Effect of silver nanoparticles (AgNPs) exposure on microRNA expression and global DNA methylation in endothelial cells EA.hy926

The aim of this study was to determine the effect of AgNPs on the epigenome of endothelial cells EA.hy926, including the levels of expression of microRNAs (miRNAs) and global DNA methylation patterns. In addition, evaluation of the expression of inflammatory genes and the levels of VCAM-1 protein (miRNA-126 target) was performed. The expression levels of analyzed miRNAs (microRNAs-126, 155 and 146) were reduced significantly and there were not observed changes in inflammatory gene expression. Regarding the levels of protein vascular cell adhesion molecule 1 (VCAM-1), they increase significantly to 0.5 μM AgNPs at 24 h of exposure. As far as DNA methylation is concerned, we found that AgNPs induce a state of global hyper-methylation. In conclusion, it was demonstrated that direct contact between AgNPs and endothelial cells resulted in the dysregulation of highly enriched and vastly functional miRNAs and DNA hypermethylation, that may have multiple effects on endothelium function and integrity.     

药物透过血脑屏障靶向传递系统的研究

脑组织受血脑屏障(BBB)的保护阻止了某些有害物质的侵入,但同时也限制了药物的组织摄取而无法实现药物的疗效。本文概括了目前已被证实的可提高跨BBB药物递送途径即:化学传递、生物学传递、短暂性开放血脑屏障、特洛伊木马分子运载、纳米技术的应用等方法。系统地综述了有关药物透过血脑屏障靶向传递的思路和研究方法。     

In vitro assessments of nanomaterial toxicity

Nanotechnology has grown from a scientific interest to a major industry with both commodity and specialty nanomaterial exposure to global populations and ecosystems. Sub-micron materials are currently used in a wide variety of consumer products and in clinical trials as drug delivery carriers and imaging agents. Due to the expected growth in this field and the increasing public exposure to nanomaterials, both from intentional administration and inadvertent contact, improved characterization and reliable toxicity screening tools are required for new and existing nanomaterials. This review discusses current methodologies used to assess nanomaterial physicochemicial properties and their in vitro effects. Current methods lack the desired sensitivity, reliability, correlation and sophistication to provide more than limited, often equivocal, pieces of the overall nanomaterial performance parameter space, particularly in realistic physiological or environmental models containing cells, proteins and solutes. Therefore, improved physicochemical nanomaterial assays are needed to provide accurate exposure risk assessments and genuine predictions of in vivo behavior and therapeutic value. Simpler model nanomaterial systems in buffer do not accurately duplicate this complexity or predict in vivo behavior. A diverse portfolio of complementary material characterization tools and bioassays are required to validate nanomaterial properties in physiology.     

Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential responses related to surface properties

Surface properties are critical to assess effects of ultrafine-TiO(2) particles. The aim of this study was to assess lung toxicity in rats of newly developed, well characterized, ultrafine-TiO(2) particles and compare them to TiO(2) samples in two different size ranges and surface modifications. Groups of rats were intratracheally instilled with doses of 1 or 5mg/kg of either two ultrafine rutile TiO(2) particles (uf-1 or uf-2); rutile R-100 fine-TiO(2) (F-1); 80/20 anatase/rutile P25 ultrafine-TiO(2) (uf-3); or alpha-quartz particles. Phosphate-buffered saline (PBS) solution instilled rats served as vehicle controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24h, 1 week, 1 and 3 months. The ranking of lung inflammation/cytotoxicity/cell proliferation and histopathological responses was quartz>uf-3>F-1=uf-1=uf-2. Exposures to quartz and to a lesser degree, uf-3 anatase/rutile TiO(2) particles produced pulmonary inflammation, cytotoxicity and adverse lung tissue effects. In contrast, exposures to F-1 fine-TiO(2) particles or to uf-1/uf-2 ultrafine-TiO(2) particle-types produced transient inflammation. We conclude that differences in responses to anatase/rutile uf-3 TiO(2) particles versus the rutile uf-1 and uf-2 TiO(2) particles could be related to crystal structure, inherent pH of the particles, or surface chemical reactivity. Thus, based on these results, inhaled rutile ultrafine-TiO(2) particles are expected to have a low risk potential for producing adverse pulmonary health effects. Finally, the results demonstrate that exposures to ultrafine-TiO(2) particle-types can produce differential pulmonary effects, based upon their composition, and crystal structure. Thus, the lung toxicity of anatase/rutile uf-3 should not be viewed as representative for all ultrafine-TiO(2) particle-types.     

