Alginate Beads Containing Cerium-Doped Mesoporous Glass and Curcumin: Delivery and Stabilization of Therapeutics.

Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce3+/Ce4+ and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce3+/Ce4+. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing.

Controlled decoration of nanoceria on the surface of MoS2nanoflowers to improve the biodegradability and biocompatibility inDrosophila melanogastermodel.

In recent years, nanozymes based on two-dimensional (2D) nanomaterials have been receiving great interest for cancer photothermal therapy. 2D materials decorated with nanoparticles (NPs) on their surface are advantageous over conventional NPs and 2D material based systems because of their ability to synergistically improve the unique properties of both NPs and 2D materials. In this work, we report a nanozyme based on flower-like MoS2nanoflakes (NFs) by decorating their flower petals with NCeO2using polyethylenimine (PEI) as a linker molecule. A detailed investigation on toxicity, biocompatibility and degradation behavior of fabricated nanozymes in wild-typeDrosophila melanogastermodel revealed that there were no significant effects on the larval size, morphology, larval length, breadth and no time delay in changing larvae to the third instar stage at 7-10 d for MoS2NFs before and after NCeO2decoration. The muscle contraction and locomotion behavior of third instar larvae exhibited high distance coverage for NCeO2decorated MoS2NFs when compared to bare MoS2NFs and control groups. Notably, the MoS2and NCeO2-PEI-MoS2NFs treated groups at 100µg ml-1covered a distance of 38.2 mm (19.4% increase when compared with control) and 49.88 mm (no change when compared with control), respectively. High-resolution transmission electron microscopy investigations on the new born fly gut showed that the NCeO2decoration improved the degradation rate of MoS2NFs. Hence, nanozymes reported here have huge potential in various fields ranging from biosensing, cancer therapy and theranostics to tissue engineering and the treatment of Alzheimer's disease and retinal therapy.

Combinatory Effects of Cerium Dioxide Nanoparticles and Acetaminophen on the Liver-A Case Study of Low-Dose Interactions in Human HuH-7 Cells.

The interactions between pharmaceuticals and nanomaterials and its potentially resulting toxicological effects in living systems are only insufficiently investigated. In this study, two model compounds, acetaminophen, a pharmaceutical, and cerium dioxide, a manufactured nanomaterial, were investigated in combination and individually. Upon inhalation, cerium dioxide nanomaterials were shown to systemically translocate into other organs, such as the liver. Therefore we picked the human liver cell line HuH-7 cells as an in vitro system to investigate liver toxicity. Possible synergistic or antagonistic metabolic changes after co-exposure scenarios were investigated. Toxicological data of the water soluble tetrazolium (WST-1) assay for cell proliferation and genotoxicity assessment using the Comet assay were combined with an untargeted as well as a targeted lipidomics approach. We found an attenuated cytotoxicity and an altered metabolic profile in co-exposure experiments with cerium dioxide, indicating an interaction of both compounds at these endpoints. Single exposure against cerium dioxide showed a genotoxic effect in the Comet assay. Conversely, acetaminophen exhibited no genotoxic effect. Comet assay data do not indicate an enhancement of genotoxicity after co-exposure. The results obtained in this study highlight the advantage of investigating co-exposure scenarios, especially for bioactive substances.

Chemo-Protective Potential of Cerium Oxide Nanoparticles against Fipronil-Induced Oxidative Stress, Apoptosis, Inflammation and Reproductive Dysfunction in Male White Albino Rats.

