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"Edgar, Kevin"
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Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting
Despite being first described 45 years ago, the existence of a distinct diabetic cardiomyopathy remains controversial. Nonetheless, it is widely accepted that the diabetic heart undergoes characteristic structural and functional changes in the absence of ischaemia and hypertension, which are independently linked to heart failure progression and are likely to underlie enhanced susceptibility to stress. A prominent feature is marked collagen accumulation linked with inflammation and extensive extracellular matrix changes, which appears to be the main factor underlying cardiac stiffness and subclinical diastolic dysfunction, estimated to occur in as many as 75% of optimally controlled diabetics. Whether this characteristic remodelling phenotype is primarily driven by microvascular dysfunction or alterations in cardiomyocyte metabolism remains unclear. Although hyperglycaemia regulates multiple pathways in the diabetic heart, increased reactive oxygen species (ROS) generation is thought to represent a central mechanism underlying associated adverse remodelling. Indeed, experimental and clinical diabetes are linked with oxidative stress which plays a key role in cardiomyopathy, while key processes underlying diabetic cardiac remodelling, such as inflammation, angiogenesis, cardiomyocyte hypertrophy and apoptosis, fibrosis and contractile dysfunction, are redox sensitive. This review will explore the relative contributions of the major ROS sources (dysfunctional nitric oxide synthase, mitochondria, xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases) in the diabetic heart and the potential for therapeutic targeting of ROS signalling using novel pharmacological and non-pharmacological approaches to modify specific aspects of the remodelling phenotype in order to prevent and/or delay heart failure development and progression.
Journal Article
Chlorination of hydroxyethyl cellulose enables selective functionalization
Chemical modification of cellulose is challenging due to its low reactivity and poor solubility. Halogenation followed by displacement reactions has been demonstrated to be a valuable strategy for appending new functionalities to the anhydroglucose rings of cellulose and cellulose derivatives. In this paper, we report a simple and efficient pathway to modify the inexpensive, commercial cellulose ether, hydroxyethyl cellulose (HEC). First, methanesulfonyl chloride (MsCl) in N, N-dimethyl formamide (DMF) can selectively chlorinate the terminal primary hydroxyl groups from hydroxyethyl cellulose (HEC), thereby affording high terminal chloride content. Then, the resulting chlorinated HEC undergoes displacement reactions with various nucleophiles including azide (NaN3), amine (1-methylimidazole), and thiols (3-mercaptopropionic acid and 2-mercaptoethanol). All products were characterized by NMR and FT-IR spectroscopic methods. Exploiting this strategy, we prepared a library of HEC derivatives, including cationic and anionic derivatives, which are of great interest in various applications including as surfactants, in gas separation membranes, and as crystallization inhibitors in amorphous solid dispersions for oral drug bioavailability enhancement.
Journal Article
Photo-curable, double-crosslinked, in situ-forming hydrogels based on oxidized hydroxypropyl cellulose
Chemoselective oxidation of oligo(hydroxypropyl)-substituted polysaccharides affords ketones at side chain termini, which readily condense to in situ-forming hydrogels with amine-containing polymers. This type of imine-crosslinked hydrogel displays several interesting and practically valuable properties including injectability, self-healing, tunable moduli, and ability to respond to multiple types of stimulus, so that these are promising materials for biomedical applications. As oligo(hydroxypropyl)-substituted polysaccharides are multi-functional and have the potential to be further chemically modified, a variety of useful motifs and interesting properties can be incorporated into these hydrogel systems. In this study, methacrylate groups were appended to oxidized hydroxypropyl cellulose (Ox-HPC) by esterification, conveying to the hydrogel the ability to be cured by exposure to ultraviolet (UV) radiation and reinforced by this second crosslinking mechanism. Hydrogel modulus was greatly enhanced (from 1800 Pa to 14 kPa) by UV curing. These hydrogels exhibit self-healing and injectability properties both before and after UV curing, suggesting that these materials have promise, including for 3D printing and biomedical applications. Overall, this work demonstrates synthesis, preparation, and photo-responsive properties of methacrylate-functionalized Ox-HPC/Chitosan hydrogels, broadening the family and utility of oligo(hydroxypropyl)-substituted, polysaccharide-based hydrogels.Graphic abstractUV-induced crosslinking of acrylated Ox-HPC/chitosan hydrogel.
