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Subcutaneous microbubble administration in connection with contrast enhanced ultrasound (CEUS) imaging is showing promise as a noninvasive and sensitive way to detect tumor draining sentinel lymph nodes (SLNs) in patients with breast cancer. Moreover, there is potential to harness the results from these approaches to directly estimate cancer burden, since some microbubble formulas, such as the Sonazoid used in this study, are rapidly phagocytosed by macrophages, and the macrophage concentration in a lymph node is inversely related to the cancer burden. This work presents a mathematical model that can approximate a rate constant governing macrophage uptake of Sonazoid, k i , given dynamic CEUS Sonazoid imaging data. Twelve healthy women were injected with 1.0 ml of Sonazoid in an upper-outer quadrant of one of their breasts and SLNs were imaged in each patient immediately after injection, and then at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection. The mathematical model developed was fit to the dynamic CEUS data from each subject resulting in a mean ± sd of 0.006 ± 0.005 h -1 and 0.4 ± 0.1 h -1 for relative lymphatic flow ( EF l ) and k i , respectively. Furthermore, the roughly 25% sd of the k i measurement was similar to the sd that would be expected from realistic noise simulations for a stable 0.4 h -1 value of k i , suggesting that macrophage concentration is highly consistent among cancer-free SLNs. These results, along with the significantly smaller variance in k i measurement observed compared to relative lymphatic flow suggest that k i may be a more precise and promising approach of estimating macrophage abundance, and inversely cancer burden. Future studies comparing tumor-free to tumor-bearing nodes are planned to verify this hypothesis., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-β antibody (named aAβ-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer's disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAβ-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAβ-BTRA-NC was well-tolerated by the animals up to 300 μmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAβ-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAβ-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 μmol/kg b.w. of metal ions. Intravenously administered aAβ-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAβ-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAβ-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications.

Molybdenum, lithium, and tungsten are constituents of many products, and exposure to these elements potentially occurs at work. Therefore it is important to determine at what levels they are toxic, and thus we set out to review their pulmonary toxicity, genotoxicity, and carcinogenicity. After pulmonary exposure, molybdenum and tungsten are increased in multiple tissues; data on the distribution of lithium are limited. Excretion of all three elements is both via faeces and urine. Molybdenum trioxide exerted pulmonary toxicity in a 2-year inhalation study in rats and mice with a lowest-observed-adverse-effect concentration (LOAEC) of 6.6 mg Mo/m 3 . Lithium chloride had a LOAEC of 1.9 mg Li/m 3 after subacute inhalation in rabbits. Tungsten oxide nanoparticles resulted in a no-observed-adverse-effect concentration (NOAEC) of 5 mg/m 3 after inhalation in hamsters. In another study, tungsten blue oxide had a LOAEC of 63 mg W/m 3 in rats. Concerning genotoxicity, for molybdenum, the in vivo genotoxicity after inhalation remains unknown; however, there was some evidence of carcinogenicity of molybdenum trioxide. The data on the genotoxicity of lithium are equivocal, and one carcinogenicity study was negative. Tungsten seems to have a genotoxic potential, but the data on carcinogenicity are equivocal. In conclusion, for all three elements, dose descriptors for inhalation toxicity were identified, and the potential for genotoxicity and carcinogenicity was assessed., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Monocrotaline (MCT) is a pyrrolizidine alkaloid that can induce hepatic sinusoidal damage, pulmonary hypertension, renal toxicity, and heart disease. Monocrotaline N-oxide (MNO), the primary metabolite of MCT, is less toxic; however, it can convert back to MCT to exhibit its toxicity. This study developed and validated a rapid and sensitive LC-MS/MS method for the simultaneous determination of MCT and monocrotaline N-oxide in rat plasma. The method has a linearity over the concentration range of 1-2000 ng/mL with correlation coefficients (r) >0.997 for each analyte. The results of selectivity, matrix effect, accuracy and precision, and recovery were all within the acceptance criteria. The validated method has been successfully applied to study pharmacokinetic behaviors and bioavailability of MCT in rats. MCT was rapidly absorbed (T max : 0.400 ± 0.149 h) after oral administration, and the absolute bioavailability of MCT was 78.2%., (© 2021 John Wiley & Sons, Ltd.)

The current understanding of osteoarthritis is developing from a mechanical disease caused by cartilage wear to a complex biological response involving inflammation, oxidative stress and other aspects. Nanoparticles are widely used in drug delivery due to its good stability in vivo and cell uptake efficiency. In addition to the above advantages, metal/metal oxide NPs, such as cerium oxide and manganese dioxide, can also simulate the activity of antioxidant enzymes and catalyze the degradation of superoxide anions and hydrogen peroxide. Degrading of metal/metal oxide nanoparticles releases metal ions, which may slow down the progression of osteoarthritis by inhibiting inflammation, promoting cartilage repair and inhibiting cartilage ossification. In present review, we focused on recent research works concerning osteoarthritis treating with metal/metal oxide nanoparticles, and introduced some potential nanoparticles that may have therapeutic effects., (© 2021. The Author(s).)

Vanadium dioxide nanoparticles (VO 2 NPs) have been massively produced and widely applied due to their excellent metal-insulator transition property, making it extremely urgent to evaluate their safety, especially for low-dose long-term respiratory occupational exposure. Here, we report a comprehensive cytotoxicity and genotoxicity study on VO 2 NPs to lung cell lines A549 and BEAS-2B following a long-term exposure. A commercial VO 2 NP, S-VO 2 , was used to treat BEAS-2B (0.15-0.6 μg/mL) and A549 (0.3-1.2 μg/mL) cells for four exposure cycles, and each exposure cycle lasted for 4 consecutive days; then various bioassays were performed after each cycle. Significant proliferation inhibition was observed in both cell lines after long-term exposure of S-VO 2 at low doses that did not cause apparent acute cytotoxicity; however, the genotoxicity of S-VO 2 , characterized by DNA damage and micronuclei, was only observed in A549 cells. These adverse effects of S-VO 2 were exposure time-, dose- and cell-dependent, and closely related to the solubility of S-VO 2 . The oxidative stress in cells, i.e., enhanced reactive oxygen species (ROS) generation and suppressed reduced glutathione, was the main toxicity mechanism of S-VO 2 . The ROS-associated mitochondrial damage and DNA damage led to the genotoxicity, and cell proliferation retard, resulting in the cellular viability loss. Our results highlight the importance and urgent necessity of the investigation on the long-term toxicity of VO 2 NPs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Methods: Herein, we report Mn 3+ -rich manganese oxide (MnO x )-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnO x shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes in vitro . Furthermore, the in vivo biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. Results: In the tumor region, the MnO x shell is quickly decomposed to produce Mn 3+ and oxygen (O 2 ) to directly generate singlet oxygen ( 1 O 2 ). The resulting Mn 2+ transforms endogenous H 2 O 2 into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn 2+ ions and ZGGOs also exhibit excellent T 1 -weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Conclusion: Both the responsive dual-mode imaging and simultaneous self-supplied O 2 for the production of 1 O 2 and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The experiment was performed in support of a Japanese initiative to investigate the biological effects of irradiation from residual neutron-activated radioactivity that resulted from the A-bombing. Radionuclide 56 Mn (T 1/2  = 2.58 h) is one of the main neutron-activated emitters during the first hours after neutron activation of soil dust particles. In our previous studies (2016-2017) related to irradiation of male Wistar rats after dispersion of 56 MnO 2 powder, the internal doses in rats were found to be very inhomogeneous: distribution of doses among different organs ranged from 1.3 Gy in small intestine to less than 0.0015 Gy in some of the other organs. Internal doses in the lungs ranged from 0.03 to 0.1 Gy. The essential pathological changes were found in lung tissue of rats despite a low level of irradiation. In the present study, the dosimetry investigations were extended: internal doses in experimental mice and rats were estimated for various activity levels of dispersed neutron-activated 56 MnO 2 powder. The following findings were noted: (a) internal radiation doses in mice were several times higher in comparison with rats under similar conditions of exposure to 56 MnO 2 powder. (b) When 2.74 × 10 8  Bq of 56 MnO 2 powder was dispersed over mice, doses of internal irradiation ranged from 0.81 to 4.5 Gy in the gastrointestinal tract (small intestine, stomach, large intestine), from 0.096 to 0.14 Gy in lungs, and doses in skin and eyes ranged from 0.29 to 0.42 Gy and from 0.12 to 0.16 Gy, respectively. Internal radiation doses in other organs of mice were much lower. (c) Internal radiation doses were significantly lower in organs of rats with the same activity of exposure to 56 MnO 2 powder (2.74 × 10 8  Bq): 0.09, 0.17, 0.29, and 0.025 Gy in stomach, small intestine, large intestine, and lungs, respectively. (d) Doses of internal irradiation in organs of rats and mice were two to four times higher when they were exposed to 8.0 × 10 8  Bq of 56 MnO 2 (in comparison with exposure to 2.74 × 10 8  Bq of 56 MnO 2 ). (e) Internal radiation doses in organs of mice were 7-14 times lower with the lowest 56 MnO 2 amount (8.0 × 10 7  Bq) in comparison with the highest amount, 8.0 × 10 8  Bq, of dispersed 56 MnO 2 powder. The data obtained will be used for interpretation of biological effects in experimental mice and rats that result from dispersion of various levels of neutron-activated 56 MnO 2 powder, which is the subject of separate studies.

