Preserving Retinal Structure and Function with the Novel Nitroxide Antioxidant, DCTEIO.

Oxidative stress is a major contributor to progressive neurodegenerative disease and may be a key target for the development of novel preventative and therapeutic strategies. Nitroxides have been successfully utilised to study changes in redox status (biological probes) and modulate radical-induced oxidative stress. This study investigates the efficacy of DCTEIO (5,6-dicarboxy-1,1,3,3-tetraethyllisoindolin-2-yloxyl), a stable, kinetically-persistent, nitroxide-based antioxidant, as a retinal neuroprotectant. The preservation of retinal function following an acute ischaemic/reperfusion (I/R) insult in the presence of DCTEIO was quantified by electroretinography (ERG). Inflammatory responses in retinal glia were analysed by GFAP and IBA-1 immunohistochemistry, and retinal integrity assessed by histology. A nitroxide probe combined with flow cytometry provided a rapid technique to assess oxidative stress and the mitigation offered by antioxidant compounds in cultured 661W photoreceptor cells. DCTEIO protected the retina from I/R-induced damage, maintaining retinal function. Histological analysis showed preservation of retinal integrity with reduced disruption and disorganisation of the inner and outer nuclear layers. I/R injury upregulated GFAP expression, indicative of retinal stress, which was significantly blunted by DCTEIO. The number of 'activated' microglia, particularly in the outer retina, in response to cellular stress was also significantly reduced by DCTEIO, potentially suggesting reduced inflammasome activation and cell death. DCTEIO mitigated oxidative stress in 661W retinal cell cultures, in a dose-dependent fashion. Together these findings demonstrate the potential of DCTEIO as a neuroprotective therapeutic for degenerative diseases of the CNS that involve an ROS-mediated component, including those of the retina e.g. age-related macular degeneration and glaucoma.

Plasmonic Silver-Nanoparticle-Catalysed Hydrogen Abstraction from the C(sp3 )-H Bond of the Benzylic Cα atom for Cleavage of Alkyl Aryl Ether Bonds.

Selective activation of the C(sp3 )-H bond is an important process in organic synthesis, where efficiently activating a specific C(sp3 )-H bond without causing side reactions remains one of chemistry's great challenges. Here we report that illuminated plasmonic silver metal nanoparticles (NPs) can abstract hydrogen from the C(sp3 )-H bond of the Cα atom of an alkyl aryl ether ß-O-4 linkage. The intense electromagnetic near-field generated at the illuminated plasmonic NPs promotes chemisorption of the ß-O-4 compound and the transfer of photo-generated hot electrons from the NPs to the adsorbed molecules leads to hydrogen abstraction and direct cleavage of the unreactive ether Cß -O bond under moderate reaction conditions (≈90 °C). The plasmon-driven process has certain exceptional features: enabling hydrogen abstraction from a specific C(sp3 )-H bond, along with precise scission of the targeted C-O bond to form aromatic compounds containing unsaturated, substituted groups in excellent yields.

Surface-Plasmon-Enhanced Transmetalation between Copper and Palladium Nanoparticle Catalyst.

Surface-plasmon-mediated phenylacetylide intermediate transfer from the Cu to the Pd surface affords a novel mechanism for transmetalation, enabling wavelength-tunable cross-coupling and homo-coupling reaction pathway control. C-C bond forming Sonogashira coupling and Glaser coupling reactions in O2 atmosphere are efficiently driven by visible light over heterogeneous Cu and Pd nanoparticles as a mixed catalyst without base or other additives. The reaction pathway can be controlled by switching the excitation wavelength. Shorter wavelengths (400-500 nm) give the Glaser homo-coupling diyne, whereas longer wavelength irradiation (500-940 nm) significantly increases the degree of cross-coupling Sonogashira coupling products. The ratio of the activated intermediates of alkyne to the iodobenzene is wavelength dependent and this regulates transmetalation. This wavelength-tunable reaction pathway is a novel way to optimize the product selectivity in important organic syntheses.

Self-supporting covalent organic framework membranes synthesized through two different processes: solvothermal annealing and solvent vapor annealing.

