Mechanisms underlying cytotoxicity induced by engineered nanomaterials: a review of in vitro studies

Engineered nanomaterials are emerging functional materials with technologically interesting properties and a wide range of promising applications, such as drug delivery devices, medical imaging and diagnostics, and various other industrial products. However, concerns have been expressed about the risks of such materials and whether they can cause adverse effects. Studies of the potential hazards of nanomaterials have been widely performed using cell models and a range of in vitro approaches. In the present review, we provide a comprehensive and critical literature overview on current in vitro toxicity test methods that have been applied to determine the mechanisms underlying the cytotoxic effects induced by the nanostructures. The small size, surface charge, hydrophobicity and high adsorption capacity of nanomaterial allow for specific interactions within cell membrane and subcellular organelles, which in turn could lead to cytotoxicity through a range of different mechanisms. Finally, aggregating the given information on the relationships of nanomaterial cytotoxic responses with an understanding of its structure and physicochemical properties may promote the design of biologically safe nanostructures

Physical activity level and lifestyle-related risk factors from Catalan physicians.

BACKGROUND: Physicians' own Physical Activity (PA) and other health-related habits influence PA promotion. The current study identifies the PA level, according to the current PA recommendations and other health-related habits of physicians from the Catalan Medical Council. METHODS: 2400 physicians (30-55 years) were randomly selected; each received a self-administered mailed questionnaire identifying medical specialization, work setting, health self-perception, body mass index (BMI), PA, and smoking habits. RESULTS: 762 physicians responded (52% female). Almost 1 in 2 (49.3%) exercised sufficiently, nearly all self-perceived good health, while 80.5% were nonsmokers. Almost 6 in 10 males reported overweight or obesity (56.9%) versus 18.2% of females. Active physicians dominated specific groups: (1) aged 45-55 years, (2) specializing either in primary care or surgery, (3) working in the private sector, (4) BMI < 25 kg/m2, (5) perceiving themselves in good health, or (6) having free leisure time. CONCLUSIONS: Only half of Catalan physicians met current PA recommendations; male physicians were particularly at risk for overweight/obesity. Overweight and under-exercise were associated with private workplaces and positive health perceptions, meaning that it is it is now possible to target inactive and/or overweight Catalan physicians in future interventions

A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms

Abstract Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP‐9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP‐9 3′UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP‐9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis‐related locomotor hyperactivity in Mmp‐9 heterozygous mice. We propose a novel mechanism that involves MMP‐9‐dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP‐9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients

Radio data challenge the broadband modelling of GRB160131A afterglow

Context. Gamma-ray burst (GRB) afterglows originate from the interaction between the relativistic ejecta and the surrounding medium. Consequently, their properties depend on several aspects: radiation mechanisms, relativistic shock micro-physics, circumburst environment, and the structure and geometry of the relativistic jet. While the standard afterglow model accounts for the overall spectral and temporal evolution for a number of GRBs, its validity limits emerge when the data set is particularly rich and constraining, especially in the radio band. Aims. We aimed to model the afterglow of the long GRB160131A (redshift $z = 0.972$), for which we collected a rich, broadband, and accurate data set, spanning from $6\times10^{8}$ to $7\times10^{17}$ Hz in frequency, and from 330 s to 160 days post burst in time. Methods. We modelled the spectral and temporal evolution of this GRB afterglow through two approaches: the adoption of empirical functions to model optical/X-rays data set, later assessing their compatibility with the radio domain; the inclusion of the entire multi-frequency data set simultaneously through the Python package named sAGa (Software for AfterGlow Analysis), to come up with an exhaustive and self-consistent description of the micro-physics, geometry, and dynamics of the afterglow. Results. From deep broadband analysis (from radio to X-ray frequencies) of the afterglow light curves, GRB160131A outflow shows evidence of jetted emission. Moreover, we observe dust extinction in the optical spectra, and energy injection in the optical/X-ray data. Radio spectra are characterised by several peaks, that could be due to either interstellar scintillation (ISS) effects or a multi-component structure. Conclusions. The inclusion of radio data in the broadband set of GRB160131A makes a self-consistent modelling hardly attainable within the standard model of GRB afterglows.Comment: 36 pages, 16 figures, 8 tables, accepted by A&A; v2: updated Acknowledgement

Nanoparticles incorporating pH-responsive surfactants as a viable approach to improve the intracellular drug delivery