Glioblastoma (GBM) is a malignant brain tumour with a dismal prognosis, despite best treatment by surgical resection, radiation therapy (RT) and chemotherapy with temozolomide (TMZ). Nanoparticle (NP) therapy is an emerging consideration due to the ability of NPs to be formulated and cross the blood brain barrier. Lanthanum oxide (La 2 O 3 ) NPs are therapeutically advantageous due to the unique chemical properties of lanthanum making it cytotoxic to cancers, and able to enhance existing anti-cancer treatments. However, La 2 O 3 NPs have yet to be thoroughly investigated in brain tumors. We show that these NPs can reach the brain after venous injection, penetrate into GBM cells via endocytosis, dissociate to be cytotoxic, and enhance the therapeutic effects of RT and TMZ. The mechanisms of cell death by La 2 O 3 NPs were found to be multifaceted. Increasing NP concentration was correlated to increased intrinsic and extrinsic apoptosis pathway markers in a radical oxygen species (ROS)-dependent manner, as well as involving direct DNA damage and autophagic pathways within GBM patient-derived cell lines. NP interactions to sensitize GBM to RT and TMZ were shown to involve these pathways by enhancing ROS and apoptotic mechanisms. We therefore demonstrate the therapeutic potential of La 2 O 3 NPs to treat GBM cells in vitro, and encourage translational exploration in the future.

From the point of view of drug efficacy and safety, pharmacokinetic profiles of both In this work, a sensitive and reliable liquid chromatographic-tandem mass spectrometric method was established for simultaneous determination of sutetinib and N-oxide metabolite (SNO) in human plasma and further applied to a pharmacokinetic study. Analytes were extracted from plasma samples (100 μl) via acetonitrile-induced protein precipitation and separated on a C 18 column using ammonium acetate with ammonium hydroxide and acetonitrile as the mobile phase. Positive electrospray ionization was carried out through multiple reaction monitoring with transitions of m/z 440.2 → 367.1 and 446.2 → 367.1 for sutetinib and SNO, respectively. The method was linear within the concentration range of 0.5-100 ng/ml for both analytes. The precision, accuracy, selectivity, recovery and matrix effect of this method all met the requirements of bioanalytical guidance. In addition, a plasma stability assessment demonstrated unexpected results. Sutetinib was prone to form covalent conjugates with plasma albumin in vitro. The degree of covalent binding increased with increasing temperature, resulting in a significant decrease in its plasma concentrations. However, SNO could not easily bind with albumin owing to steric hindrance or electronegativity. Furthermore, sutetinib and SNO remained stable when blood and plasma samples were kept on wet ice. The validated method was successfully employed for the pharmacokinetic evaluation of sutetinib in patients with advanced malignant solid tumors., (© 2020 John Wiley & Sons, Ltd.)

Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO 2 ) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO 2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO 2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO 2 -CQ NPs). Results: HSA-MnO 2 -CQ NPs NPs efficiently generated O 2 and increased pH in vitro after reaction with H + /H 2 O 2 and then released the encapsulated CQ in a H + /H 2 O 2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO 2 -CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare., Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model., Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells., Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy., Competing Interests: P. Zhang, A. Darmon, J. Marill, N. Mohamed Anesary, and S. Paris are employees of Nanobiotix. The authors report no other conflicts of interest in this work., (© 2020 Zhang et al.)

Based on the wide use of cobalt substances in a range of important technologies, it has become important to predict the toxicological properties of new or lesser-studied substances as accurately as possible. We studied a group of 6 cobalt substances with inorganic ligands, which were tested for their bioaccessibility (surrogate measure of bioavailability) through in vitro bioelution in simulated gastric and intestinal fluids. Representatives of the group also underwent in vivo blood kinetics and mass balance tests, and both oral acute and repeated dose toxicity (RDT) testing. We were able to show a good correlation between high in vitro bioaccessibility with high in vivo bioavailability and subsequent high in vivo toxicity; consequently, low in vitro bioaccessibility correlated well with low in vivo bioavailability and low in vivo toxicity. In vitro bioelution in simulated gastric fluid was the most precise predictor of the difference in the oral RDT lowest observed adverse effect levels of 2 compounds representing the highly and poorly bioaccessible subset of substances. The 2 compounds cobalt dichloride hexahydrate and tricobalt tetraoxide differed by a factor of 440 in their in vitro bioaccessibility and by a factor of 310 in their RDT lowest observed adverse effect level. In summary, this set of studies shows that solubility, specifically in vitro bioelution in simulated gastric fluid, is a good, yet conservative, predictor of in vivo bioavailability and oral systemic toxicity of inorganic cobalt substances. Bioelution data are therefore an invaluable tool for grouping and read across of cobalt substances for hazard and risk assessment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology.)