Fipronil (FIP) is an insecticide commonly used in many fields, such as agriculture, veterinary medicine, and public health, and recently it has been proposed as a potential endocrine disrupter. The purpose of this study was to inspect the reproductive impacts of FIP and the possible protective effects of cerium nanoparticles (CeNPs) on male albino rats. Rats received FIP (5 mg/kg bwt; 1/20 LD50), CeNPs (35 mg/kg bwt) and FIP+CeNPs per os daily for 28 days. Serum testosterone levels, testicular oxidative damage, histopathological and immunohistochemical changes were evaluated. FIP provoked testicular oxidative damage as indicated by decreased serum testosterone (≈60%) and superoxide dismutase (≈50%), glutathione peroxidase activity (≈46.67%) and increased malondialdehyde (≈116.67%) and nitric oxide (≈87.5%) levels in testicular tissues. Furthermore, FIP induced edematous changes and degeneration within the seminiferous tubules, hyperplasia, vacuolations, and apoptosis in the epididymides. In addition, FIP exposure upregulated interleukin-1ß (IL-1ß), nitric oxide synthase 2 (NOS), caspase-3 (Casp3) and downregulated the Burkitt-cell lymphomas (BCL-2), inhibin B proteins (IBP), and androgen receptor (Ar) mRNA expressions Casp3, nitric oxide synthase (iNOS), ionized calcium-binding adapter molecule 1(IBA1), and IL-1ß immunoreactions were increased. Also, reduction of proliferating cell nuclear antigen (PCNA), mouse vasa homologue (MVH), and SOX9 protein reactions were reported. Interestingly, CeNPs diminished the harmful impacts of FIP on testicular tissue by decreasing lipid peroxidation, apoptosis and inflammation and increasing the antioxidant activities. The findings reported herein showed that the CeNPs might serve as a supposedly new and efficient protective agent toward reproductive toxicity caused by the FIP insecticide in white male rats.

Aortic Oxidative Stress, Inflammation and DNA Damage Following Pulmonary Exposure to Cerium Oxide Nanoparticles in a Rat Model of Vascular Injury.

Pulmonary exposure to cerium oxide nanoparticles (CeO2 NPs) can occur either at the workplace, or due to their release in the environment. Inhaled CeO2 NPs are known to cross the alveolar-capillary barrier and reach various parts of the body, including the vasculature. The anticancer drug cisplatin (CP) causes vascular damage. However, the effects CeO2 NPs on vascular homeostasis in a rat model of CP-induced vascular injury remain unclear. Here, we assessed the impact and underlying mechanism of pulmonary exposure to CeO2 NPs on aorta in rats given a single intraperitoneal injection of cisplatin (CP, 6 mg/kg) to induce vascular damage. Six days later, the rats were intratracheally instilled with either CeO2 NPs (1 mg/kg) or saline (control), and various variables were studied 24 h thereafter in the aortic tissue. The concentration of reduced glutathione and the activity of catalase were significantly increased in the CP + CeO2 NPs group compared with both the CP + saline and the CeO2 NPs groups. The activity of superoxide dismutase was significantly decreased in the CP + CeO2 NPs group compared with both the CP + saline and CeO2 NPs groups. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) by the nuclei of smooth muscles and endocardial cells assessed by immunohistochemistry was significantly augmented in CeO2 NPs versus saline, in CP + saline versus saline, and in CP + CeO2 NPs versus CeO2 NPs. Moreover, the concentrations of total nitric oxide, lipid peroxidation and 8-hydroxy-2-deoxyguanosine were significantly elevated in the CP + CeO2 NPs group compared with both the CP + saline and the CeO2 NPs groups. Similarly, compared with both the CP + saline and CeO2 NPs groups, the combination of CP and CeO2 NPs significantly elevated the concentrations of interleukin-6 and tumour necrosis factor-α. Additionally, aortic DNA damage assessed by Comet assay was significantly increased in CeO2 NPs compared with saline, and in CP + saline versus saline, and all these effects were significantly aggravated by the combination of CP and CeO2 NPs. We conclude that pulmonary exposure to CeO2 NPs aggravates vascular toxicity in animal model of vascular injury through mechanisms involving oxidative stress, Nrf2 expression, inflammation and DNA damage.

Functionalized cerium oxide nanoparticles mitigate the oxidative stress and pro-inflammatory activity associated to the portal vein endothelium of cirrhotic rats.

