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A brief overview of toxicity of CuO NPs to individual organisms with a broad range of taxa is summarized and the mechanisms of their action are discussed.
Abstract Objectives Recently, we found that dental bonding substances tested alone or in combination with composites are far more cytotoxic than composite materials alone. These data are in line with ...several cytotoxicity reports but contradict in vivo studies showing the beneficial effects of bonding materials. The aims of the present study were to develop a preparation method for composite specimens modelling conditions in the oral cavity and to analyse the influence of bonding substances on the cytotoxicity of six different composite materials. Methods Cylindrical composite specimens were prepared in polyethylene blocks containing 5 mm diameter cylindrical holes (cylinder height 2 mm), covered with a polyethylene foil and light cured from one end for 40 s. In a second series of experiments, composite specimens were combined with bonding materials. Bonding was applied onto the polyethylene foil in one or two layers and light cured according to the manufacturers’ instructions. Subsequently, polyethylene moulds were placed on top of the bonding materials and composites prepared as described above. After unilateral light curing from the top of the cylindrical holes, visual confirmation of adherence at the base was obtained. Specimens were added to the cultures immediately after production or after preincubation for 7 days under cell culture conditions. Specimens were incubated with L-929 fibroblasts for 72 h and cell numbers determined by flow cytometry. To evaluate the degree of conversion (DC) of bonding materials cured with and without air inhibition a third series of experiments was performed. FTIR spectroscopic measurements were made on thin-films of dentin-bonding agents, cured under both an-aerobic and aerobic conditions, to determine degree of conversion. Results Cytotoxicities of all six tested composites were significantly different ( p < 0.0001) and diminished after 7 days of preincubation ( p < 0.0001). Bonding substances had no statistically significant influence on the cytotoxicity of composite materials ( p = 0.159). A highly significant statistical reduction in the degree of conversion for each resin cured under air inhibition conditions was documented ( p < 0.01). Significance Our study demonstrates that cell culture toxicity data are highly model dependent and that internationally standardized test protocols for toxicity screening of dental materials in line with the existing standards are clearly needed to obtain comparable results.
Organisms in the aquatic environment are exposed to a variety of substances of numerous chemical classes. The unintentional co-occurrence of pharmaceuticals and other contaminants of emerging concern ...may pose risk to non-target organisms. In this study, individual and binary mixture toxicity experiments of selected pharmaceuticals (ibuprofen and ciprofloxacin) and chlorophenols (2.4-dichlorophenol (2,4-DCP) and 3-chlorophenol (3-CP)) have been performed with freshwater algae Chlorella vulgaris. All experiments have been carried out according to the 96-h algal growth inhibition test OECD No. 201. Binary mixture tests were conducted using proportions of the respective IC50s in terms of toxic unit (TU). The mixture concentration-response curve was compared to predicted effects based on both the concentration addition (CA) and the independent action (IA) model. Additionally, the Combination Index (CI)-isobologram equation method was used to assess toxicological interactions of the binary mixtures.
All substances individually tested had a significant effect on C. vulgaris population density and revealed IC50 values <100mgL−1 after exposure period of 96-h. The toxic ranking of these four compounds to C. vulgaris was 2,4-DCP>ciprofloxacin>3-CP>ibuprofen. Generally, it can be concluded from this study that toxic mixture effects of all tested chemicals to C. vulgaris are higher than the individual effect of each mixture component. It could be demonstrated that IC50 values of the tested mixtures predominately lead to additive effects. The CA model is appropriate to estimate mixture toxicity, while the IA model tends to underestimate the joint effect. The CI-isobologram equation method predicted the mixtures accurately and elicited synergism at low effect levels for the majority of tested combinations.
•This is the first report on binary mixture toxicities of studied chemicals to algae.•Tested mixtures are more toxic than their individual components.•CI-isobologram method appear suitable for accurate prediction of mixture toxicity•Joint effects of chemicals having different mode of action were predictable by CA.•Effects of the studied chemicals on non-target organism, algae, were emphasized.