Ethnopharmacological Relevance: Pyrrolizidine alkaloids (PAs) are a group of phytotoxins widely present in about 3% of flowering plants. Many PA-containing herbal plants can cause liver injury. Our previous studies demonstrated that PA N-oxides are also hepatotoxic, with toxic potency much lower than the corresponding PAs, due to significant differences in their toxicokinetic fates., Aim of Study: This study aimed to investigate the oral absorption of PAs and PA N-oxides for better understanding of their significant differences in toxicokinetics and toxic potency., Materials and Methods: The oral absorption of PAs and PA N-oxides in rats and in rat in situ single pass intestine perfusion model was investigated. The intestinal permeability and absorption mechanisms of five pairs of PAs and PA N-oxides were evaluated by using Caco-2 monolayer model., Results: The plasma concentrations of total PAs and PA N-oxides within 0-60 min were significantly lower in rats orally treated with a PA N-oxide-containing herbal alkaloid extract than with a PA-containing herbal alkaloid extract at the same dose, indicating that the absorption of PA N-oxides was lower than that of PAs. Using the rat in situ single pass intestine perfusion model, less cumulative amounts of retrorsine N-oxide in mesenteric blood were observed compared to that of retrorsine. In Caco-2 monolayer model, all five PAs showed absorption with P app AtoB values [(1.43-16.26) × 10 -6  cm/s] higher than those of corresponding N-oxides with P app AtoB values lower than 1.35 × 10 -6  cm/s. A further mechanistic study demonstrated that except for senecionine N-oxide, retrorsine N-oxide, and lycopsamine N-oxide, all PAs and PA N-oxides investigated were absorbed via passive diffusion. While, for these 3 PA N-oxides, in addition to passive diffusion as their primary transportation, efflux transporter-mediated active transportation was also involved but to a less extent with the efflux ratio of 2.31-3.41. Furthermore, a good correlation between lipophilicity and permeability of retronecine-type PAs and their N-oxides with absorption via passive diffusion was observed, demonstrating that PAs have a better oral absorbability than that of the corresponding PA N-oxides., Conclusion: We discovered that among many contributors, the lower intestinal absorption of PA N-oxides was the initiating contributor that caused differences in toxicokinetics and toxic potency between PAs and PA N-oxides., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Inflammatory macrophage (Mφ)-mediated atherosclerosis is a leading cause of mortality and morbidity worldwide. Photothermal therapy (PTT) has been demonstrated as an efficient strategy in killing target cells, and its application in the treatment of inflammation in atherosclerosis is developing. However, the choice of nanomaterials, mechanisms, and side effects are seldom considered. In this study, semiconductor nanomaterials, that is, MoO 2 nanoclusters, were synthesized and used for the first time in PTT for inflammatory Mφ-mediated atherosclerosis. Based on cell differential phagocytosis, the optimum amount of MoO 2 and treatment time were selected to exert the maximum ablation effect on Mφ and minimal damage on endothelial cells without requiring additional target or selective groups. Moreover, MoO 2 -based PTT shows an excellent therapeutic effect on atherosclerosis by eliminating Mφ in animal models, with no significant side effects observed. This study explores a new method of nanotechnology and pharmaceutical development by using and optimizing cost-effective metal oxide nanostructures in the treatment of atherosclerosis and motivates further research on minimizing the side effects of related materials.

Benefiting from lower operational costs and energy requirements than do hydrometallurgical and pyrometallurgical processes in metal recovery, the bioleaching of LiCoO 2 through the use of sulfur-oxidizing and iron-oxidizing bacteria has drawn increasing attention. However, the bioleaching mechanism of LiCoO 2 has not been clearly elaborated. In the present study, the effects of the energy source of bacteria, such as Fe 2+ , pyrite and S 0 , and the products of bacterial oxidation, such as Fe 3+ and sulfuric acid, on the chemical leaching of LiCoO 2 were studied. The results indicated that lithium was dissolved by acid, and cobalt was released by the reduction of Fe 2+ and acid dissolution. The recovery of Li + and Co 2+ could be significantly improved by pH adjustment. Finally, optimal recoveries of Li + and Co 2+ were observed in the pyrite group, reaching 91.4% and 94.2%, respectively. By using pyrite as the energy source, the role of bacteria in bioleaching of LiCoO 2 was investigated. The results showed that bacteria could produce sulfuric acid by oxidizing pyrite to promote the mobilization of Li + and Co 2+ . The recovery of lithium and cobalt could be increased to 100.0% and 99.3% by bacteria. Moreover, extracellular polymeric substances secreted by bacteria were found to be a factor for the improvement of Li + and Co 2+ recovery., (Copyright © 2019 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Lead (Pb) is an important pollutant and is released into the environment in many forms. Different lead compounds have a variety of solubilities and so may impact on lead bioavailability and toxicity when added to soil. In this experimental study, we investigated the bioavailability of Pb in soil spiked with 300, 900 and 1500 mg/kg of Pb-acetate, PbCl 2 and PbO using lettuce and wallaby grass. The concentration of Pb in the shoots of both species from control soils (2-3 mg/kg) was similar to previously reported concentrations in plants grown on uncontaminated soils. The Pb concentrations in the plant shoots increased with Pb concentrations in soil for lettuce (R 2  = 0.526, P < 0.001) and wallaby grass (R 2  = 0.776, P < 0.001). This study demonstrated that Pb bioavailability in soil was not affected by the type of Pb compound added to the soil for both plant species up to 1500 mg/kg Pb concentrations. Instead, the Pb concentration in the plant was best predicted by the total concentration of lead in the soil, irrespective of the original lead compound added to the soil. This research suggests that the original Pb compounds that contaminated the soil are unlikely to be an important factor in assessing Pb bioavailability, and hence risk, in soils., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

To evaluate the properties of experimental mineral trioxide aggregate (MTA) resin-modified materials for root-end filling procedures, varying their compositions regarding the addition of hydroxiapatite (HA) or dicalcium phosphate dihydrate, with or without chlorhexidine digluconate. White MTA (Angelus, Londrina, Brazil) was used as a reference material. Degree of conversion (DC) was evaluated by Fourier transformed infrared (FTIr) spectroscopy (n = 5). Flowability (n = 3) and radiopacity (n = 3) were evaluated following ISO 6876:2001 methods. For splitting tensile strength analysis, cylindrical samples (n = 10) were subjected to compressive load using a universal testing machine (Instron Corporation, Norwood, MA). Water sorption and solubility tests were performed according to ISO 4049:2009 methods. Calcium ion release and pH analysis (n = 10) were evaluated using a pH meter (Orion, Watsonville, CA). Cytotoxicity (n = 8) of materials extracts was evaluated as cell viability percentage. Statistical analysis was performed using Kolmogorov-Smirnov for normal distribution and data was subjected to one-way ANOVA and Tukey test (α = 0.05). Addition of chlorhexidine digluconate reduced DC mean values for experimental materials (<50%). White MTA demonstrated lower flowability (5.3 mm) and higher radiopacity (9.8 mm Al), splitting tensile strength (9.1 MPa), solubility (8.2 μg/mm 3 ), calcium ion release (~26.5 ppm), cytotoxicity (55.2%), and pH mean values (10.8), when compared to experimental materials. All groups demonstrated a decrease in calcium release (<85%) and pH (<13%). Formulation containing HA demonstrated similar pH values after 28 days when compared to white MTA. Evaluated experimental resin-modified MTA based materials without chlorhexidine digluconate showed satisfactory results for all physico-chemical properties tested and cytotoxicity. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2195-2201, 2019., (© 2019 Wiley Periodicals, Inc.)

The rapid industrialization and urbanization of intra- and peri-urban areas at the world scale are responsible for the degradation of the quality of edible crops, because of their contamination with airborne pollutants. Their consumption could lead to serious health risks. In this work, we aim to investigate the phytotoxicity induced by foliar transfer of atmospheric particles of industrial/urban origin. Leaves of cabbage plants (Brassica oleracea var. Prover) were contaminated with metal-rich particles (PbSO 4 CuO and CdO) of micrometer size. A trichloroacetic acid (TCA) treatment was used to inhibit the synthesis of the epicuticular waxes in order to investigate their protective role against metallic particles toxicity. Besides the location of the particles on/in the leaves by microscopic techniques, photosynthetic activity measurements, genotoxicity assessment, and quantification of the gene expression have been studied for several durations of exposure (5, 10, and 15 days). The results show that the depletion of epicuticular waxes has a limited effect on the particle penetration in the leaf tissues. The stomatal openings appear to be the main pathway of particles entry inside the leaf tissues, as demonstrated by the overexpression of the BolC.CHLI1 gene. The effects of particles on the photosynthetic activity are limited, considering only the photosynthetic F v /F m parameter. The genotoxic effects were significant for the contaminated TCA-treated plants, especially after 10 days of exposure. Still, the cabbage plants are able to implement repair mechanisms quickly, and to thwart the physiological effects induced by the particles. Finally, the foliar contamination by metallic particles induces no serious damage to DNA, as observed by monitoring the BolC.OGG1 gene.