BACKGROUND AND AIMS: The occurrence of endothelial alterations in the liver and in the splanchnic vasculature of cirrhotic patients and experimental models of liver diseases has been demonstrated. However, the pathological role of the portal vein endothelium in this clinical context is scarcely studied and, therefore, deserves attention. In this context, we aimed to investigate whether pathological endothelial activation occurs in the portal vein of cirrhotic rats. METHODS: Cirrhosis was induced in wistar rats by CCl4 inhalation. We generated immortalized endothelial cells from the portal vein of control (CT-iPVEC) and cirrhotic rats (CH-iPVEC) by retroviral transduction of the SV40 T antigen. We assessed differential gene expression and intracellular reactive oxygen species (ROS) levels in iPVECs and in portal veins of control and cirrhotic rats. Finally, we assessed the therapeutic effectiveness of cerium oxide nanoparticles (CeO2NP) on reversing PVEC activation and macrophage polarization. RESULTS: CH-iPVECs overexpressed collagen-I, endothelin-1, TIMP-1, TIMP-2, IL-6 and PlGF genes. These results were consistent with the differential expression showed by whole portal veins from cirrhotic rats. In addition, CH-iPVECs showed a significant increase in intracellular ROS and the capacity of potentiating M1 polarization in macrophages. The treatment of CH-iPVECs with CeO2NPs blocked intracellular ROS formation and IL-6 and TIMP-2 gene overexpression. In agreement with the in vitro results, the chronic treatment of cirrhotic rats with CeO2NPs also resulted in the blockade of both ROS formation and IL-6 gene overexpression in whole portal veins. CONCLUSIONS: Endothelial cells from portal vein of cirrhotic rats depicted an abnormal phenotype characterized by a differential gene expression and the induction of M1 polarization in macrophages. We identified the excess of intracellular reactive oxygen species (ROS) as a major contributor to this altered phenotype. In addition, we demonstrated the utility of the nanomaterial cerium oxide as an effective antioxidant capable of reverse some of these pathological features associated with the portal vein in the cirrhosis condition.

Retinal long term neuroprotection by Cerium Oxide nanoparticles after an acute damage induced by high intensity light exposure.

Cerium Oxide nanoparticles are antioxidant agents with autoregenerative radical scavenging activities, effective in preventing degeneration of photoreceptors of an albino rat when intravitreally injected prior to exposure to high intensity light. In this study, we performed a post injury administration of nanoceria and a long term analysis of their neuroprotective properties in order to better simulate the therapeutic treatment as it is carried out on patients with age related macular degeneration, and while photoreceptor degeneration is ongoing. We also injected nanoceria labelled with fluorescein isothiocianate in order to analyze their persistence after a single administration in a damaged retina and to investigate how long they both maintain their neuroprotective properties and where they localize in the retina. We demonstrated that after a single intravitreal injection, nanoceria remained in the retina for a long time and retained their neuroprotective properties. All these data form excellent bases for future clinical applications.

Iron plaque reduces cerium uptake and translocation in rice seedlings (Oryza sativa L.) exposed to CeO2 nanoparticles with different sizes.

This study aims to assess the role of iron plaque (IP) on cerium (Ce) uptake and translocation by rice after CeO2 nanoparticles (NPs) exposure over a 4 days period. A hydroponic experiment was performed under two IP levels (low and high) combined with two CeO2 NPs size (14 nm and 25 nm). It was found that CeO2 NPs as the main form was absorbed by rice due to limited NPs dissolution in hydroponic solution. IP significantly reduced surface-Ce, root-Ce and shoot-Ce accumulation, irrespective of CeO2 NPs sizes. The reduced uptake of Ce was more obvious in NP25 than NP14. Ce accumulations decreased with increasing IP amounts. In IP treatments, the interactive attraction between NPs and root surface was weakened through the enhancement of hydrodynamic diameters and the reduction of ζ-potential of CeO2 NPs in solution, as well as the reduction of |ζ| values of rice root, which reduced the Ce bioaccumulation in rice. PCA indicated the negative correlation between surface-Ce (IP-C-Ce and IP-A-Ce) and NPs size, and between shoot-Ce/root-Ce and IP-Fe/tissue-Fe. IP also decreased Ce translocation from root to shoot. A full life study indicated the reduction effect of IP on surface-Ce, root-Ce, shoot-Ce and grain-Ce accumulations. These findings are significant as they imply that the IP formation is a promising approach for preventing Ce accumulation in rice, which would regulate Ce uptake by rice in the following growth stages and decrease the health risk of CeO2 NPs exposure in agricultural environment.

