Iron Deficiency Alters the Day‐Night Variation in Monoamine Levels in Mice

Monoamine metabolism in the central nervous system is altered by dietary iron deficiency, with a stronger effect seen during the active than rest span of the circadian cycle. In this report, we examined changes in intracellular and extracellular monoamine levels, synthetic enzymes, transporter and receptor densities, and responses to amphetamine‐induced dopamine (DA) efflux in iron‐deficient and iron‐sufficient mice. Extracellular striatal DA levels were 15–20% higher in all groups during the active dark phase compared to the inactive light phase, with correspondingly lower dopamine transporter (DAT) and higher tyrosine hydroxylase levels. Iron deficiency decreased DAT density by 20% and 28% in the light and dark phases, respectively, and elevated the DOPAC/DA ratio only in the dark, indicating that iron deficiency does interact with the normal diurnal cues for cyclicity. Enhanced DA efflux after amphetamine stimulation indicates no limitation on monoamine synthesis and release and is consistent with altered synaptic efficacy and perhaps recycling of DA in iron deficiency. These experimental findings provide new evidence that brain iron insufficiency does have a differential effect on the DA system at different biological times of the day and night and may be causally related to the phasic motor symptoms observed in Restless Legs Syndrome.     

Uptake and Metabolism of Iron Oxide Nanoparticles in Brain Cells

Magnetic iron oxide nanoparticles (IONPs) are used for various applications in biomedicine, for example as contrast agents in magnetic resonance imaging, for cell tracking and for anti-tumor treatment. However, IONPs are also known for their toxic effects on cells and tissues which are at least in part caused by iron-mediated radical formation and oxidative stress. The potential toxicity of IONPs is especially important concerning the use of IONPs for neurobiological applications as alterations in brain iron homeostasis are strongly connected with human neurodegenerative diseases. Since IONPs are able to enter the brain, potential adverse consequences of an exposure of brain cells to IONPs have to be considered. This article describes the pathways that allow IONPs to enter the brain and summarizes the current knowledge on the uptake, the metabolism and the toxicity of IONPs for the different types of brain cells in vitro and in vivo.     

Cell Labeling and Targeting with Superparamagnetic Iron Oxide Nanoparticles

Targeted delivery of cells and therapeutic agents would benefit a wide range of biomedical applications by concentrating the therapeutic effect at the target site while minimizing deleterious effects to off-target sites. Magnetic cell targeting is an efficient, safe, and straightforward delivery technique. Superparamagnetic iron oxide nanoparticles (SPION) are biodegradable, biocompatible, and can be endocytosed into cells to render them responsive to magnetic fields. The synthesis process involves creating magnetite (Fe₃O₄) nanoparticles followed by high-speed emulsification to form a poly(lactic-co-glycolic acid) (PLGA) coating. The PLGA-magnetite SPIONs are approximately 120 nm in diameter including the approximately 10 nm diameter magnetite core. When placed in culture medium, SPIONs are naturally endocytosed by cells and stored as small clusters within cytoplasmic endosomes. These particles impart sufficient magnetic mass to the cells to allow for targeting within magnetic fields. Numerous cell sorting and targeting applications are enabled by rendering various cell types responsive to magnetic fields. SPIONs have a variety of other biomedical applications as well including use as a medical imaging contrast agent, targeted drug or gene delivery, diagnostic assays, and generation of local hyperthermia for tumor therapy or tissue soldering.     