Journal Article
Cellulose esters in drug delivery
Cellulose esters have played a vital role in the development of modern drug delivery technology. They possess properties that are not only well-suited to the needs of pharmaceutical applications, but that enable construction of drug delivery systems that address critical patient needs. These properties include very low toxicity, endogenous and/or dietary decomposition products, stability, high water permeability, high Tg, film strength, compatibility with a wide range of actives, and ability to form micro- and nanoparticles. This suite of properties has enabled the creation of a wide range of drug delivery systems employing cellulose esters as key ingredients. The following is a review of the most important types of these systems, and of the critical roles played by cellulose esters in making them work, focusing on more recent developments.
Journal Article
BH4 supplementation reduces retinal cell death in ischaemic retinopathy
Dysregulation of nitric oxide (NO) production can cause ischaemic retinal injury and result in blindness. How this dysregulation occurs is poorly understood but thought to be due to an impairment in NO synthase function (NOS) and nitro-oxidative stress. Here we investigated the possibility of correcting this defective NOS activity by supplementation with the cofactor tetrahydrobiopterin, BH
4
. Retinal ischaemia was examined using the oxygen-induced retinopathy model and BH
4
deficient Hph-1 mice used to establish the relationship between NOS activity and BH
4
. Mice were treated with the stable BH
4
precursor sepiapterin at the onset of hypoxia and their retinas assessed 48 h later. HPLC analysis confirmed elevated BH
4
levels in all sepiapterin supplemented groups and increased NOS activity. Sepiapterin treatment caused a significant decrease in neuronal cell death in the inner nuclear layer that was most notable in WT animals and was associated with significantly diminished superoxide and local peroxynitrite formation. Interestingly, sepiapterin also increased inflammatory cytokine levels but not microglia cell number. BH
4
supplementation by sepiapterin improved both redox state and neuronal survival during retinal ischaemia, in spite of a paradoxical increase in inflammatory cytokines. This implicates nitro-oxidative stress in retinal neurones as the cytotoxic element in ischaemia, rather than enhanced pro-inflammatory signalling.
Journal Article
A Versatile Method for Preparing Polysaccharide Conjugates via Thiol-Michael Addition
Polysaccharide conjugates are important renewable materials. If properly designed, they may for example be able to carry drugs, be proactive (e.g., with amino acid substituents) and can carry a charge. These aspects can be particularly useful for biomedical applications. Herein, we report a simple approach to preparing polysaccharide conjugates. Thiol-Michael additions can be mild, modular, and efficient, making them useful tools for post-modification and the tailoring of polysaccharide architecture. In this study, hydroxypropyl cellulose (HPC) and dextran (Dex) were modified by methacrylation. The resulting polysaccharide, bearing α,β-unsaturated esters with tunable DS (methacrylate), was reacted with various thiols, including 2-thioethylamine, cysteine, and thiol functional quaternary ammonium salt through thiol-Michael addition, affording functionalized conjugates. This click-like synthetic approach provided several advantages including a fast reaction rate, high conversion, and the use of water as a solvent. Among these polysaccharide conjugates, the ones bearing quaternary ammonium salts exhibited competitive antimicrobial performance, as supported by a minimum inhibitory concentration (MIC) study and tracked by SEM characterization. Overall, this methodology provides a versatile route to polysaccharide conjugates with diverse functionalities, enabling applications such as antimicrobial activity, gene or drug delivery, and biomimicry.