Rigid, freestanding covalent organic framework (COF-1) membranes have been synthesized from 1,4-benzenediboronic acid (BDBA) precursors using two different approaches: room temperature solvent-vapour annealing (SVA) and solvothermal annealing (SA). Characterization of films using Fourier-transform infrared (FTIR) spectroscopy, x-ray diffraction (XRD), and various microscopies shows that the films obtained through the two different routes vary in their retained BDBA proportion, crystal size and macroscale morphology. Gas adsorption measurements give specific surface areas of 579 ± 7 m2 g-1 and 739 ± 11 m2 g-1 respectively, suggesting that the average porosity of these films is competitive with bulk-synthesized COF-1 particles. The films have a stratified structure, with a dense, thin top layer and a thicker, sponge-like base layer. Using nanoindentation, we measured the Young's modulus at the top surface of the SVA and SA films to be 3.64 ± 1.20 GPa and 3.33 ± 0.12 GPa respectively, with the smaller uncertainty for the SA film attributed to a more uniform morphology. These measurements provide useful experimental data pertaining to COF-1 mechanical properties, furnishing information relevant to the use of these free-standing membranes in applications such as gas filtration or storage.

Nitroxides affect neurological deficits and lesion size induced by a rat model of traumatic brain injury.

Research has attributed tissue damage post-traumatic brain injury (TBI) to two-pronged effects, increased reactive oxygen species (ROS) and impairment of endogenous antioxidant defence systems, underpinned by manganese superoxide dismutase (MnSOD). Novel antioxidant nitroxides have been shown to mimic MnSOD to ameliorate oxidative stress related disorders. This study aimed to investigate the effects of two nitroxides, CTMIO and DCTEIO, on the neurological outcomes following moderate TBI in rats induced by a weight drop device. The rats were immediately treated with CTMIO and DCTEIO (40 mM in drinking water) post-injury for up to 2 weeks. The brains were histologically examined at 24 h and 6 weeks post injury. DCTEIO reduced the lesion size at both 24h and 6 weeks, with normalised performance in sensory, motor and cognitive tests at 24h post-injury. Astrogliosis was heightened by DCTEIO at 24h and still elevated at 6 weeks in this group. In TBI brains, cellular damage was evident as reflected by changes in markers of mitophagy and autophagy (increased fission marker dynamin-related protein (Drp)-1, and autophagy marker light chain 3 (LC3)A/B and reduced fusion marker optic atrophy (Opa)-1). These were normalised by DCTEIO treatment. CTMIO, on the other hand, seems to be toxic to the injured brains, by increasing injury size at 6 weeks. In conclusion, DCTEIO significantly improved tissue repair and preserved neurological function in rats with TBI possibly via a mitophagy mechanism. This study provides evidence for DCTEIO as a promising new option to alleviate lesion severity after moderate TBI, which is not actively treated.

Relationship between Atmospheric PM-Bound Reactive Oxygen Species, Their Half-Lives, and Regulated Pollutants: Investigation and Preliminary Model.

The concentration, nature, and persistence of particulate matter (PM)-bound reactive oxygen species (ROS) are of significant interest in understanding how atmospheric pollution affects health. However, the inherent difficulties in their measurement, particularly regarding the so-called "short-lived" ROS, have limited our understanding of their persistence and concentrations in the atmosphere. This paper aims to address this limitation through the analysis of PM-bound ROS measurements from the Particle Into Nitroxide Quencher (PINQ) system at an atmospheric monitoring site in the city of Heshan, Guangdong Province, China. The measured daily average and standard deviation for the measurement period was 0.050 ± 0.017 nmol·m-3. The averaged measured concentration of ROS per mass of PM and standard deviation was 0.0012 ± nmol·mg. The dataset was also correlated with standard pollutants, and a simplified model was constructed to separate the contributions of short-lived (t1/2 = 5 min) and long-lived (t1/2 ∼ infinity) ROS to total concentration using ozone, carbon monoxide, and PM mass. This showed that the short-lived ROS contribute an average of 33% of the daily PM-bound ROS burden over the measurement period, up to 52% of daily average on elevated days, and up to 71% for hourly averages. These results highlight the need for accurate measurements of short-lived ROS and provide the starting point for a general model to predict PM-bound ROS concentrations using widely available standard pollutants for future epidemiological research.

