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It is demonstrated that carboxylic acid-functionalized titanium dioxide (TiO 2 ) NPs produce significantly higher levels of reactive oxygen species (ROS) after visible light irradiation (400–800 nm, 1600 mW/cm 2 ) in comparison to nonfunctionalized TiO 2 NPs. The level of ROS produced under these irradiation conditions was not capable of generating oxidatively induced DNA damage in a cell-free system for TiO 2 concentrations of 0.5 mg/L or 5 mg/L. In addition, specific incorporation of the acrylic acid-functionalized TiO 2 NPs into dental composites allowed us to utilize the generated ROS to enhance photopolymerization (curing and degree of vinyl conversion (DC)) of resin adhesives and create mechanically superior and biocompatible materials for dental applications. Incorporation of the TiO 2 NPs into selected dental composites increased the mean DC values by ≈7%. The modified TiO 2 materials and dental composite materials were extensively characterized using thermogravimetric analysis, electron microscopy, Fourier transform infrared spectroscopy, and electron paramagnetic resonance. Notably, dental adhesives incorporated with acrylic acid-functionalized TiO 2 NPs produced stronger bonds to human teeth following visible light curing in comparison to traditional dental adhesives not containing NPs with an increase in the shear bond strength of ≈29%. In addition, no leaching of the incorporated NPs was detectable from the dental adhesives after 2500 thermal cycles using inductively coupled plasma-optical emission spectroscopy, indicating that biocompatibility of the adhesives was not compromised after extensive aging. These findings suggest that NP-induced ROS may be useful to produce enhanced nanocomposite materials for selected applications in the medical device field. Statement of Significance Titanium dioxide nanoparticles (TiO 2 NPs) have unique photocatalytic, antibacterial and UV-absorbing properties that make them beneficial additives in adhesives and composites. However, there is concern that the reactive oxygen species (ROS) produced by photoactivated TiO 2 NPs might pose toxicological risks. We demonstrate that it is possible to incorporate acid-functionalized TiO 2 NPs into dental resins which can be applied as dental adhesives to human teeth. The ROS generated by these NPs through visible-light irradiation may be utilized to increase the degree of vinyl conversion of resins, leading to adhesives that have an enhanced shear-bond strength to human teeth. Investigation into the potential genotoxicity of the NPs and their potential for release from dental composites indicated a low risk of genotoxic effects. [ABSTRACT FROM AUTHOR]

Abstract: Manganese (Mn) is an essential trace element required for normal function and development. However, exposure to this metal at elevated levels may cause manganism, a progressive neurodegenerative disorder with neurological symptoms similar to idiopathic Parkinson''s disease (IPD). Elevated body burdens of Mn from exposure to parental nutrition, vapors in mines and smelters and welding fumes have been associated with neurological health concerns. The underlying mechanism of Mn neurotoxicity remains unclear. Accordingly, the present study was designed to investigate the toxic effects of Mn2+ in human neuroblastoma SH-SY5Y cells. Mn2+ caused a concentration dependent decrease in SH-SY5Y cellular viability compared to controls. The LD50 value was 12.98μM Mn2+ (p <0.001 for control vs. 24h Mn treatment). Both TUNEL and annexin V/propidium iodide (PI) apoptosis assays confirmed the induction of apoptosis in the cells following exposure to Mn2+ (2μM, 62μM or 125μM). In addition, Mn2+ induced both the formation and accumulation of DNA single strand breaks (via alkaline comet assay analysis) and oxidatively modified thymine bases (via gas chromatography/mass spectrometry analysis). Pre-incubation of the cells with characteristic antioxidants, either 1mM N-acetylcysteine (NAC) or 1mM glutathione (GSH) reduced the level of DNA strand breaks and the formation of thymine base lesions, suggesting protection against oxidative cellular damage. Our findings indicate that (1) exposure of SH-SY5Y cells to Mn promotes both the formation and accumulation of oxidative DNA damage, (2) SH-SY5Y cells with accumulated DNA damage are more likely to die via an apoptotic pathway and (3) the accumulated levels of DNA damage can be abrogated by the addition of exogenous chemical antioxidants. This is the first known report of Mn2+-induction and antioxidant protection of thymine lesions in this SH-SY5Y cell line and contributes new information to the potential use of antioxidants as a therapeutic strategy for protection against Mn2+-induced oxidative DNA damage. [Copyright &y& Elsevier]