A novel pharmacological approach of herbal mediated cerium oxide and silver nanoparticles with improved biomedical activity in comparison with Lawsonia inermis.

Diabetes mellitus is one of the threatening, non-communicable and chronic ailments worldwide since ancient times to the current stage of human existence. The utilization of nanoparticles as a medicine in the treatment of diabetes is an attractive proposition. In the present study, herbal mediated cerium oxide nanoparticles (HMCeO2 NPs), herbal mediated silver nanoparticles (HMAg NPs) and Lawsonia intermix extract (LIE) was evaluated for them for in-vivo hypoglycemic effect and compared the potency. The resulting HMCeO2 NPs, HMAg NPs and Lawsonia inermis have been characterized by different analytical equipments such as X-ray Diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Particle size analyzer (PSA), Field emission scanning electron microscope (FESEM) and High resolution transmission electron microscope (HRTEM). The synthesized NPs and Lawsonia inermis extract were assessed for toxicity by using acute oral toxicity using female albino mice (s) model by following OECD-425 guidelines. In in-vivo hypoglycemic animal model, the male wistar rats with weight varying between 180-200 gms were grouped as: normal control: did not receive any treatment, diabetic control (saline): received a single intraperitoneal dose of Streptozotocin (40 mg/kg), standard: received a single daily oral dose of 50 mg/kg body weight, HMCeO2 NPs: received single daily oral dose of 100 mg/kg, 200 mg/kg, HMAg NPs: received a single daily oral dose of 100 mg/kg, 200 mg/kg, and Lawsonia inermis: received a single daily oral dose of 100 mg/kg, 200 mg/kg. The herbal mediated NPs were considered safe as they have not shown toxic effects. From the current study results, it may conclude that, due to the advanced biological and pharmacological characters, the HMAg NPs depicted more potent hypoglycemic activity than that of LIE and CeO2 NPs.

Oxygen Vacancies Enhanced CeO2:Gd Nanoparticles for Sensing a Tumor Vascular Microenvironment by Magnetic Resonance Imaging.

The specific characteristics of the tumor vascular microenvironment such as microvascular permeability and water diffusion have been demonstrated to play essential roles in the evaluation of infiltration of tumors. However, at present, there are few contrast agents (CAs) for magnetic resonance imaging to enhance the sensitivity for acquiring this vital information. Herein, we develop Gd-doped (CeO2:Gd) nanoparticles as CAs to detect the tumor vascular microenvironment with high sensitivity. The lattice oxygen vacancies on the surface of CeO2:Gd nanoparticles could bind considerable water molecules to improve the r1 value, achieving an excellent dynamic contrast-enhanced perfusion weighted imaging performance for the measurement of microvascular permeability. Diffusion limiting of water molecules by oxygen vacancies of CeO2:Gd nanoparticles further enhances the diffusion-weighted magnetic resonance imaging signal in vitro and in vivo. Excitingly, the strategy is not only essential for obtaining tumor vascular microenvironment information but also offers a way for further research in the design of magnetic resonance CAs.

Multifunctional antioxidant nanoliposome-mediated delivery of PTEN plasmids restore the expression of tumor suppressor protein and induce apoptosis in prostate cancer cells.