Arginine-glycine-aspartate (RGD)-carrying microbubbles (MBs) have been utilized as a specific contrast agent for glycoprotein IIb/IIIa (α IIb β 3 integrin)-expressing activated platelets in ultrasound molecular imaging. Recently, we found that surface modification with lactadherin provides the RGD motif on the surface of phosphatidylserine-containing clinically available MBs, Sonazoid. Here, we examined the potential of lactadherin-bearing Sonazoid MBs to be targeted MBs for glycoprotein IIb/IIIa using the custom-designed in vitro settings with recombinant α IIb β 3 integrin, activated platelets or erythrocyte-rich human clots. By modification of the surface with lactadherin, a large number of Sonazoid MBs were attached to the α IIb β 3 integrin-coated and platelet-immobilized plate. Additionally, the video intensity of clots after incubation with lactadherin-bearing Sonazoid MBs was significantly higher than that with unmodified Sonazoid MBs, implying the number of attached Sonazoid MBs was increased by the modification with lactadherin. Our results suggest that the lactadherin-bearing Sonazoid MBs have the potential to be thrombus-targeted MBs., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

A hybrid nanosystem with impeccable cellular imaging and antioxidant functionality is demonstrated. The microwave irradiation-derived molybdenum trioxide nanoparticles (MoO 3 NPs) were surface-functionalized with the cationic dye molecule, methylene blue (MB), which enables superior UV-visible absorbance and fluorescence emission wavelengths potential for bioimaging. The radical scavenging property of the pristine MoO 3 NPs and MoO 3 -MB NPs were studied in vivo using Caenorhabditis elegans as the model system. Heat shock-induced oxidative stress in C. elegans was significantly resolved by the MoO 3 -MB NPs, in agreement with the in vitro radical scavenging study by electron paramagnetic resonance spectroscopy. Hybrid nanostructures of MoO 3 -MB demonstrate synergistic benefits in intracellular imaging with intrinsic biocompatibility and antioxidant behavior, which can facilitate application as advanced healthcare materials toward bioimaging and clinical therapeutics.

In Caenorhabditis elegans, mutation of mlt-7 causes the deficits in epidermal barrier. Using the nematodes with epidermal-specific RNA interference (RNAi) knockdown of mlt-7 as a genetic tool, we found that epidermal-specific RNAi knockdown of mlt-7 resulted in a susceptibility to graphene oxide (GO) toxicity, and enhanced GO accumulation in the body. Epidermal-development related proteins of BLI-1 and IFB-1 acted as downstream targets of MLT-7, and mediated the function of MLT-7 in maintaining the epidermal barrier. Antimicrobial proteins of NLP-30 and CNC-2 also acted as downstream targets of MLT-7 in the regulation of GO toxicity. Epidermal-specific RNAi knockdown of nlp-30 or cnc-2 enhanced GO toxicity and accumulation in bli-1(RNAi) or ifb-1(RNAi) nematodes. Our data highlights the importance of maintaining normal epidermal barrier for nematodes against the GO toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A Mn 3 O 4 nanoparticle (NP)-based dual-modality probe has been developed for tumor positron emission tomography (PET)/magnetic resonance (MR) imaging. The dual-modality imaging probe was constructed by modifying multifunctional polyethyleneimine (PEI)-coated Mn 3 O 4 NPs with folic acid (FA), followed with the radiolabeling with 64 Cu. The formed imaging probe was utilized for PET/MR imaging of human cervical cancer mouse xenografts, which overexpress folate receptor (FR). The PEI-coated Mn 3 O 4 NPs were synthesized using a solvothermal approach via decomposition of acetylacetone manganese. Multifunctional groups, including fluorescein isothiocyanate (FI), PEGylated FA, and NOTA chelator, were then sequentially loaded onto the surface of the amine groups of the Mn 3 O 4 NPs. The remaining PEI amines were neutralized by the acetylation reaction. The resulting NOTA-FA-FI-PEG-PEI-Ac-Mn 3 O 4 NPs were fully characterized and evaluated in vitro and successfully radiolabeled with 64 Cu for tumor PET/MR imaging in small animals. In vivo blocking experiments were performed to determine the FR binding specificity of NPs. PET imaging results demonstrated that 64 Cu-labeled Mn 3 O 4 NPs display good tracer uptake in the FR-expressing HeLa tumors (tumor-to-muscle (T/M) ratio: 5.35 ± 0.31 at 18 h postinjection (pi)) and substantially reduced tracer uptake in the FR-blocked HeLa tumors (T/M ratio: 2.78 ± 0.68 at 18 h pi). The ex vivo data, including PET imaging and biodistribution, further confirmed the tumor binding specificity of the 64 Cu-labeled Mn 3 O 4 NPs. Moreover, the FR-targeted Mn 3 O 4 NPs exhibited efficient T 1 -weighted MR imaging (MRI), leading to the precise tumor MRI at 18 h pi. PET/MR imaging with the 64 Cu-NOTA-FA-FI-PEG-PEI-Ac-Mn 3 O 4 NPs may offer a new quantitative approach to precisely measure the FR in tumors. The strategy of incorporating PEI nanotechnology into the construction of new biomaterials may be applied for the construction of novel nanoplatforms for cancer diagnosis and therapy.

Background: The Traditional Chinese Medicine, arsenic trioxide (ATO, As 2 O 3 ) could inhibit growth and induce apoptosis in a variety of solid tumor cells, but it is severely limited in the treatment of glioma due to its poor BBB penetration and nonspecifcity distribution in vivo., Purpose: The objective of this study was encapsulating ATO in the modified PAMAM den-drimers to solve the problem that the poor antitumor effect of ATO to glioma, which provide a novel angle for the study of glioma treatment., Methods: The targeting drug carrier (RGDyC-mPEG-PAMAM) was synthesized based on Arg-Gly-Asp (RGDyC) and αvβ3 integrin targeting ligand, and conjugated to PEGylated fifth generation polyamidoamine dendrimer (mPEG-PAMAM). It was characterized by nuclear magnetic resonance, fourier transform infrared spectra, Nano-particle size-zeta potential analyzer,etc. The in vitro release characteristics were studied by dialysis bag method. MTT assay was used to investigate the cytotoxicity of carriers and the antitumor effect of ATO formulation. In vitro blood-brain barrier (BBB) and C6 cell co-culture models were established to investigate the inhibitory effect of different ATO formulation after transporting across BBB. Pharmacokinetic and antitumor efficacy studies were investigated in an orthotopic murine model of C6 glioma., Results: The prepared RGDyC-mPEG-PAMAM was characterized for spherical dendrites, comparable size (21.60±6.81 nm), and zeta potential (5.36±0.22 mV). In vitro release showed that more ATO was released from RGDyC-mPEG-PAMAM/ATO (79.5%) at pH 5.5 than that of pH 7.4, during 48 hours. The cytotoxicity of PEG-modified carriers was lower than that of the naked PAMAM on both human brain microvascular endothelial cells and C6 cells. In in vitro BBB model, modification of RGDyC heightened the cytotoxicity of ATO loaded on PAMAM, due to an increased uptake by C6 cells. The results of cell cycle and apoptosis analysis revealed that RGDyC-mPEG-PAMAM/ATO arrested the cell cycle in G2-M and exhibited threefold increase in percentage of apoptosis to that in the PEG-PAMAM/ATO group. Compared with ATO-sol group, both RGDyC-mPEG-PAMAM/ATO and mPEG-PAMAM/ATO groups prolonged the half-life time, increased area under the curve, and improved antitumor effect, significantly. While the tumor volume inhibitory of RGDyC-mPEG-PAMAM/ATO was 61.46±12.26%, it was approximately fourfold higher than the ATO-sol group, and twofold to the mPEG-PAMAM/ATO group., Conclusion: In this report, RGDyC-mPEG-PAMAM could enhance the antitumor of ATO to glioma, it provides a desirable strategy for targeted therapy of glioma., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Photodynamic therapy (PDT) holds promise in biochemical study and tumor treatment. A novel multifunctional nanosystem CaO 2 /MnO 2 @polydopamine (PDA)-methylene blue (MB) nanosheet (CMP-MB) was designed. CaO 2 nanoparticles were encapsulated by MnO 2 nanosheet, and then PDA was coated on the surface of CaO 2 /MnO 2 nanosheets, which could adsorb photosensitizer MB through hydrophobic interaction or π-π stacking. In this nanosystem, CaO 2 /MnO 2 had the ability of self-production of oxygen, which solved the problem of tumor hypoxia largely. Moreover, it is worth mentioning that the fluorescence of MB was suppressed by MnO 2 , while its emission was triggered in the simulated tumor microenvironment. Therefore, CMP-MB nanosheet could be used to switch-control cell imaging potentially. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide testing and Live/Dead assay confirmed CMP-MB nanosheet had fewer side effects without illumination while it destroyed Hela cell with the illumination of light. Vitro cell experiment demonstrated CMP-MB nanosheet could achieve tumor microenvironment responsive imaging and inhibit tumor cell growth under illumination effectively. Therefore, the system has great potential for PDT application and switch-control tumor cell imaging. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2544-2552, 2018., (© 2018 Wiley Periodicals, Inc.)