Abstract: Ultrafine superparamagnetic iron oxide nanoparticles (USPION) hold great potential for revolutionising biomedical applications such as MRI, localised hyperthermia, and targeted drug delivery. Though evidence is increasing regarding the influence of nanoparticle physico-chemical features on toxicity, data however, is lacking that assesses a range of such characteristics in parallel. We show that iron redox state, a subtle though important physico-chemical feature of USPION, dramatically modifies the cellular uptake of these nanoparticles and influences their induction of DNA damage. Surface chemistry was also found to have an impact and evidence to support a potential mechanism of oxidative DNA damage behind the observed responses has been demonstrated. As human exposure to ferrofluids is predicted to increase through nanomedicine based therapeutics, these findings are important in guiding the fabrication of USPION to ensure they have characteristics that support biocompatibility. [Copyright &y& Elsevier]

Abstract: Dietary supplements that contain bitter orange (Citrus aurantium) fruit as an integrated component have rapidly replaced ephedra-containing dietary supplements for use as weight loss products. However, the safety of bitter orange-containing supplements has been questioned because synephrine, an adrenergic alkaloid and a key component of bitter orange fruit, has potential adverse health effects. Conflicting reports have stated that synephrine exists as the para (p) and/or meta (m) positional isomers in some bitter orange-containing supplements and this is problematic because the p- and m-isomers have distinctly different pharmacological and metabolic activities. Two liquid chromatographic (LC) methods have been developed for the baseline separation and quantitation of p- and m-synephrine in bitter orange-containing supplements. An isocratic LC method that utilizes ultraviolet (UV) absorbance detection and a gradient LC method that utilizes tandem mass spectrometry (MS/MS) detection were optimized for separation of the isomers within a run time of 25min. Terbutaline was utilized as an internal standard compound in both LC methods. The LC/UV and LC/MS/MS methods demonstrated limits of quantitation (LOQs) for synephrine of ≈30ng (on-column) and ≈0.02ng (on-column), respectively, and each method exhibited analytical linearity over three orders of magnitude. Both LC methods were used to evaluate the synephrine levels in a limited selection of commercially available bitter orange-containing supplements. Significantly, m-synephrine was not detected in any of the tested dietary supplements. [Copyright &y& Elsevier]

Abstract: Heparins and low molecular weight heparins (LMWHs) are heterogeneous glycosaminoglycans derived from natural sources that are prescribed as anticoagulants. In this work, a direct-infusion electrospray ionization mass spectrometry (ESI-MS) method was applied to the quantitative analysis of known disaccharides in various native heparins and LMWHs after digestion with heparinase enzymes. Disaccharide ΔUA2S→GlcNS6S was found to compose the majority of all samples analyzed (81–88%). The values were significantly higher than those reported by previously published methods. The disaccharide isomer pair ΔUA→GlcNS6S/ΔUA2S→GlcNS was also detected in all samples at lower levels (11–19%). While digestion with heparinases I and II revealed a limited number of disaccharides, the addition of heparinase III to digests led to the detection of disaccharide ΔUA2S→GlcNAc6S in native porcine heparin. This result indicated the importance of utilizing all three heparinases to gain maximum information when analyzing heparin and LMWH digests. This method displayed good between-day (4–6%) and between-digest (1–2%) reproducibility in separate experiments. To determine if the digestion matrix was suppressing the signal of low-abundance disaccharides, several disaccharides were exogenously added at low levels (1–10pmol/mg) to a quenched digest reaction. Analysis revealed that low level disaccharides were detectable in this matrix above the limits of detection (0.1–0.2pmol/mg) and quantitation (0.2–0.7pmol/mg). While this method was unable to distinguish between disaccharide isomers, it utilized simple mass spectrometry instrumentation to provide useful quantitative data for characterizing preparations of native heparin and LMWH, which could be used to compare various marketed preparations of these popular anticoagulants. [Copyright &y& Elsevier]