Handling of Iron Oxide and Silver Nanoparticles by Astrocytes

Metal-containing nanoparticles (NPs) are currently used for various biomedical applications. Since such NPs are able to enter the brain, the cells of this organ have to deal with NPs and with NP-derived metal ions. In brain, astrocytes are considered to play a key function in regulating metal homeostasis and in protecting other brain cells against metal toxicity. Thus, among the different types of brain cells, especially astrocytes are of interest regarding the uptake and the handling of metal-containing NPs. This article summarizes the current knowledge on the consequences of an exposure of astrocytes to NPs. Special focus will be given to magnetic iron oxide nanoparticles (IONPs) and silver nanoparticles (AgNPs), since the biocompatibility of these NPs has been studied for astrocytes in detail. Cultured astrocytes efficiently accumulate IONPs and AgNPs in a time-, concentration- and temperature-dependent manner by endocytotic processes. Astrocytes are neither acutely damaged by the exposure to high concentrations of NPs nor by the prolonged intracellular presence of large amounts of accumulated NPs. Although metal ions are liberated from accumulated NPs, NP-derived iron and silver ions are not exported from astrocytes but are rather stored in proteins such as ferritin and metallothioneins which are synthesized in NP-treated astrocytes. The efficient accumulation of large amounts of metal-containing NPs and the upregulation of proteins that safely store NP-derived metal ions suggest that astrocytes protect the brain against the potential toxicity of metal-containing NPs.     

Temperature-Tunable Iron Oxide Nanoparticles for Remote-Controlled Drug Release

Herein, we report the successful development of a novel nanosystem capable of an efficient delivery and temperature-triggered drug release specifically aimed at cancer. The water-soluble 130.1 ± 0.2 nm iron oxide nanoparticles (IONPs) were obtained via synthesis of a monodispersed iron oxide core stabilized with tetramethylammonium hydroxide pentahydrate (TMAOH), followed by coating with the thermoresponsive copolymer poly-(NIPAM-stat-AAm)-block-PEI (PNAP). The PNAP layer on the surface of the IONP undergoes reversible temperature-dependent structural changes from a swollen to a collapsed state resulting in the controlled release of anticancer drugs loaded in the delivery vehicle. We demonstrated that the phase transition temperature of the prepared copolymer can be precisely tuned to the desired value in the range of 36°C–44°C by changing the monomers ratio during the preparation of the nanoparticles. Evidence of modification of the IONPs with the thermoresponsive copolymer is proven by ATR-FTIR and a quantitative analysis of the polymeric and iron oxide content obtained by thermogravimetric analysis. When loaded with doxorubicin (DOX), the IONPs-PNAP revealed a triggered drug release at a temperature that is a few degrees higher than the phase transition temperature of a copolymer. Furthermore, an in vitro study demonstrated an efficient internalization of the nanoparticles into the cancer cells and showed that the drug-free IONPs-PNAP were nontoxic toward the cells. In contrast, sufficient therapeutic effect was observed for the DOX-loaded nanosystem as a function of temperature. Thus, the developed temperature-tunable IONPs-based delivery system showed high potential for remotely triggered drug delivery and the eradication of cancer cells.

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-014-0131-x) contains supplementary material, which is available to authorized users.KEY WORDS: drug delivery, IONPs, remote-triggered drug release, thermoresponsive copolymer, tunable LCST     

磁性氧化铁纳米颗粒及其磁共振成像应用

磁性氧化铁纳米颗粒在磁共振成像方面的应用,已经在全世界范围内得到了广泛的关注,相关研究也被各国科学家高度重视.目前,磁性氧化铁纳米颗粒正在从早期的基于被动识别的肝部磁共振造影,快速转向基于主动识别的磁共振分子影像应用.本文将围绕磁性氧化铁纳米颗粒的生物体内应用,着重介绍磁性纳米颗粒的制备及其在疾病诊断,尤其是在肿瘤早期...     

Exposure to Palladium Nanoparticles Affects Serum Levels of Cytokines in Female Wistar Rats

Background

Information currently available on the impact of palladium on the immune system mainly derives from studies assessing the biological effects of palladium salts. However, in the last years, there has been a notable increase in occupational and environmental levels of fine and ultrafine palladium particles released from automobile catalytic converters, which may play a role in palladium sensitization. In this context, the evaluation of the possible effects exerted by palladium nanoparticles (Pd-NPs) on the immune system is essential to comprehensively assess palladium immunotoxic potential.

Aim

Therefore, the aim of this study was to investigate the effects of Pd-NPs on the immune system of female Wistar rats exposed to this xenobiotic for 14 days, by assessing possible quantitative changes in a number of cytokines: IL-1α, IL-2, IL-4, IL-6, IL-10, IL-12, GM-CSF, INF-γ and TNF-α.