Background and Objective: Nefopam is a non-opioid, non-steroidal, central analgesic thought to act via multiple mechanisms including potent inhibition of serotonin-norepinephrine reuptake and modulation of voltage-sensitive calcium and sodium channels. There has been a resurgence in its use for postoperative pain and neuropathic pain. Dosing route-dependent metabolism and clinical effects have been described following intravenous and oral nefopam. N-desmethylnefopam and nefopam N-oxide are metabolites of clinical interest. We sought to develop a joint pharmacokinetic model to simultaneously describe the plasma and urinary pharmacokinetics of nefopam and the two metabolites following an oral pharmacological dose of [ 14 C]-nefopam to healthy volunteers, and to estimate inter-individual variability in their pharmacokinetics., Methods: Pharmacokinetic data for the parent and metabolites were analyzed simultaneously using NONMEM ® (nonlinear mixed-effect modeling) v7.3. The modeling process evaluated, in part, one- and two-compartment linear pharmacokinetic models for nefopam and a single compartment for each of the two metabolites. Pathways for presystemic metabolism of both metabolites were explored., Results: The final structural model simultaneously described the plasma and urinary pharmacokinetics of nefopam and the two metabolites. It consists of a central compartment for nefopam and for each of the two metabolites, as well as a peripheral compartment for the parent, and the associated urine compartments. The rapid formation and appearance of the N-oxide in plasma, characterized by concentrations that peak earlier than the parent, could be described by presystemic formation in the gastrointestinal tract., Conclusions: A descriptive, robust and predictive parent-metabolite model has been developed using a population mixed-effects approach to characterize the pharmacokinetics of nefopam and its metabolites simultaneously in healthy subjects following oral administration of nefopam. The model may be used for dose selection, analysis of sparse data, identification of intrinsic and extrinsic factors, and to model the clinical effects of each analyte.

Following inhalation of an aerosol of relatively insoluble particles, it is usually found that the fractional dissolution rate of material retained in the lungs decreases with time, and the amount remaining undissolved can be represented simply by a decreasing exponential function with two or more components. A few exceptions are known, in which the dissolution rate increases with time. The most important in the context of radiological protection is probably that of 238 Pu dioxide. Several published comprehensive data sets, from animal studies and accidental human exposures, have been analysed using the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection. The HRTM contains a simplified representation of particle dissolution in the respiratory tract, suitable for routine radiological protection purposes. Still, it was found to have sufficient flexibility to represent the measurement data in most of these cases. Although the 238 Pu dioxide showed a wide range of behaviour in the different studies, there was good agreement between the absorption behaviour modelled for two studies involving 'ceramic' 238 Pu dioxide as used in spacecraft radioisotope thermoelectric generators: a long-term experimental study in dogs and an accidental exposure involving a group of workers.

Lead nanoparticles (NPs) are released into air from metal processing, road transport or combustion processes. Inhalation exposure is therefore very likely to occur. However, even though the effects of bulk lead are well known, there is limited knowledge regarding impact of Pb NPs inhalation. This study focused on acute and subchronic exposures to lead oxide nanoparticles (PbO NPs). Mice were exposed to PbO NPs in whole body inhalation chambers for 4-72 h in acute experiment (4.05 × 10 6 PbO NPs/cm 3 ), and for 1-11 weeks in subchronic experiment (3.83 × 10 5 particles/cm 3 in lower and 1.93 × 10 6 particles/cm 3 in higher exposure group). Presence of NPs was confirmed in all studied organs, including brain, which is very important considering lead neurotoxicity. Lead concentration gradually increased in all tissues depending on the exposure concentration and duration. The most burdened organs were lung and kidney, however liver and brain also showed significant increase of lead concentration during exposure. Histological analysis documented numerous morphological alterations and tissue damage, mainly in lung, but also in liver. Mild pathological changes were observed also in kidney and brain. Levels of glutathione (reduced and oxidized) were modulated mainly in lung in both, acute and subchronic exposures. Increase of lipid peroxidation was observed in kidney after acute exposure. This study characterized impacts of short to longer-term inhalation exposure, proved transport of PbO NPs to secondary organs, documented time and concentration dependent gradual increase of Pb concentration and histopathological damage in tissues.

Rechargeable Li-ion batteries (LIB) are increasingly produced and used worldwide. LIB electrodes are made of micrometric and low solubility particles, consisting of toxicologically relevant elements. The health hazard of these materials is not known. Here, we investigated the respiratory hazard of three leading LIB components (LiFePO 4 or LFP, Li 4 Ti 5 O 12 or LTO, and LiCoO 2 or LCO) and their mechanisms of action. Particles were characterized physico-chemically and elemental bioaccessibility was documented. Lung inflammation and fibrotic responses, as well as particle persistence and ion bioavailability, were assessed in mice after aspiration of LIB particles (0.5 or 2 mg); crystalline silica (2 mg) was used as reference. Acute inflammatory lung responses were recorded with the 3 LIB particles and silica, LCO being the most potent. Inflammation persisted 2 m after LFP, LCO and silica, in association with fibrosis in LCO and silica lungs. LIB particles persisted in the lungs after 2 m. Endogenous iron co-localized with cobalt in LCO lungs, indicating the formation of ferruginous bodies. Fe and Co ions were detected in the broncho-alveolar lavage fluids of LFP and LCO lungs, respectively. Hypoxia-inducible factor (HIF) -1α, a marker of fibrosis and of the biological activity of Co ions, was upregulated in LCO and silica lungs. This study identified, for the first time, the respiratory hazard of LIB particles. LCO was at least as potent as crystalline silica to induce lung inflammation and fibrosis. Iron and cobalt, but not lithium, ions appear to contribute to LFP and LCO toxicity, respectively.