Quantification of Particle-Bound Organic Radicals in Secondary Organic Aerosol.

The chemical composition and evolution of secondary organic aerosol (SOA) in the atmosphere represents one of the largest uncertainties in our current understanding of air quality. Despite vast research, the toxicological mechanisms relating to adverse human health effects upon exposure to particulate matter are still poorly understood. Particle-bound reactive oxygen species (ROS) may substantially contribute to observed health effects by influencing aerosol oxidative potential (OP). The role of radicals in both the formation and aging of aerosol, as well as their contribution to aerosol OP, remains highly uncertain. The profluorescent spin trap BPEAnit (9,10-bis(phenylethynyl)anthracenenitroxide), previously utilized to study combustion-generated aerosol, has been applied to provide the first estimate of particle-bound radical concentrations in SOA. We demonstrate that SOA from different atmospherically important VOC precursors have different particle-bound radical concentrations, estimated for the ozonolysis of α-pinene (0.020 ± 0.0050 nmol/µg), limonene (0.0059 ± 0.0010 nmol/µg), and ß-caryophyllene (0.0025 ± 0.00080 nmol/µg), highlighting the potential importance of OH-initiated formation of particle-bound organic radicals. Additionally, the lifetime of particle-bound radical species in α-pinene SOA was estimated, and a pseudo-first-order rate constant of k = 7.3 ± 1.7 × 10-3 s-1 was derived, implying a radical lifetime on the order of minutes.

Application of a Fluorescent Probe for the Online Measurement of PM-Bound Reactive Oxygen Species in Chamber and Ambient Studies.

This manuscript details the application of a profluorescent nitroxide (PFN) for the online quantification of radical concentrations on particulate matter (PM) using an improved Particle Into Nitroxide Quencher (PINQ). A miniature flow-through fluorimeter developed specifically for use with the 9,10-bis(phenylethynyl)anthracene-nitroxide (BPEAnit) probe was integrated into the PINQ, along with automated gas phase corrections through periodic high efficiency particle arrestor (HEPA) filtering. The resulting instrument is capable of unattended sampling and was operated with a minimum time resolution of 2.5 min. Details of the fluorimeter design and examples of data processing are provided, and results from a chamber study of side-stream cigarette smoke and ambient monitoring campaign in Guangzhou, China are presented. Primary cigarette smoke was shown to have both short-lived (t1/2 = 27 min) and long-lived (t1/2 = indefinite) PM-bound reactive oxygen species (ROS) components which had previously only been observed in secondary organic aerosol (SOA).

Selective Oxidation of 5-Hydroxymethylfurfural to 2,5-Furandicarboxylic Acid Using O2 and a Photocatalyst of Co-thioporphyrazine Bonded to g-C3N4.

Selective oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) is one of the key reactions for producing chemical commodities from biomass and their derivatives. The challenge for this reaction is to develop an efficient catalytic process that can be conducted under mild conditions (room temperature and atmospheric pressure, using oxygen molecules in air as the oxidant) and a recyclable catalyst. Herein we report a photocatalyst of cobalt thioporphyrazine (CoPz) dispersed on g-C3N4 (abbreviated as CoPz/g-C3N4), which exhibits excellent catalytic activity toward the selective oxidation of HMF into FDCA under simulated sunlight using oxygen molecules in air as a benign oxidant. For example, an FDCA yield of 96.1% in an aqueous solution at pH = 9.18 is achieved at ambient temperature and air pressure. At lower pH (4.01), the product generated is 2,5-diformylfuran. Hence, it is possible to control the reaction outcome by control of the pH of the reaction system. g-C3N4 itself is not a suitable catalyst for the selective oxidation because under the experimental conditions g-C3N4 generates hydroxyl radicals that initiate processes that oxidize HMF directly to CO2 and H2O. CoPz on the other hand activates O2 to give singlet oxygen (1O2), which more controllably oxidizes HMF to FDCA albeit at a more moderate yield (36.2%). The strong interaction between the CoPz and g-C3N4 in the CoPz/g-C3N4 catalyst is experimentally evidenced, which not only improves accessibility of the CoPz sites and makes the catalyst recyclable but also disables the hydroxyl radical generation by g-C3N4 and promotes 1O2 generation on the CoPz sites, significantly enhancing the catalytic performance. This study demonstrates the potential for efficient non-noble metal photocatalysts for organic transformations driven by sunlight.