Prostate cancer is the second leading cause of cancer death in men and about one in nine will be diagnosed in his lifetime. Loss of PTEN has been considered as one of the major factors leading to the origin of prostate cancer through modulating PI3K/AKT signaling pathways. In this study, we have prepared a multifunctional antioxidant nanoliposome containing PTEN plasmid and cerium oxide nanoparticles (CeNPs). The efficient delivery of PTEN plasmid to human prostate cancer cells (PC-3) leads to restoration of the expression of lost PTEN protein in the cell cytoplasm. The delivered superoxide dismutase (SOD)-mimetic CeNPs were also found to decrease the cytoplasmic free radical levels in prostate cancer cells. The above two activities induced DNA fragmentation and micronucleus formation in prostate cancer cells. Furthermore, it was also found that these multifunctional antioxidant nanoliposomes inhibit the PI3K/AKT signaling pathway to negatively regulate the cell viability of prostate cancer cells. The mRNA expression pattern of other relevant proteins predominantly involved in cancer cell proliferation and apoptosis suggested that the high PTEN expression could control the synthesis of oncogenic proteins. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3152-3164, 2018.

Nanoceria-loaded injectable hydrogels for potential age-related macular degeneration treatment.

The major purpose of this article is to evaluate oligochitosan coated cerium oxide nanoparticles (OCCNPs) alginate laden injectable hydrogels and their potential treatment for age-related macular degeneration (AMD). The water soluble OCCNPs were loaded within injectable hydrogels as antioxidative agents. The release of OCCNPs from hydrogel, radical scavenging properties, and biocompatibility were evaluated and calculated in vitro. The effects of OCCNP laden hydrogel downregulating expression of angiogenic proteins and proinflammatory cytokines were quantified in human retinal pigment epithlium-19 (ARPE-19) and umbilical endothelium cell lines. The hydrogels behaved with moderate swelling and controllable degradation. The laden OCCNPs were released in a controlled manner in vitro during two months of testing. The OCCNP loaded hydrogels exhibited robust antioxidative properties in oxygen radical absorbance capacity tests and reduced apoptosis in H2 O2 -induced ARPE-19 cells. Furthermore, OCCNP loaded injectable hydrogels are biocompatible and suppressed the ipopolysaccharides-induced inflammation response in ARPE-19 cells, and inhibited expression of vascular endothelium growth factor in human ARPE-19 and umbilical endothelium cell lines. The alginate-gelatin injectable hydrogel loaded OCCNPs are biocompatible and have high potential in protecting cells from apoptosis, angiogenesis, and production of proinflammatory cytokines in AMD cellular models. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2795-2804, 2018.

Radiosensitizing Effect of Cerium Oxide Nanoparticles on Human Leukemia Cells.

BACKGROUND: Radiotherapy is an important protocol in the treatment of cancers, but radioresistance of cancerous cells is a challenge in cancer treatment. OBJECTIVE: The aim of this study was to evaluate the radiosensitizing effect of Cerium oxide Nanoparticles (CNPs) on human promyelocytic leukemia cells (HL-60). METHOD: HL-60 cells were treated with CNPs at different concentrations (10-100 µg/ml) and exposed to Ionizing Radiation (IR). The genotoxicity effects of CNPs or/and IR were assessed by micronuclei assay in HL-60 cells. RESULTS: It was found that CNPs increased the frequencies of micronuclei in HL-60 cells. CNPs pretreatment to irradiation significantly increased the IR-induced micronuclei incidences in HL-60 cells. The present study demonstrates CNPs to be an effective sensitizer on DNA damage induced by IR in HL-60 cells. CONCLUSION: These findings suggest the potential application of CNPs as a highly effective radiosensitizer for the treatment of leukemia.

Effect of exposure to CeO2 nanoparticles on ram spermatozoa during storage at 4 °C for 96 hours.