Methods

Twenty rats were randomly divided into four exposure groups and one of control. Animals were given a single tail vein injection of vehicle (control group) and different concentrations of Pd-NPs (0.012, 0.12, 1.2 and 12 μg/kg). A multiplex biometric enzyme linked immunosorbent assay was used to evaluate cytokine serum levels.

Results

The mean serum concentrations of all cytokines decreased after the administration of 0.012 μg/kg of Pd-NPs, whereas exceeded the control levels at higher exposure doses. The highest concentration of Pd-NPs (12 μg/kg) induced a significant increase of IL-1α, IL-4, IL-6, IL-10, IL-12, GM-CSF and INF-γ compared to controls.

Discussion and Conclusions

These results demonstrated that Pd-NP exposure can affect the immune response of rats inducing a stimulatory action that becomes significant at the highest administered dose. Our findings did not show an imbalance between cytokines produced by CD4⁺ T helper (Th) cells 1 and 2, thus suggesting a generalized stimulation of the immune system with a simultaneous activation and polarization of the naïve T cells towards Th1 and Th2 phenotype.     

Heterobifunctional PEG Ligands for Bioconjugation Reactions on Iron Oxide Nanoparticles

Ever since iron oxide nanoparticles have been recognized as promising scaffolds for biomedical applications, their surface functionalization has become even more important. We report the synthesis of a novel polyethylene glycol-based ligand that combines multiple advantageous properties for these applications. The ligand is covalently bound to the surface via a siloxane group, while its polyethylene glycol backbone significantly improves the colloidal stability of the particle in complex environments. End-capping the molecule with a carboxylic acid introduces a variety of coupling chemistry possibilities. In this study an antibody targeting plasminogen activator inhibitor-1 was coupled to the surface and its presence and binding activity was assessed by enzyme-linked immunosorbent assay and surface plasmon resonance experiments. The results indicate that the ligand has high potential towards biomedical applications where colloidal stability and advanced functionality is crucial.     

Effects of Repeated Low-dose Soman Exposure on Monoamine Levels in Different Brain Structures in Mice

In order to better understand the effects of repeated low-dose exposure to organophosphorus (OPs) on physiological and behavioural functions, we analysed the levels of endogenous monoamines (serotonin and dopamine) in different brain areas after repeated exposure of mice to sublethal dose of soman. Animals were injected once a day for 3 days with 0.12 LD50 of soman (47 μg/kg, i.p.). They did not show either severe signs of cholinergic toxicity or pathological changes in brain tissue. 24 h after the last injection of soman, inhibition of cholinesterase was similar in plasma and brain (32% and 37% of inhibition respectively). Afterwards, recovery of cholinesterase activity was faster in the plasma than in the brain. Dopamine levels were not significantly modified. On the other hand, we observed a significant modification of the serotoninergic system. An increase of the 5-HIAA/5-HT ratio was maintained for 2 and 4 weeks after exposure in the hippocampus and the striatum respectively. This study provides the first evidence of a modification of the 5-HT turnover in the hippocampus and the striatum after repeated low-dose intoxication with a nerve agent. Further experiments are necessary to evaluate the relationship between these modifications and the unexpected neuropsychological disorders usually reported after chronic exposure of organophosphorus.     

Effect of Endoxylanase and Iron Oxide Nanoparticles on Performance and Histopathological Features in Broilers

Biological Trace Element Research - Endoxylanase enzyme is used as poultry feed additive to degrade anti-nutritional factors like non-starch polysaccharides. Moreover, iron is one of the most...     

Gold-Coated Superparamagnetic Iron Oxide Nanoparticles Attenuate Collagen-Induced Arthritis after Magnetic Targeting

Biological Trace Element Research - Fluoride can induce neurotoxicity, but the mechanism is not clear. In this study, we explored the role of autophagy in F−-induced neurotoxicity of Wistar...     