Nanoparticle‐based approaches to immune tolerance for the treatment of autoimmune diseases

Autoimmune diseases are caused by antigenically complex immune responses of the adaptive and innate immune system against specific cells, tissues or organs. Antigen‐specific approaches for induction of immune tolerance in autoimmunity, based on the use of antigenic peptides or proteins, have failed to deliver the desired therapeutic results in clinical trials. These approaches, which are largely relying on triggering clonal anergy and/or deletion of defined autoreactive specificities, do not address the overwhelming antigenic, molecular, and cellular complexity of most autoimmune diseases, which involve various immune cells and ever‐growing repertoires of antigenic epitopes on numerous self‐antigens. Advances in the field of regulatory T‐cell (Treg) biology have suggested that Treg cells might be able to afford dominant tolerance provided they are properly activated and expanded in vivo. More recently, nanotechnology has introduced novel technical advances capable of modulating immune responses. Here, we review nanoparticle‐based approaches designed to induce immune tolerance, ranging from approaches that primarily trigger clonal T‐cell anergy or deletion to approaches that trigger Treg cell formation and expansion from autoreactive T‐cell effectors. We will also highlight the therapeutic potential and positive outcomes in numerous experimental models of autoimmunity.     

European regulation affecting nanomaterials - review of limitations and future recommendations

After learning about the potential risks associated with various specific nanomaterials, concerns have been raised about adequacy of existing regulation in Europe and what should be done to address any potential regulatory gaps related to nanomaterials. Understanding the limitations of the current regulation in regard to nanomaterials is a starting point in a democratic and transparent process towards adapting existing laws and facilitating an informed discussion about which kind of regulatory options best address the identified limitations. In the following we will introduce key pieces of European legislation affecting nanomaterials, analyze their limitations, and provide a number of recommendations on how these can be overcome. We find that, although nanomaterials are in principle covered by the scope of many of the existing legislative frameworks, it is often unclear, if current regulations are actually applicable when it comes to specific nanomaterials and their diverse applications. Main limitations seem to be: that requirements to do safety evaluations are triggered by production volumes by tonnage not tailored to the nanoscale, the profound lack of (eco)toxicological data, and that thresholds values and occupational exposure limits cannot be established with existing methodologies.     

Neurodegenerative and neurological disorders by small inhaled particles

The world⿿s population is steadily ageing and as a result, health conditions related to ageing, such as dementia, have become a major public health concern. In 2001, it was estimated that there were almost 5 million Europeans suffering from Alzheimer⿿s disease (AD) and this figure has been projected to almost double by 2040. About 40% of people over 85 suffer from AD, and another 10% from Parkinson⿿s disease (PD). The majority of AD and PD cases are of sporadic origin and environmental factors play an important role in the aetiology. Epidemiological research identified airborne particulate matter (PM) as one of the environmental factors potentially involved in AD and PD pathogenesis. Also, cumulating evidence demonstrates that the smallest sizes of the inhalable fraction of ambient particulate matter, also referred to as ultrafine particulate matter or nano-sized particles, are capable of inducing effects beyond the respiratory system. Translocation of very small particles via the olfactory epithelium in the nose or via uptake into the circulation has been demonstrated through experimental rodent studies with engineered nanoparticles. Outdoor air pollution has been linked to several health effects including oxidative stress and neuroinflammation that may ultimately result in neurodegeneration and cognitive impairment. This review aims to evaluate the relationship between exposure to inhaled ambient particles and neurodegeneration.     

A Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health Risks

Nanotechnology has emerged at the forefront of science research and technology development. Carbon nanotubes (CNTs) are major building blocks of this new technology. They possess unique electrical, mechanical, and thermal properties, with potential wide applications in the electronics, computer, aerospace, and other industries. CNTs exist in two forms, single-wall (SWCNTs) and multi-wall (MWCNTs). They are manufactured predominately by electrical arc discharge, laser ablation and chemical vapor deposition processes; these processes involve thermally stripping carbon atoms off from carbon-bearing compounds. SWCNT formation requires catalytic metals. There has been a great concern that if CNTs, which are very light, enter the working environment as suspended particulate matter (PM) of respirable sizes, they could pose an occupational inhalation exposure hazard. Very recently, MWCNTs and other carbonaceous nanoparticles in fine (<2.5 μm) PM aggregates have been found in combustion streams of methane, propane, and natural-gas flames of typical stoves; indoor and outdoor fine PM samples were reported to contain significant fractions of MWCNTs. Here we review several rodent studies in which test dusts were administered intratracheally or intrapharyngeally to assess the pulmonary toxicity of manufactured CNTs, and a few in vitro studies to assess biomarkers of toxicity released in CNT-treated skin cell cultures. The results of the rodent studies collectively showed that regardless of the process by which CNTs were synthesized and the types and amounts of metals they contained, CNTs were capable of producing inflammation, epithelioid granulomas (microscopic nodules), fibrosis, and biochemical/toxicological changes in the lungs. Comparative toxicity studies in which mice were given equal weights of test materials showed that SWCNTs were more toxic than quartz, which is considered a serious occupational health hazard if it is chronically inhaled; ultrafine carbon black was shown to produce minimal lung responses. The differences in opinions of the investigators about the potential hazards of exposures to CNTs are discussed here. Presented here are also the possible mechanisms of CNT pathogenesis in the lung and the impact of residual metals and other impurities on the toxicological manifestations. The toxicological hazard assessment of potential human exposures to airborne CNTs and occupational exposure limits for these novel compounds are discussed in detail. Environmental fine PM is known to form mainly from combustion of fuels, and has been reported to be a major contributor to the induction of cardiopulmonary diseases by pollutants. Given that manufactured SWCNTs and MWCNTs were found to elicit pathological changes in the lungs, and SWCNTs (administered to the lungs of mice) were further shown to produce respiratory function impairments, retard bacterial clearance after bacterial inoculation, damage the mitochondrial DNA in aorta, increase the percent of aortic plaque, and induce atherosclerotic lesions in the brachiocephalic artery of the heart, it is speculated that exposure to combustion-generated MWCNTs in fine PM may play a significant role in air pollution-related cardiopulmonary diseases. Therefore, CNTs from manufactured and combustion sources in the environment could have adverse effects on human health.     

Monitoring of human populations for early markers of cadmium toxicity: A review

Exposure of human populations to cadmium (Cd) from air, food and water may produce effects in organs such as the kidneys, liver, lungs, cardiovascular, immune and reproductive systems. Since Cd has been identified as a human carcinogen, biomarkers for early detection of susceptibility to cancer are of an importance to public health. The ability to document Cd exposure and uptake of this element through biological monitoring is a first step towards understanding its health effects. Interpretation and application of biological monitoring data for predicting human health outcomes require correlation with biological measures of organ system responses to the documented exposure. Essential to this understanding is the detection and linkage of early biological responses toxic effects in target cell populations. Fortunately, advances in cell biology have resulted in the development of pre-clinical biological markers (biomarkers) that demonstrate measurable and characteristic molecular changes in organ systems following chemical exposures that occur prior to the onset of overt clinical disease or development of cancer. Technical advances have rendered a number of these biomarkers practical for monitoring Cd-exposed human populations. Biomarkers will be increasingly important in relation to monitoring effects from the exposure to new Cd-based high technology materials. For example, cadmium-selenium (CdSe), nano-materials made from combinations of these elements have greatly altered cellular uptake characteristics due to particle size. These differences may greatly alter effects at the target cell level and hence risks for organ toxicities from such exposures. The value of validated biomarkers for early detection of systemic Cd-induced effects in humans cannot be underestimated due to the rapid expansion of nano-material technologies. This review will attempt to briefly summarize the applications, to date, of biomarker endpoints for assessing target organ system effects in humans and experimental systems from Cd exposure. Further, it will attempt to provide a prospective look at the possible future of biomarkers. The emphasis will be on the detection of early toxic effects from exposure to Cd in new products such as nano-materials and identification of populations at special risk for Cd toxicity.     

纳米材料氧化石墨烯的细胞毒性机制研究进展

氧化石墨烯是一种新型二维碳纳米材料,可对职业暴露人群构成潜在的健康风险。本文从氧化应激、物理损伤和酶活性紊乱等分子机制综述了氧化石墨烯及其衍生物的细胞毒性研究进展,讨论当前细胞毒性减轻机制的研究热点,以期为我国石墨烯材料职业健康风险防控和生物安全性评估提供参考依据。