Predicting a graphene-like WB4 nanosheet with a double Dirac cone, an ultra-high Fermi velocity and significant gap opening by spin-orbit coupling.

The zero-band gap nature of graphene prevents it from performing as a semi-conductor in modern electronics. Although various graphene modification strategies have been developed to address this limitation, the very small band gap of these materials and the suppressed charge carrier mobility of the devices developed still significantly hinder graphene's applications. In this work, a two dimensional (2D) WB4 monolayer, which exhibits a double Dirac cone, was conceived and assessed using density functional theory (DFT) methods, which would provide a sizable band gap while maintaining higher charge mobility with a Fermi velocity of 1.099 × 106 m s-1. Strong spin-orbit-coupling can generate an observable band gap of up to 0.27 eV that primarily originates from the d-orbit of the heavy metal atom W; therefore a 2D WB4 nanosheet would be operable at room temperature (T = 300 K) and would be a promising candidate to fabricate nanoelectronics in the upcoming post-silicon era. The phonon-spectrum and ab initio molecular dynamics calculations further demonstrate the dynamic and thermal stability of such nanosheets, thus, suggesting a potentially synthesizable Dirac material.

Two-dimensional GeP3 as a high capacity electrode material for Li-ion batteries.

Two-dimensional (2D) materials are promising for use in lithium (Li) electrodes due to their high surface ratio. By using density functional theory (DFT) calculations, we investigate the adsorption and diffusion of Li on a newly predicted 2D GeP3 material [Nano Lett., 2016, 17, 1833]. The most favourable adsorption sites for Li are identified, and a semiconducting to metallic transition induced by Li adsorption is found, which indicates excellent electrical conductivity. The GeP3 monolayer has an estimated capacity of 648 mA h g-1, which is almost twice that of commercially used graphite (375 mA h g-1). During full Li intercalation, the GeP3 layer undergoes only 1.2% lattice parameter reduction. Moreover, GeP3 possesses the advantages of a small diffusion barrier (∼0.5 eV) and low average open-circuit voltages (∼0.4 V). Our results highlight a new class of promising anode materials, i.e. 2D phosphide, as potential rechargeable lithium batteries with ultrahigh-capacity, superior ionic conductivity, and low average open-circuit voltage.

Catalytic transformation of aliphatic alcohols to corresponding esters in O2 under neutral conditions using visible-light irradiation.

Selective oxidation of aliphatic alcohols under mild and base-free conditions is a challenging process for organic synthesis. Herein, we report a one-pot process for the direct oxidative esterification of aliphatic alcohols that is significantly enhanced by visible-light irradiation at ambient temperatures. The new methodology uses heterogenerous photocatalysts of gold-palladium alloy nanoparticles on a phosphate-modified hydrotalcite support and molecular oxygen as a benign oxidant. The alloy photocatalysts can absorb incident light, and the light-excited metal electrons on the surface of metal nanoparticles can activate the adsorbed reactant molecules. Tuning the light intensity and wavelength of the irradiation can remarkably change the reaction activity. Shorter wavelength light (<550 nm) drives the reaction more efficiently than light of longer wavelength (e.g., 620 nm), especially at low temperatures. The phosphate-exchanged hydrotalcite support provides sufficient basicity (and buffer) for the catalytic reactions; thus, the addition of base is not required. The photocatalysts are efficient and readily recyclable. The findings reveal the first example of using "green" oxidants and light energy to drive direct oxidative esterification of aliphatic alcohols under base-free, mild conditions.

Polyaromatic Profluorescent Nitroxide Probes with Enhanced Photostability.

Novel profluorescent mono- and bis-isoindoline nitroxides linked to napthalimide and perylene diimide structural cores are described. These nitroxide-fluorophore probes display strongly suppressed fluorescence in comparison to their corresponding non-radical diamagnetic methoxyamine derivatives. The perylene-based probe possessing two isoindoline systems tethered through ethynyl linkages was shown to be the most photostable in solution, demonstrating significantly enhanced longevity over the 9,10-bis(phenylethynyl)anthracene fluorophore used in previous profluorescent nitroxide probes.