Objectives: The arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first-line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated., Methods: Effects of ATO on platelet aggregation and adhesion were evaluated in vitro and in thirty-two complete remission (CR) and four newly diagnosed APL patients. Furthermore, concentrations of plasma total arsenic were monitored in APL patients via ICP-MS., Results: The inhibition of platelet function, either aggregation or adhesion, did occur in vitro when the concentration of ATO reached 2 μmol/L. However, in CR APL patients receiving ATO with normal platelet count, the platelets responded normally when being activated and so did those in the newly diagnosed patients with thrombocytopenia. Our data further showed that the conventional dosage of ATO reached a plasma concentration substantially below the required concentration to inhibit platelets., Conclusions: In the first-line treatment of APL, the use of ATO is safe and effective and does not compromise the hemostatic potential that may eventually increase ED rate., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tagging recognition group(s) on superparamagnetic iron oxide is known to aid localisation (imaging), stimulation and separation of biological entities using magnetic resonance imaging (MRI) and magnetic agitation/separation (MAS) techniques. Despite the wide applicability of iron oxide nanoparticles in T 2 -weighted MRI and MAS, the quality of the images and safe manipulation of the exceptionally delicate neural cells in a live brain are currently the key challenges. Here, we demonstrate the engineered manganese oxide clusters-iron oxide core-shell nanoparticle as an MR dual-modal contrast agent for neural stem cells (NSCs) imaging and magnetic manipulation in live rodents. As a result, using this engineered nanoparticle and associated technologies, identification, stimulation and transportation of labelled potentially multipotent NSCs from a specific location of a live brain to another by magnetic means for self-healing therapy can therefore be made possible.

Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Lead is well known environmental pollutant, which can cause toxic effects in multiple organ systems. However, the influence of lead oxide nanoparticles, frequently emitted to the environment by high temperature technological processes, is still concealed. Therefore, we investigate lead oxide nanoparticle distribution through the body upon their entry into lungs and determine the microscopic and ultramicroscopic changes caused by the nanoparticles in primary and secondary target organs., Methods: Adult female mice (ICR strain) were continuously exposed to lead oxide nanoparticles (PbO-NPs) with an average concentration approximately 10 6 particles/cm 3 for 6 weeks (24 h/day, 7 days/week). At the end of the exposure period, lung, brain, liver, kidney, spleen, and blood were collected for chemical, histological, immunohistochemical and electron microscopic analyses., Results: Lead content was found to be the highest in the kidney and lungs, followed by the liver and spleen; the smallest content of lead was found in brain. Nanoparticles were located in all analysed tissues and their highest number was found in the lung and liver. Kidney, spleen and brain contained lower number of nanoparticles, being about the same in all three organs. Lungs of animals exposed to lead oxide nanoparticles exhibited hyperaemia, small areas of atelectasis, alveolar emphysema, focal acute catarrhal bronchiolitis and also haemostasis with presence of siderophages in some animals. Nanoparticles were located in phagosomes or formed clusters within cytoplasmic vesicles. In the liver, lead oxide nanoparticle exposure caused hepatic remodeling with enlargement and hydropic degeneration of hepatocytes, centrilobular hypertrophy of hepatocytes with karyomegaly, areas of hepatic necrosis, occasional periportal inflammation, and extensive accumulation of lipid droplets. Nanoparticles were accumulated within mitochondria and peroxisomes forming aggregates enveloped by an electron-dense mitochondrial matrix. Only in some kidney samples, we observed areas of inflammatory infiltrates around renal corpuscles, tubules or vessels in the cortex. Lead oxide nanoparticles were dispersed in the cytoplasm, but not within cell organelles. There were no significant morphological changes in the spleen as a secondary target organ. Thus, pathological changes correlated with the amount of nanoparticles found in cells rather than with the concentration of lead in a given organ., Conclusions: Sub-chronic exposure to lead oxide nanoparticles has profound negative effects at both cellular and tissue levels. Notably, the fate and arrangement of lead oxide nanoparticles were dependent on the type of organs.

Several efficient stabilizing amendments have been recently proposed for the remediation of metal(loid)-contaminated soils. However, information on their interactions with plants, which is a crucial factor in soil environments, are still scarce. An amorphous manganese oxide (AMO) synthesized from organic compounds and nano zerovalent iron (nZVI) have been previously tested as promising stabilizing agents usable both for the stabilization of metals and As. Experiments with rhizoboxes were performed in order to evaluate their influence on the mobility of metal(loid)s in the bulk soil and rhizosphere of sunflower (Helianthus annuus L.) together with their impact on metal uptake and biomass yield. Generally, AMO proved more efficient than nZVI in all stages of experiment. Furthermore, the AMO effectively reduced water- and 0.01 M CaCl 2 -extractable fractions of Cd, Pb and Zn. The decreased bioavailability of contaminating metal(loid)s resulted in significant increase of microbial activity in AMO-amended soil. Together with metal(loid) extractability, the AMO was also able to significantly reduce the uptake of metals and ameliorate plant growth, especially in the case of Zn, since this metal was taken up in excessive amounts from the control soil causing strong phytotoxicity and even death of young seedlings. On the other hand, AMO application lead to significant release of Mn that was readily taken up by plants. Resulting Mn concentrations in biomass exceeded toxicity thresholds while plants were showing emergent Mn phytotoxicity symptoms. We highlight the need of such complex studies involving plants and soil biota when evaluating the efficiency of stabilizing amendments in contaminated soils., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The aim of this study was to evaluate and compare the calcium (Ca2+) and hydroxide (OH-) ion release of 4 artificially produced pulp capping materials (MTA, Biodentin, TheraCal LC, Calsimol) used for indirect pulp capping treatment., Methods: In total, 70 freshly extracted human third molar teeth were used for the study. Cavities of extracted teeth were prepared by round burs. The remaining dentin thickness (1 ± 0.3 mm) tissue was measured by a micrometer and cone beam computerized tomography. Indirect pulp capping was performed in the cavities using Calcimol, MTA, TheraCal LC and Biodentin. The leached Ca2+ were measured using optical emission spectrometry and the release of OH- ions using a pH meter. The measurements were performed after 24 hours, 7 days and 28 days in saline solution. Statistical analysis was performed using 1-way and 2-way analysis of variance (ANOVA) tests (p<0.05)., Results: Ca2+ ions were detected in treated saline solution during the experimental period for all materials. All the measurements of Biodentin and Theracal LC levels for Ca2+ ions were higher than those of the other materials (p<0.05). For all materials, Ca2+-ion release increased during the first 7 days followed by a linear decrease during the subsequent study periods. The Biodentine group showed the highest OH- ion rates compared to the other materials in the 24-hour examination period, while the scores gradually decreased during the subsequent measurement periods (p<0.05)., Conclusions: Tricalcium silicate materials such as Biodentine and TheraCal LC used in this study may be preferable for indirect pulp capping because of their stimulation of hard tissue formation and ion-releasing ability.

Graphene, a 2D carbon material has found vast application in biomedical field because of its exciting physico-chemical properties. The large planar sheet like structure helps graphene to act as an effective carrier of drug or biomolecules in enormous amount. However, limited data available on the biocompatibility of graphene upon interaction with the biological system prompts us to evaluate their toxicity in animal model. In this study organ distribution, clearance and toxicity of PEGylated reduced nanographene (PrGO) on Swiss Albino mice was investigated after intraperitoneal and intravenous administration. Biodistribution and blood clearance was monitored using confocal Raman mapping and indicated that PrGO was distributed on major organs such as brain, liver, kidney, spleen and bone marrow. Presence of PrGO in brain tissue suggests that it has the potential to cross blood brain barrier. Small amount of injected PrGO was found to excrete via urine. Repeated administration of PrGO induced acute liver injury, congestion in kidney and increased splenocytes proliferation in days following exposure. Hence the result of the study recommended that PrGO should undergo intensive safety assessment before clinical application or validated to be safe for medical use., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In severe cases of status asthmaticus, when conventional therapies fail, volatile anesthetic agents remain a therapeutic option. When delivered outside of the operating room setting, specialized delivery techniques are needed to ensure the safe and effective use of volatile anesthetic agents. We present a 16-year-old adolescent with status asthmaticus who required the therapeutic administration of the volatile anesthetic agent, sevoflurane, in the pediatric intensive care unit (PICU). Although initially effective in reducing bronchospasm, progressive hypercarbia developed due to defective functioning of the carbon dioxide absorber of the anesthesia machine. This failure occurred as the soda lime compartment filled with water accumulated from circuit humidification and continuous albuterol therapy. The role of volatile anesthetic agents in the treatment of status asthmaticus in the PICU is discussed, options for delivery outside of the operating room presented, and potential problems with delivery reviewed.