BACKGROUND: Cerium oxide nanoparticles (CeO2 NPs) are able to store and release oxygen, conferring them scavenger activity against oxidative stress. However, their effects in reproductive systems are not yet well understood. The aim of the study was to investigate the effects of exposure of refrigerated ram semen to CeO2 NPs for 96 h on the main structural and kinematic parameters of spermatozoa. METHODS: The ejaculates of 5 Sarda rams were collected, pooled and diluted in a soybean lecithin extender. Samples were exposed to increasing doses of CeO2 NPs (0, 44 and 220 µg/mL) and stored at 4 °C for 96 h. Analyses of kinematic parameters (computer assisted sperm analysis, CASA), integrity of membranes (PI/PSA staining), ROS production (H2DCFDA staining) and DNA damage (sperm chromatin structure assay with acridine orange, SCSA) were performed every 24 h (0, 24, 48, 72 and 96 h of incubation). The experiment was carried out in 6 replicates. Data were analysed by repeated measures ANOVA with Bonferroni's as post hoc test. When the assumption of normality was not met (ROS), non-parametric Kruskal-Wallis rank test was carried out. RESULTS: Exposure of ram spermatozoa to increasing doses of CeO2 NPs had a beneficial effect on the main motility parameters from 48 h of incubation onward. Velocity of sperm cells was enhanced in the groups exposed to CeO2 NPs compared to the control. Incubation with NPs had beneficial effects on the integrity of plasma membranes of spermatozoa, with higher percentage of damaged cells in the control group compared to the exposed ones. Production of ROS was not affected by exposure to NPs and its levels rose at 96 h of incubation. The integrity of DNA remained stable throughout the 96 h of storage regardless of co-incubation with NPs. CONCLUSIONS: We reported beneficial effects of CeO2 NPs on kinematic and morphologic parameters of ram semen, such as motility and membrane integrity following 96 h of exposure. Furthermore, we also proved no genotoxic effects of CeO2 NPs. These effects could not be related to an antioxidant activity of CeO2 NPs, since ROS levels in exposed cells were similar to those of unexposed ones.

Targeted Delivery and Redox Activity of Folic Acid-Functionalized Nanoceria in Tumor Cells.

Cerium oxide nanoparticles (nanoceria) are promising catalytic nanomaterials that are widely reported to modulate intracellular reactive oxygen species (ROS). In this study, nanoceria were synthesized by flame spray pyrolysis and functionalized with a cell-targeting ligand, folic acid (FA). The surface functionalization of nanoceria was stable, and FA enhanced the uptake of nanoceria via folate receptors. Internalized nanoceria and FA-nanoceria were localized predominantly in the cytoplasm. FA-nanoceria modulated intracellular ROS to a greater extent than the nanoceria in colon carcinoma cells, but induced ROS in ovarian cancer cells, likely due to their enhanced uptake. Together these data demonstrated that the functionalization of nanoceria with FA modulated their endocytosis and redox activity, and they may find application in the delivery of anticancer drugs in the future.

Cerium oxide and barium sulfate nanoparticle inhalation affects gene expression in alveolar epithelial cells type II.