Design of Redox/Radical Sensing Molecules via Nitrile Imine-Mediated Tetrazole-ene Cycloaddition (NITEC).

The current study introduces a novel synthetic avenue for the preparation of profluorescent nitroxides via nitrile imine-mediated tetrazole-ene cycloaddition (NITEC). The photoinduced cycloaddition was performed under metal-free, mild conditions allowing the preparation of a library of the nitroxide functionalized pyrazolines and corresponding methoxyamines. High reaction rates and full conversion were observed, with the presence of the nitroxide having no significant impact on the cycloaddition performance. The formed products were investigated with respect to their photophysical properties in order to quantify their "switch on/off" behavior. The fluorescence quenching performance is strongly dependent on the distance between the chromophore and the free radical spin as demonstrated theoretically and experimentally. Highest levels of fluorescence quenching were achieved for pyrazolines with the nitroxide directly fused to the chromophore. Importantly, the pyrazoline profluorescent nitroxides were shown to efficiently act as sensors for redox/radical processes.

Dynamic, in vivo, real-time detection of retinal oxidative status in a model of elevated intraocular pressure using a novel, reversibly responsive, profluorescent nitroxide probe.

Changes to the redox status of biological systems have been implicated in the pathogenesis of a wide variety of disorders including cancer, Ischemia-reperfusion (I/R) injury and neurodegeneration. In times of metabolic stress e.g. ischaemia/reperfusion, reactive oxygen species (ROS) production overwhelms the intrinsic antioxidant capacity of the cell, damaging vital cellular components. The ability to quantify ROS changes in vivo, is therefore essential to understanding their biological role. Here we evaluate the suitability of a novel reversible profluorescent probe containing a redox-sensitive nitroxide moiety (methyl ester tetraethylrhodamine nitroxide, ME-TRN), as an in vivo, real-time reporter of retinal oxidative status. The reversible nature of the probe's response offers the unique advantage of being able to monitor redox changes in both oxidizing and reducing directions in real time. After intravitreal administration of the ME-TRN probe, we induced ROS production in rat retina using an established model of complete, acute retinal ischaemia followed by reperfusion. After restoration of blood flow, retinas were imaged using a Micron III rodent fundus fluorescence imaging system, to quantify the redox-response of the probe. Fluorescent intensity declined during the first 60 min of reperfusion. The ROS-induced change in probe fluorescence was ameliorated with the retinal antioxidant, lutein. Fluorescence intensity in non-Ischemia eyes did not change significantly. This new probe and imaging technology provide a reversible and real-time response to oxidative changes and may allow the in vivo testing of antioxidant therapies of potential benefit to a range of diseases linked to oxidative stress.

Photocatalytic conversion of sugars to 5-hydroxymethylfurfural using aluminium(III) and fulvic acid.

5-hydroxymethylfurfural (HMF) is a valuable and essential platform chemical for establishing a sustainable, eco-friendly fine-chemical and pharmaceutical industry based on biomass. The cost-effective production of HMF from abundant C6 sugars requires mild reaction temperatures and efficient catalysts from naturally abundant materials. Herein, we report how fulvic acid forms complexes with Al3+ ions that exhibit solar absorption and photocatalytic activity for glucose conversion to HMF in one-pot reaction, in good yield (~60%) and at moderate temperatures (80 °C). When using representative components of fulvic acid, catechol and pyrogallol as ligands, 70 and 67% HMF yields are achieved, respectively, at 70 °C. Al3+ ions are not recognised as effective photocatalysts; however, complexing them with fulvic acid components as light antennas can create new functionality. This mechanism offers prospects for new green photocatalytic systems to synthesise a range of substances that have not previously been considered.

Two-photon fluorescence microscopy imaging of cellular oxidative stress using profluorescent nitroxides.