Journal Article
Influence of cross-section shape on structure and properties of Lyocell fibers
Three kinds of Lyocell fibers with different cross-sections including circular, H-shape, and Y-shape (abbreviated as O-, H-, and Y-Lyocell) were prepared by a dry-jet wet spinning method. The effects of cross-sectional shape on structure and properties of Lyocell fibers were evaluated. The results showed H-Lyocell and Y-Lyocell exhibited triangular and dumbbell cross-sections, respectively, due to die swell. Both non-roundness factor and crystallinity of different cross-sectional Lyocell fibers were in the order of H-Lyocell > Y-Lyocell > O-Lyocell. All cross-sectional Lyocell fibers showed similar values of fineness and tensile strength. The profiled Lyocell fibers were superior to circular Lyocell fibers in terms of luster, dyeing properties, and moisture regain. The dye uptake and fixation rate of Lyocell fibers were influenced by shape in the order H-Lyocell > Y-Lyocell > O-Lyocell; while for luster and moisture regain the order was Y-Lyocell > H-Lyocell > O-Lyocell. Profiled Lyocell fibers are expected to open broader prospects in different textile or composite fields due to their various advantages versus conventional circular Lyocell fibers.
Journal Article
In situ forming hydrogels based on oxidized hydroxypropyl cellulose and Jeffamines
Oligo(hydroxypropyl)-substituted polysaccharides can be chemoselectively oxidized to introduce ketone groups at the termini of the side chains. These ketone-substituted polysaccharides, including oxidized hydroxypropyl cellulose, have been shown to be suitable components for preparation of in situ forming, all-polysaccharide hydrogels where chitosan is the reactive partner. This class of hydrogels exhibits several advantages including injectability, the ability to self-heal, and the absence of small molecule crosslinkers, therefore they have considerable promise for biomedical applications. Their strong potential inspires us to broaden the range of their application to include thermoresponsive hydrogels. Herein, we design and prepare a series of oxidized hydroxypropyl cellulose hydrogels by reaction with Jeffamines. Jeffamines themselves are polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide triblock copolymers with two terminal amines. They display thermal responsivity, and are biocompatible with some tissues and under some circumstances. The mechanical properties of these Jeffamine/oxidized hydroxypropyl cellulose hydrogels were characterized by rheometry, revealing that hydrogel storage modulus could be tuned (3, 300–21, 000 Pa) by controlling temperature (25–60 °C) and Jeffamine chain length (600, 900, 1900 g/mol). Furthermore, these hydrogels display self-healing properties and high swelling ratios. Hydrogel microstructures were characterized by scanning electron microscopy. We investigated the potential for drug incorporation into the hydrogels. Overall, this study demonstrated synthesis and potential of these Jeffamine/oxidized hydroxypropyl cellulose hydrogels for in situ formation and thermally responsive behavior, thereby broadening the family of oxidized hydroxypropyl cellulose-based hydrogels.
Journal Article
Structure and properties of flax vs. lyocell fiber-reinforced polylactide stereocomplex composites
A commonly used natural cellulose fiber (flax) and a regenerated cellulose fiber (Lyocell) were used at 20 wt% to reinforce polylactide stereocomplex (sc-PLA) composites. Composites were prepared by melt compounding cellulose fibers and an equivalent proportion of PLLA/PDLA, followed by injection molding. The structures and properties of these two kinds of cellulose fiber/sc-PLA composites were compared and evaluated. The results showed that the total crystallinity and stereocomplex crystallite content of composites could be increased by reinforcing with cellulose fibers, and Lyocell fibers were more effective in accelerating crystallinity and the formation of stereocomplex crystallites than flax fibers. Mechanical properties of Lyocell fibers were much poorer than those of flax fibers, and the interfacial adhesion values of Lyocell/sc-PLA composites were inferior to those of flax/sc-PLA composites. Lyocell/sc-PLA composites showed higher impact strength and similar tensile strength vs. flax/sc-PLA composites, but the Young’s modulus values of Lyocell/sc-PLA composites were lower than those of flax/sc-PLA composites. The Vicat softening temperatures of both flax/sc-PLA and Lyocell/sc-PLA composites were increased to nearly 100 °C higher than that of PLLA. Lyocell/sc-PLA composites showed the highest Vicat softening temperature of ~ 170 °C.
Journal Article