Mitochondrial dysfunction, which is directly involved in Parkinson’s disease (PD), is characterized by the production of reactive oxygen species (ROS) and aberrant energy metabolism. Thus, regulating ...mitochondrial function might be an effective strategy to treat PD. However, the blood–brain barrier (BBB) presents a significant challenge for the intracerebral delivery of drugs. Here, we synthesized a zeolitic imidazolate framework 8-coated Prussian blue nanocomposite (ZIF-8@PB), which was encapsulated with quercetin (QCT), a natural antioxidant, to treat PD. ZIF-8@PB-QCT exhibited superior near-infrared radiation (NIR) response and penetrated through the BBB to the site of mitochondrial damage guided by the photothermal effect. In the mice model of PD, the QCT released from ZIF-8@PB-QCT significantly increased the adenosine triphosphate levels, reduced the oxidative stress levels, and reversed dopaminergic neuronal damage as well as PD-related behavioral deficits without any damage to the normal tissues. Furthermore, we explored the underlying neuroprotective mechanism of ZIF-8@PB-QCT that was mediated by activating the PI3K/Akt signaling pathway. Thus, combined with noninvasive NIR radiation, the biocompatible ZIF-8@PB-QCT nanocomposite could be used to treat neurodegenerative diseases.
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•The effects of polyester fibers on soil animals were studied for the first time.•Enchytraeid reproduction decreased up to 30% but only by long fibers in soil.•Isopod energy reserves ...and feeding activity were affected by fibers in soil.•Polyester fibers were not very harmful to soil invertebrates in 21–28-days exposure.•Polyester fibers can enter terrestrial food webs by ingestion by soil invertebrates.
Polyester fiber is one of the most abundant types of microplastics in the environment. A major proportion of the fibers entering wastewater treatment plants end up in sewage sludge, which is used as a soil fertilizer in many countries. As their impacts in the terrestrial environment are still poorly understood, we studied the effects of polyester fibers on enchytraeids (Enchytraeus crypticus), springtails (Folsomia candida), isopods (Porcellio scaber) and oribatid mites (Oppia nitens), all playing an important role in soil decomposer food webs. We exposed these invertebrates in the laboratory to short (12 µm–2.87 mm) and long (4–24 mm) polyester fibers, spiked in soil or in food at five concentrations ranging from 0.02% to 1.5% (w/w) and using five replicates. Overall the effects of polyester fibers on the soil invertebrates were slight. Energy reserves of the isopods were slightly affected by both fiber types, and enchytraeid reproduction decreased up to 30% with increasing fiber concentration, but only for long fibers in soil. The low ingestion of long fibers by the enchytraeids suggests that this negative impact arose from a physical harm outside the organism, or from indirect effects resulting from changes in environmental conditions. The short fibers were clearly ingested by enchytraeids and isopods, with the rate of ingestion positively related to fiber concentration in the soil. This study shows that polyester fibers are not very harmful to soil invertebrates upon short-term exposure. However, longer lasting, multigeneration studies with functional endpoints are needed to reveal the possible long-term effects on soil invertebrates and their role in the decomposition process. This study also shows that polyester fibers can enter terrestrial food web via ingestion of fibers by soil invertebrates.
In this study, the uptake and elimination of ZnO and CuO nanoparticles in Daphnia magna was tested. Daphnids were exposed during 10 days to sublethal concentrations of ZnO and CuO nanoparticles and ...corresponding metal salts (ZnCl2 and CuCl2.2H2O), after which they were transferred to unexposed medium for another 10 days. At different times during the exposure and none-exposure, the total and internal zinc or copper concentration of the daphnids was determined and the nanoparticles were localized in the organism using electron microscopy. The exposure concentrations were characterized by measuring the dissolved, nanoparticle and aggregated fraction in the medium. The results showed that the ZnO nanoparticles quickly dissolved after addition to the medium. Contrarily, only a small fraction (corresponding to the dissolved metal salt) of the CuO nanoparticles dissolved, while most of these nanoparticles formed large aggregates. Despite an initial increase in zinc and copper concentration during the first 48 h to 5 day exposure, the body concentration reached a plateau level that was comparable for the ZnO nanoparticles and ZnCl2, but much higher for the CuO nanoparticles (with visible aggregates accumulating in the gut) than CuCl2.2H2O. During the remaining exposure and subsequent none-exposure phase, the zinc and copper concentration decreased fast to concentrations comparable with the unexposed daphnids. The results indicate that D. magna can regulate its internal zinc and copper concentration after exposure to ZnO and CuO nanoparticles, similar as after exposure to metal salts. The combined dissolution, accumulation and toxicity results confirm that the toxicity of ZnO and CuO nanoparticles is caused by the dissolved fraction.
•ZnO nanoparticles (NPs) quickly dissolve after addition to the medium.•Most CuO NPs aggregate in the medium, while only a small fraction dissolves.•Daphnids exposed to the NPs can regulate their internal zinc and copper concentration.•CuO NPs accumulate in the gut but do not penetrate cells or tissues.•The toxicity of ZnO and CuO NPs to daphnids is caused by the dissolved fraction.
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