Quantitative feature - activity relationships (QFAR) approach was applied to prediction of bioavailability of metal oxide nanoparticles. ZnO, CuO, Co 3 O 4 , and TiO 2 nanoxides were considered. The computational model for bioavailability of investigated species is asserted. The model was calculated using the Monte Carlo method. The CORAL free software (http://www.insilico.eu/coral) was used in this study. The developed model was tested by application of three different splits of data into the training and validation sets. So-called, quasi-SMILES are used to represent the conditions of action of metal oxide nanoparticles. A new paradigm of building up predictive models of endpoints related to nanomaterials is suggested. The paradigm is the following "An endpoint is a mathematical function of available eclectic data (conditions)". Recently, the paradigm has been checked up with endpoints related to metal oxide nanoparticles, fullerenes, and multi-walled carbon-nanotubes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sonazoid is an ultrasound contrast agent based on microbubbles (MB) containing perfluorobutane (PFB) gas. Sonazoid is approved in Japan, Korea and Norway for contrast-enhanced ultrasonography of focal liver lesions and focal breast lesions (Japan only). The objective of this study was to determine the pharmacokinetics (PKs) and safety of Sonazoid in Chinese healthy volunteers (HVs) and to evaluate the potential for ethnic differences in PKs between Chinese and Caucasian HVs. Sonazoid was administered as an intra-venous bolus injection at the clinical dose of 0.12 μL or 0.60 μL MB/kg body weight to two groups of eight Chinese HVs. Expired air and blood samples were collected and analyzed using a validated gas chromatographic tandem mass spectrometry method, and the main PK parameters were calculated. The highest PFB concentrations in blood were observed shortly after intra-venous administration of Sonazoid, and elimination of PFB was rapid. In the 0.12 μL MB/kg body weight cohort, PFB concentrations above the limit of quantification were observed for only 10 to 15 min post-injection. In the 0.60 μL MB/kg body weight cohort, PFB concentrations above the limit of quantification were observed for 60 min post-injection, and the shape of the elimination curve suggested a biphasic elimination profile. The maximum observed concentration (C max ) values of PFB in blood were 2.3 ± 1.1 and 19.1 ± 9.2 ng/g for the 0.12 and 0.60 μL MB/kg body weight dose groups (mean ± standard deviation). Area under the curve values were 10.1 ± 2.7 and 90.1 ± 38.3 ng × min/g for the 0.12 and 0.60 μL MB/kg body weight dose groups. C max values of PFB in exhaled air were 0.35 ± 0.2 and 2.4 ± 0.7 ng/mL for the 0.12 and 0.60 μL MB/kg body weight dose groups. Assessment of laboratory parameters, vital signs, oxygen saturation and electrocardiograms revealed no changes indicative of a concern. The PK profile and safety data generated in the Chinese HVs were comparable to previous data for Caucasian HVs., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Manganese (Mn) is neurotoxic and can induce manganism, a Parkinson-like disease categorized as being a serious central nervous system irreversible neurodegenerative disease. An increased risk of developing symptoms of Parkinson disease has been linked to work-related exposure, for example, for workers in agriculture, horticulture, and people living near areas with frequent use of Mn-containing pesticides. In this study, the focus was placed on neurochemical effects of Mn. Rats were dosed intraperitoneally with 0.9% NaCl (control), 1.22 mg Mn (as MnO 2 )/kg bodyweight (bw)/day, or 2.5 mg Mn (as MnCl 2 )/kg bw/day for 7 d/wk for 8 or 12 weeks. This dosing regimen adds relevant new knowledge about Mn neurotoxicity as a consequence of low-dose subchronic Mn dosing. Manganese concentrations increased in the striatum, the rest of the brain, and in plasma, and regional brain neurotransmitter concentrations, including noradrenaline, dopamine (DA), 5-hydroxytrytamine, glutamate, taurine, and γ-amino butyric acid, and the activity of acetylcholinesterase changed. Importantly, a target parameter for Parkinson disease and manganism, the striatal DA concentration, was reduced after 12 weeks of dosing with MnCl 2 . Plasma prolactin concentration was not significantly affected due to a potentially reduced dopaminergic inhibition of the prolactin release from the anterior hypophysis. No effects on the striatal α-synuclein and synaptophysin protein levels were detected.

Pharmaceutical industries spend more money in developing new and efficient methods for delivering successful drugs for anticancer therapy. Electrospun nanofibers and nanoparticles loaded with drugs have versatile biomedical applications ranging from wound healing to anticancer therapy. We aimed to attempt for fabricating elastomeric poly (l-lactic acid-co-ε-caprolactone) (PLACL) with Aloe Vera (AV), magnesium oxide (MgO) nanoparticles, curcumin (CUR) and β-cyclodextrin (β-CD) composite nanofibers to control the growth of MCF-7 cells for breast cancer therapy. The study focused on the interaction of MgO nanoparticle with CUR and β-CD inhibiting the proliferation of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. FESEM micrographs of fabricated electrospun PLACL, PLACL/AV, PLACL/AV/MgO, PLACL/AV/MgO/CUR and PLACL/AV/MgO/β-CD nanofibrous scaffolds achieved bead free, random and uniform nanofibers with fiber diameter in the range of 786±286, 507±171, 334±95, 360±94 and 326±80nm respectively. Proliferation of MCF-7 cells was decreased by 65.92% in PLACL/AV/MgO/CUR with respect to PLACL/AV/MgO nanofibrous scaffolds on day 9. The obtained results proved that 1% CUR interacting with MgO nanoparticles showed higher inhibition of MCF-7 cells among all other nanofibrous scaffolds thus serving as a promising biocomposite material system for the breast cancer therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Extensive industrial and military uses of tungsten have raised the possibilities of human occupational and environmental exposure to nanoparticles of this metal, with concomitant health concerns. The goal of this study was to investigate the potential mechanism of pulmonary toxicity associated with inhaled tungsten (IV) oxide nanoparticles (WO 3 NPs) in Golden Syrian Hamsters. Animals exposed to WO 3 NPs via inhalation were divided into three groups - control and two treatment groups exposed to either 5 or 10 mg/m 3 of aerosolized WO 3 NPs for 4 h/day for four days. A long-term exposure study (4 h/day for eight days) was also carried out using an additional three groups. Pulmonary toxicity assessed by examining changes in cell numbers, lactate dehydrogenase activity, alkaline phosphatase activity, total protein content, TNF-α, and HMGB1 levels in bronchoalveolar lavage fluids showed a significant difference when compared to control (P < 0.05). The molecular mechanism was established by assessing protein expression of cathepsin B, TXNIP, NLRP3, ASC, IL-1β and caspase-1. Western blot analysis indicated a 1.5 and 1.7 fold changes in NLRP3 in treatment groups (5 mg/m 3 , P < 0.05 and 10 mg/m 3 , P < 0.01, respectively), whereas levels of cathepsin B were 1.3 fold higher in lung tissue exposed to WO 3 NPs suggesting activation of inflammasome pathway. Morphological changes studied using light and electron microscopy showed localization of nanoparticles and subsequent perturbation in airway epithelia, macrophages, and interstitial areas of alveolar structures. Results from the current study indicate that inhalation exposure to WO 3 NPs may induce cytotoxicity, morphological changes, and lung injury via pyroptotic cell death pathway caused by activation of caspase-1., (© 2016 by the Society for Experimental Biology and Medicine.)