A range of varying chromophore nitroxide free radicals and their nonradical methoxyamine analogues were synthesized and their linear photophysical properties examined. The presence of the proximate free radical masks the chromophore's usual fluorescence emission, and these species are described as profluorescent. Two nitroxides incorporating anthracene and fluorescein chromophores (compounds 7 and 19, respectively) exhibited two-photon absorption (2PA) cross sections of approximately 400 G.M. when excited at wavelengths greater than 800 nm. Both of these profluorescent nitroxides demonstrated low cytotoxicity toward Chinese hamster ovary (CHO) cells. Imaging colocalization experiments with the commercially available CellROX Deep Red oxidative stress monitor demonstrated good cellular uptake of the nitroxide probes. Sensitivity of the nitroxide probes to H(2)O(2)-induced damage was also demonstrated by both one- and two-photon fluorescence microscopy. These profluorescent nitroxide probes are potentially powerful tools for imaging oxidative stress in biological systems, and they essentially "light up" in the presence of certain species generated from oxidative stress. The high ratio of the fluorescence quantum yield between the profluorescent nitroxide species and their nonradical adducts provides the sensitivity required for measuring a range of cellular redox environments. Furthermore, their reasonable 2PA cross sections provide for the option of using two-photon fluorescence microscopy, which circumvents commonly encountered disadvantages associated with one-photon imaging such as photobleaching and poor tissue penetration.

Computational design of cyclic nitroxides as efficient redox mediators for dye-sensitized solar cells.

Cyclic nitroxide radicals represent promising alternatives to the iodine-based redox mediator commonly used in dye-sensitized solar cells (DSSCs). To date DSSCs with nitroxide-based redox mediators have achieved energy conversion efficiencies of just over 5 % but efficiencies of over 15 % might be achievable, given an appropriate mediator. The efficacy of the mediator depends upon two main factors: it must reversibly undergo one-electron oxidation and it must possess an oxidation potential in a range of 0.600-0.850 V (vs. a standard hydrogen electrode (SHE) in acetonitrile at 25 °C). Herein, we have examined the effect that structural modifications have on the value of the oxidation potential of cyclic nitroxides as well as the reversibility of the oxidation process. These included alterations to the N-containing skeleton (pyrrolidine, piperidine, isoindoline, azaphenalene, etc.), as well as the introduction of different substituents (alkyl-, methoxy-, amino-, carboxy-, etc.) to the ring. Standard oxidation potentials were calculated using high-level ab initio methodology that was demonstrated to be very accurate (with a mean absolute deviation from experimental values of only 16 mV). An optimal value of 1.45 for the electrostatic scaling factor for UAKS radii in acetonitrile solution was obtained. Established trends in the values of oxidation potentials were used to guide molecular design of stable nitroxides with desired E(ox)°, and a number of compounds were suggested for potential use as enhanced redox mediators in DSSCs.

Reactions of sulfoxides with reactive oxygen species to reveal the radical chemistry of pollution-derived particulate matter.

The radical reactions of dimethylsulfoxide (DMSO) and tetrahydrothiophene-1-oxide (THTO) with reactive oxygen species (ROS) in the presence of a nitroxide radical scavenger have been evaluated both synthetically and in analytical practice. Fenton-mediated generation of oxygen-centred radicals produced several unusual products that reflect the fragmentation and ring-opening radical mechanisms of DMSO and THTO respectively. Addition of pollution-derived ROS to DMSO/THTO nitroxide solutions produced LC-MS detectable amounts of the same products isolated from the larger-scaled Fenton reactions. For air pollution analysis, these results highlight the complexity surrounding DMSO reactivity and fragmentation, and indicate that THTO produces simpler outcomes that should facilitate analysis of the processes involved.

Generation of profluorescent isoindoline nitroxides using click chemistry.

Novel profluorescent nitroxides bearing a triazole linker between the coumarin fluorophore and an isoindoline nitroxide were prepared in good yields using the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC). Nitroxides containing 7-hydroxy and 7-diethylamino substitution on their coumarin rings displayed significant fluorescence suppression, and upon reaction with methyl radicals, normal fluorescence emission was returned. The fluorescence emission for the 7-hydroxycoumarin nitroxide and its diamagnetic analogue was found to be strongly influenced by pH with maximal fluorescence emission achieved in basic solution. Solvent polarity was also shown to affect fluorescence emission. The significant difference in fluorescence output between the nitroxides and their corresponding diamagnetic analogues makes these compounds ideal tools for monitoring processes involving free-radical species.