The pH-responsive delivery systems have brought newadvances in the field of functional nanodevices and might allow more accurate and controllable delivery of specific cargoes, which is expected to result in promising applications in different clinical therapies. Here we describe a family of chitosan TPP (tripolyphosphate) nanoparticles (NPs) for intracellular drug delivery, which were designed using two pH-sensitive amino acid-based surfactants fromthe family Nα,Nε-dioctanoyl lysine as bioactive compounds. Lowand mediummolecularweight chitosan (LMW-CS and MMW-CS, respectively) were used for NP preparation, and it was observed that the size distribution for NPs with LMW-CS were smaller (~168 nm) than that for NPs prepared with MMW-CS (~310 nm). Hemolysis assay demonstrated the pH-dependent biomembrane disruptional capability of the constructed NPs. The nanostructures incorporating the surfactants cause negligible membrane permeabilization at pH 7.4. However, at acidic pH, prevailing in endosomes, membrane-destabilizing activity in an erythrocyte lysis assay became evident. When pH decreased to 6.6 and 5.4, hemolytic capability of chitosan NPs increased along with the raise of concentration. Furthermore, studies with cell culture showed that these pH-responsive NPs displayed low cytotoxic effects against 3T3 fibroblasts. The influence of chitosan molecular weight, chitosan to TPP weight ratio, nanoparticle size and nature of the surfactant counterion on the membrane-disruptive properties of nanoparticleswas discussed in detail. Altogether, the results achieved here showed that by inserting the lysine-based amphiphiles into chitosan NPs, pH-sensitive membranolytic and potentially endosomolytic nanocarriers were developed, which, therefore, demonstrated ideal feasibility for intracellular drug delivery

Al2O3 microring resonators for the detectin of a cancer biomarker in undiluted urine

: Concentrations down to 3 nM of the rhS100A4 protein, associated with human tumor development, have been detected in undiluted urine using an integrated sensor based on microring resonators in the emerging Al2O3 photonic platform. The fabricated microrings were designed for operation in the C-band (λ = 1565 nm) and exhibited a high-quality factor in air of 3.2 × 105. The bulk refractive index sensitivity of the devices was ~100 nm/RIU (for TM polarization) with a limit of detection of ~10−6 RIU. A surface functionalization protocol was developed to allow for the selective binding of the monoclonal antibodies designed to capture the target biomarker to the surface of the Al2O3 microrings. The detection of rhS100A4 proteins at clinically relevant concentrations in urine is a big milestone towards the use of biosensors for the screening and early diagnosis of different cancers. Biosensors based on this microring technology can lead to portable, multiplexed and easy-to-use point of care device

Al2O3 microresonators for passive and active sensing applications

The Al2O3 waveguide technology was explored for sensing applications. Passive microring resonators with a quality factor in air of 3.2×105 were developed with a bulk refractive index sensitivity of ~100 nm/RIU and limit of detection of ~10-6 RIU. These were functionalized to detect the biomarker rhS100A4 from urine down to concentrations of 3 nM. Furthermore, Al2O3:Yb3+ microdisk lasers were realized that exhibited single mode lasing operation in water. Their lasing wavelength was tuned by varying the bulk refractive index and a bulk refractive index sensitivity of ~20 nm/RIU with a LOD of ~3×10-6 was achieved

Determination of Methotrexate in pH-Sensitive Chitosan Nanoparticles by Validated RP-LC and UV Spectrophotometric Methods

Nanotechnology-based drug delivery systems are in constant development and, therefore, it is of great importance to have rapid, efficient and accurate analytical methodology to quantify the encapsulated drugs. Here, simple and fast methods, by reversed-phase liquid chromatography (RP-LC) and UV spectrophotometry, were developed and validated for the determination of methotrexate (MTX) in pH-sensitive chitosan nanoparticles (CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included a surfactant derived from Nα,Nε-dioctanoyl lysine with an inorganic sodium counterion. The RP-LC method was carried out on a Waters XBridgeTM C18 column (250 mm x 4.6 mm I.D., 5μm), with mobile phase consisted of potassium phosphate buffer (0.05 M, pH 3.2): acetonitrile (86:14, v/v), and UV detection set at 303 nm. The analyses of MTX content by the UV method were also accomplished at 303 nm, using 0.1 M sodium hydroxide as diluent. The measurements were linearly correlated with concentration for both methods in the 1 - 30 μg/mL range (r > 0.9999). The specificity tests showed that there was no interference of the NP components on the quantitative analyses. Precision (repeatability and intermediate precision) was demonstrated by a relative standard deviation lower than 1.5%, whereas the accuracy was assessed by the recovery of MTX from sample matrices, given mean value of ~99%. The proposed methods were applied for the analyses of MTX in different batches of NPs, and the results showed non-significant differences (p > 0.05) between the values obtained with both methodologies. Moreover, the RP-LC method was successfully used to determine the drug entrapment efficiency, and to quantify MTX during in vitro release assays and photolytic degradation studies. In conclusion, the validated methods are suitable to assay MTX in pH-sensitive CS-NPs without any interference from the polymer or surfactant