BACKGROUND: Understanding the molecular mechanisms of nanomaterial interacting with cellular systems is important for appropriate risk assessment. The identification of early biomarkers for potential (sub-)chronic effects of nanoparticles provides a promising approach towards cost-intensive and animal consuming long-term studies. As part of a 90-day inhalation toxicity study with CeO2 NM-212 and BaSO4 NM-220 the present investigations on gene expression and immunohistochemistry should reveal details on underlying mechanisms of pulmonary effects. The role of alveolar epithelial cells type II (AEII cells) is focused since its contribution to defense against inhaled particles and potentially resulting adverse effects is assumed. Low dose levels should help to specify particle-related events, including inflammation and oxidative stress. RESULTS: Rats were exposed to clean air, 0.1, 0.3, 1.0, and 3.0 mg/m3 CeO2 NM-212 or 50.0 mg/m3 BaSO4 NM-220 and the expression of 391 genes was analyzed in AEII cells after one, 28 and 90 days exposure. A total number of 34 genes was regulated, most of them related to inflammatory mediators. Marked changes in gene expression were measured for Ccl2, Ccl7, Ccl17, Ccl22, Ccl3, Ccl4, Il-1α, Il-1ß, and Il-1rn (inflammation), Lpo and Noxo1 (oxidative stress), and Mmp12 (inflammation/lung cancer). Genes related to genotoxicity and apoptosis did not display marked regulation. Although gene expression was less affected by BaSO4 compared to CeO2 the gene pattern showed great overlap. Gene expression was further analyzed in liver and kidney tissue showing inflammatory responses in both organs and marked downregulation of oxidative stress related genes in the kidney. Increases in the amount of Ce were measured in liver but not in kidney tissue. Investigation of selected genes on protein level revealed increased Ccl2 in bronchoalveolar lavage of exposed animals and increased Lpo and Mmp12 in the alveolar epithelia. CONCLUSION: AEII cells contribute to CeO2 nanoparticle caused inflammatory and oxidative stress reactions in the respiratory tract by the release of related mediators. Effects of BaSO4 exposure are low. However, overlap between both substances were detected and support identification of potential early biomarkers for nanoparticle effects on the respiratory system. Signs for long-term effects need to be further evaluated by comparison to a respective exposure setting.

Toxicological effects and ultrastructural changes induced by lanthanum and cerium in ovary and uterus of Wistar rats.

Rare earths have been widely used in a huge number of areas in industry and medicine. Therefore, they exist in the environment and possibly accumulated within the human body. However their effects in the living organism particularly in the female reproductive system are still unclear. In this work, the subcellular behavior of lanthanum and cerium was investigated through the Transmission Electron Microscopy (TEM), in different territories of the reproductive system of Wistar rats exposed intraperitoneally to soluble solution of these elements during 2 weeks. Ultrastructural investigations of ultrathin sections from uterus and ovary of treated rats revealed the existence of inclusions with high electron density and heterogeneous aspects in the lysosomes of uterus and ovary cells. Many disruptions of architecture were observed, accompanied with several changes like vacuolations, significant expansion of the endoplasmic reticulum, mitochondrial alterations and necrotic cells, demonstrating the toxicity of these elements with doses used. Phagolysosomes as well as eosinophils were also seen. Our experimental investigations revealed no intralysosomal inclusions in ultrathin sections of the uterus and ovary of pregnant control females. The original mechanism implicated in this insolubilization-concentration phenomenon of these elements, as non-soluble phosphate form, in the lysosomes is a biochemical one involving intralysosomal hydrolytic enzymes, the acid phosphatase.

The acute pulmonary and thrombotic effects of cerium oxide nanoparticles after intratracheal instillation in mice.

Cerium oxide nanoparticles (CeO2 NPs), used as a diesel fuel catalyst, can be emitted into the ambient air, resulting in exposure to humans by inhalation. Recent studies have reported the development of lung toxicity after pulmonary exposure to CeO2 NPs. However, little is known about the possible thrombotic effects of these NPs. The present study investigated the acute (24 hours) effect of intratracheal (IT) instillation of either CeO2 NPs (0.1 or 0.5 mg/kg) or saline (control) on pulmonary and systemic inflammation and oxidative stress and thrombosis in mice. CeO2 NPs induced a significant increase of neutrophils into the bronchoalveolar lavage (BAL) fluid with an elevation of tumor necrosis factor α (TNFα) and a decrease in the activity of the antioxidant catalase. Lung sections of mice exposed to CeO2 NPs showed a dose-dependent infiltration of inflammatory cells consisting of macrophages and neutrophils. Similarly, the plasma levels of C-reactive protein and TNFα were significantly increased, whereas the activities of catalase and total antioxidant were significantly decreased. Interestingly, CeO2 NPs significantly and dose dependently induced a shortening of the thrombotic occlusion time in pial arterioles and venules. Moreover, the plasma concentrations of fibrinogen and plasminogen activator inhibitor-1 were significantly elevated by CeO2 NPs. The direct addition of CeO2 NPs (1, 5, or 25 µg/mL) to mouse whole blood, collected from the inferior vena cava, in vitro neither caused significant platelet aggregation nor affected prothrombin time or partial thromboplastin time, suggesting that the thrombotic events observed in vivo may have resulted from systemic inflammation and/or oxidative stress induced by CeO2 NPs. This study concludes that acute pulmonary exposure to CeO2 NPs induces pulmonary and systemic inflammation and oxidative stress and promotes thrombosis in vivo.