RGD修饰包载超顺磁性氧化铁纳米粒用于脑胶质瘤的靶向研究

目的：采用PLGA-PEG为聚合材料,制备RGD修饰包载超顺磁性四氧化三铁纳米粒子（RGD-NP—Fe3O4）,用于脑胶质瘤细胞靶向核磁共振成像纳米探针。方法：采用沉淀法制备RGD修饰的栽超顺磁性纳米粒,考察纳米粒的粒径,电位等理化指标以及细胞毒性。通过细胞以及肿瘤球摄取实验,考察RGD．NP—Fe304的脑胶质瘤细胞靶向性。结果：制备得到的RGD-NP-Fe3O4粒径在85±7．5nm,电位为18＋1．15mV。纳米粒浓度在300μg/mL范围内,对脑胶质瘤细胞均无显著毒性。经过RGD修饰后脑胶质瘤细胞U87对纳米粒的摄取效率大大提高,纳米粒穿透肿瘤球能力显著增强。结论：RGD修饰包载超顺磁性氧化铁纳米粒是一种潜在的高效的脑胶质瘤细胞靶向诊断纳米探针和靶向给药系统。     

Uptake of Fluorescent Iron Oxide Nanoparticles by Oligodendroglial OLN-93 Cells

To investigate the cellular accumulation and intracellular localization of dimercaptosuccinate-coated iron oxide nanoparticles (D-IONPs) in oligodendroglial cells, we have synthesized IONPs that contain the fluorescent dye BODIPY (BP) in their coat (BP-D-IONPs) and have investigated the potential effects of the absence or presence of this dye on the particle uptake by oligodendroglial OLN-93 cells. Fluorescent BP-D-IONPs and non-fluorescent D-IONPs had similar hydrodynamic diameters and ζ-potentials of around 60 nm and ?58 mV, respectively, and showed identical colloidal stability in physiological media with increasing particle size and positivation of the ζ-potential in presence of serum. After exposure of oligodendroglial OLN-93 cells to BP-D-IONPs or D-IONPs in the absence of serum, the specific cellular iron content increased strongly to around 1,800 nmol/mg. This strong iron accumulation was lowered for both types of IONPs by around 50 % on exposure of the cells at 4 °C and by around 90 % on incubation in presence of 10 % serum. The accumulation of both D-IONPs and BP-D-IONPs in the absence of serum was not affected by endocytosis inhibitors, whereas in the presence of serum inhibitors of clathrin-dependent endocytosis lowered the particle accumulation by around 50 %. These data demonstrate that oligodendroglial cells efficiently accumulate IONPs by an endocytotic process which is strongly affected by the temperature and the presence of serum and that BP-D-IONPs are a reliable tool to monitor by fluorescence microscopy the uptake and cellular fate of D-IONPs.     

Evaluation of Long-Term Toxicity of Oral Zinc Oxide Nanoparticles and Zinc Sulfate in Mice

The toxicological effects of zinc oxide nanoparticles (nano-ZnOs) are related to their dissolution and interference with zinc ion homeostasis. High-soluble zinc sources may produce more severe and acute toxicity; however, the evaluation of potential toxicity of long-term exposure to nano-ZnOs and high-soluble sources of zinc remains obscure. This study aimed at evaluating effects of nano-ZnOs and zinc sulfate on development, serum and hematological parameters, and mineral concentrations in selected tissues and intestinal microbiota in mice via gastrointestinal administration for 7 weeks. Results indicated that 250 mg/kg nano-ZnOs reduced the body weight from weeks 8 to 11, increased serum glutamic-pyruvic transaminase activity, and increased the zinc concentrations of the serum, liver, and kidney while did not affect the relative organ weight, intestinal microbiota, and other mineral concentrations (Fe, Cu, and Mn) in the kidney, liver, and thigh muscle. Oral administration with 250 mg/kg zinc sulfate seemed to show more severe and acute toxicity since mice in zinc sulfate group exhibited reduced body weight from weeks 5 to 11, decreased relative pancreas weight, and increased serum glutamic-oxalacetic transaminase activity and intestinal enteric group.     

Cerium Oxide Nanoparticles Attenuate Oxidative Stress and Inflammation in the Liver of Diethylnitrosamine-Treated Mice

Biological Trace Element Research - The catalytic activity of cerium oxide nanoparticles (CeO2NPs) is responsible for its application as an antitumor agent. This activity may be due to its ability...