Four resected specimens of hepatic angiomyolipoma in which uptake of Sonazoid was observed in the postvascular phase of Sonazoid-enhanced ultrasonography were analyzed. Macrophage localization in the tumor was revealed pathologically by immunohistochemical staining for CD68. CD68-positive cells were observed in the tumor in all cases. The density of CD68-positive cells was 100/mm2, and the ratio of CD68-positive cell density in the tumor to that in the surrounding parenchyma was 32-171%. These results suggested that the uptake of the contrast agent Sonazoid was related to the density of CD68-positive cells., (© 2016 S. Karger AG, Basel.)

Purpose: AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior., Methods: Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d ) and absorption (R a ) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath ) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds., Results: The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased., Conclusion: A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs., Competing Interests: Shinya Uchida and Tsutomu Kotegawa have received advisory fees from KUREHA CORPORATION.

Background: Calcium-enriched mixture (CEM) cement is used in the field of endodontics. It is similar to mineral trioxide aggregate in its main ingredients. The present study investigated the effect of different mixing methods on the bacterial microleakage of CEM cement., Methods: A total of 55 human single-rooted human permanent teeth were decoronated so that 14-mm-long samples were obtained and obturated with AH26 sealer and gutta-percha using lateral condensation technique. Three millimeters of the root end were cut off and randomly divided into 3 groups of 15 each (3 mixing methods of amalgamator, ultrasonic and conventional) and 2 negative and positive control groups (each containing 5 samples). BHI (brain-heart infusion agar) suspension containing Enterococcus faecalis was used for bacterial leakage assessment. Statistical analysis was carried out using descriptive statistics, Kaplan-Meier survival analysis with censored data and log rank test. Statistical significance was set at P<0.05., Results: The survival means for conventional, amalgamator and ultrasonic methods were 62.13±12.44, 68.87±12.79 and 77.53±12.52 days, respectively. The log rank test showed no significant differences between the groups., Conclusions: Based on the results of the present study it can be concluded that different mixing methods had no significant effect on the bacterial microleakage of CEM cement.

Vanadium is an important ultra-trace element derived from fuel product combustion. With the development of nanotechnology, vanadium oxide nanoparticles (VO NPs) have been considered for application in various fields, thus the possibility of release into the environment and human exposure is also increasing. Considering that verification of bioaccumulation and relevant biological responses are essential for safe application of products, in this study, we aimed to identify the physicochemical properties that determine their health effects by comparing the biological effects and tissue distribution of different types of VO NPs in mice. For this, we prepared five types of VO NPs, commercial (C)-VO2 and -V2O5 NPs and synthetic (S)-VO2, -V2O3, and -V2O5 NPs. While the hydrodynamic diameter of the two types of C-VO NPs was irregular and impossible to measure, those of the three types of S-VO NPs was in the range of 125-170nm. The S- and C-V2O5 NPs showed higher dissolution rates compared to other VO NPs. We orally dosed the five types of VO NPs (70 and 210μg/mouse, approximately 2 and 6mg/kg) to mice for 28 days and compared their biodistribution and toxic effects. We found that S-V2O5 and S-V2O3 NPs more accumulated in tissues compared to other three types of VO NPs, and the accumulated level was in order of heart>liver>kidney>spleen. Additionally, tissue levels of redox reaction-related elements and electrolytes (Na(+), K(+), and Ca(2+)) were most clearly altered in the heart of treated mice. Notably, all S- and C-VO NPs decreased the number of WBCs at the higher dose, while total protein and albumin levels were reduced at the higher dose of S-V2O5 and S-V2O3 NPs. Taken together, we conclude that the biodistribution and toxic effects of VO NPs depend on their dissolution rates and size (surface area). Additionally, we suggest that further studies are needed to clarify effects of VO NPs on functions of the heart and the immune system., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although classified as metal oxides, cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles, as representative transition and rare earth oxides, exhibit distinct material properties that may result in different hazardous potential in the lung. The current study was undertaken to compare the pulmonary effects of aerosolized whole body inhalation of these nanoparticles in mice., Results: Mice were exposed to filtered air (control) and 10 or 30 mg/m(3) of each particle type for 4 days and then examined at 1 h, 1, 7 and 56 days post-exposure. The whole lung burden 1 h after the 4 day inhalation of CoO nanoparticles was 25 % of that for La2O3 nanoparticles. At 56 days post exposure, < 1 % of CoO nanoparticles remained in the lungs; however, 22-50 % of the La2O3 nanoparticles lung burden 1 h post exposure was retained at 56 days post exposure for low and high exposures. Significant accumulation of La2O3 nanoparticles in the tracheobronchial lymph nodes was noted at 56 days post exposure. When exposed to phagolysosomal simulated fluid, La nanoparticles formed urchin-shaped LaPO4 structures, suggesting that retention of this rare earth oxide nanoparticle may be due to complexation of cellular phosphates within lysosomes. CoO nanoparticles caused greater lactate dehydrogenase release in the bronchoalveolar fluid (BALF) compared to La2O3 nanoparticles at 1 day post exposure, while BAL cell differentials indicate that La2O3 nanoparticles generated more inflammatory cell infiltration at all doses and exposure points. Histopathological analysis showed acute inflammatory changes at 1 day after inhalation of either CoO or La2O3 nanoparticles. Only the 30 mg/m(3) La2O3 nanoparticles exposure caused chronic inflammatory changes and minimal fibrosis at day 56 post exposure. This is in agreement with activation of the NRLP3 inflammasome after in vitro exposure of differentiated THP-1 macrophages to La2O3 but not after CoO nanoparticles exposure., Conclusion: Taken together, the inhalation studies confirmed the trend of our previous sub-acute aspiration study, which reported that CoO nanoparticles induced more acute pulmonary toxicity, while La2O3 nanoparticles caused chronic inflammatory changes and minimal fibrosis.

During the last decades, several studies have proposed manganese (Mn) complexes as alternative contrast agents for magnetic resonance imaging (MRI). With the nanotechnology surge in recent years, different types of Mn-based nanoparticles (Nps) have been developed. However, to design effective and safe administration procedures, preliminary studies on target cells, aimed at verifying their full biocompatibility and biodegradability, are mandatory. In this study, MnO containing-Nps encapsulated in a phospholipidic shell (PL-MnO Nps) were tested in cultured cells and flow cytometry; confocal and transmission electron microscopy were combined to understand the Nps uptake mechanism, intracellular distribution and degradation pathways, as well as possible organelle alterations. The results demonstrated that PL-MnO Nps undergo rapid and massive cell internalization, and persist free in the cytoplasm before undergoing lysosomal degradation without being cytotoxic or inducing subcellular damage. Based on the results with this cell model in vitro, PL-MnO Nps thus proved to be suitably biocompatible, and may be envisaged as very promising tools for therapeutic and diagnostic applications, as drug carriers or contrast agent for MRI., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Parenteral arsenic trioxide (ATO) has been firmly established as a standard therapy for acute promyelocytic leukemia (APL). Despite widespread use of oral arsenicals in medicine historically, they had disappeared from modern pharmacopeia until oral ATO was redeveloped in Hong Kong in 2000. Since then, over 200 patients with leukemia (predominantly APL) have been treated with oral ATO in Hong Kong and China. Oral arsenic trioxide and other formulations of arsenic appear to have a clinical efficacy comparable to that of IV formulations. These drugs given orally also appear to have a slightly better safety profile, lower operational costs and improved convenience for patients. The clinical experience with oral ATO has previously been reported piecemeal as case series, pilot studies or subgroup analyses rather than in a comprehensive cohort. In this report we attempt to synthesize the published English language literature on oral arsenicals and present the argument for further development of these compounds. Systematic study of this drug with well-designed randomized multi-center clinical trials is needed to accelerate its development and incorporation into clinical practice., (Copyright © 2015 Elsevier Ltd. All rights reserved.)