Cerium oxide nanoparticles (CeO2 NPs) improve the developmental competence of in vitro-matured prepubertal ovine oocytes.

The present study investigated whether supplementation with different doses of cerium dioxide nanoparticles (CeO2 NPs) during in vitro maturation (IVM) of prepubertal ovine oocytes influenced their embryonic development in vitro. Cumulus-oocyte complexes derived from the ovaries of slaughtered prepubertal sheep underwent IVM with CeO2NPs (0, 44, 88 or 220µg mL-1). Matured oocytes were fertilised in vitro and zygotes were cultured for 7 days. The results demonstrated that CeO2NPs were internalised in the cumulus cells and not in the oocyte. The treatment with CeO2NPs did not affect nuclear maturation or intracellular levels of reactive oxygen species of the oocytes. The percentage of oocytes with regular chromatin configuration and cytoskeleton structures when treated with 44µg mL-1 CeO2NPs was similar to oocytes matured in the absence of CeO2NPs and significantly higher than those treated with 88 or 220µg mL-1 CeO2NPs. The relative quantification of transcripts in the cumulus cells of oocytes matured with 44µg mL-1 CeO2NPs showed a statistically lower mRNA abundance of BCL2-associated X protein (BAX), B-cell CLL/lymphoma 2 (BCL2) and superoxide dismutase 1 (SOD1) compared with the 0µg mL-1 CeO2 NPs group. A concentration of 44µg mL-1 CeO2NPs significantly increased the blastocyst yield and their total, inner cell mass and trophectoderm cell numbers, compared with the 0 and 220µg mL-1 groups. A low concentration of CeO2NPs in the maturation medium enhanced in vitro embryo production of prepubertal ovine oocytes.

Protective effects of cerium oxide and yttrium oxide nanoparticles on reduction of oxidative stress induced by sub-acute exposure to diazinon in the rat pancreas.

Diazinon is a kind of organophosphorus (OP) compound that is broadly used against different species of insects and pests. Oxidative stress can occur at very early stages of diazinon exposure and the pancreas is one of the main target organs for toxicity by diazinon. The aim of this study was to evaluate the protective effects of cerium oxide nanoparticles (CeO2 NPs) and yttrium oxide nanoparticles (Y2O3 NPs) against the pancreatic damage from sub-acute exposure of diazinon. Diazinon at a dose of 70mg/kg/day was given through gavage to rats once a day. Along with diazinon, trace amounts of CeO2 NPs and Y2O3 NPs (35mg/kg and 45mg/kg per day, respectively) were administered by intraperitoneal injection once a day for 2 weeks. Animals weight and blood glucose were measured during the treatment, and oxidative stress biomarkers, diabetes physiology, function and viability of cells were investigated at the end of the treatment in serum and pancreas tissues. Apoptosis of islets was examined by the flow cytometry. The high blood glucose level and significant weight loss resulting from diazinon were modified as a result of the application of the NPs. A significant recovery in oxidative stress markers, pro-insulin, insulin, C-peptide, adenosine diphosphate/adenosine triphosphate (ATP/ADP) ratio, caspase-3 and -9 activities and apoptosis-necrosis in the islets was observed. In conclusion, administration of CeO2 NPs or Y2O3 NPs only or their combination with suitable and defined dose will help to overcome the consequences from oxidant agents.