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Biomedical subjects

D P Naughton

Publications and source records attributed to D P Naughton.

At least 19 recordsLinked to original sources
PubMed2005

Metal ion chelating peptides with superoxide dismutase activity.

The superoxide dismutase activities of two novel synthetic chelating peptides are reported. The peptides comprise a polyaminocarboxylic acid chelator (EDTA) conjugated to tyrosine (ET(1)) and phenylalanine (EP(1)). Superoxide dismutase (SOD) activity was exhibited for Cu(II) but not the Fe(III) complexes. The mimetic activities were compared to bovine erythrocyte SOD (3730 U/mg) and exhibited activities of 1119 U/mg for ET(1)-Cu(II) and 551 U/mg for EP(1)-Cu(II). Thus, small alterations in structure can have significant effects on the enzymatic activity of metallopeptides. These synthetic chelators have dual potential anti-inflammatory activity by chelating deleterious non-protein bound metal ions and concomitantly affording anti-oxidant mimetic activity.

Antioxidants↗
PubMed2003

Hypoxia-induced upregulation of the glycolytic enzyme glucose-6-phosphate isomerase perpetuates rheumatoid arthritis.

Intra-articular hypoxia in the inflamed rheumatoid joint is associated with increased cell proliferation, enhanced metabolism and compromised vascular perfusion. Recent clinical studies using direct measurements of hypoxia in rheumatoid joints have delineated up to 20% of soft tissue pO(2) readings as below 10mm Hg. Increased markers for glycolysis exist in rheumatoid synovial fluid and upregulation of tissue glycolytic enzymes occurs in a rat model of synovitis. Recent reports show arthritis is provoked by linked T and B cell lymphocyte recognition of the glycolytic enzyme glucose-6-phosphate isomerase (GPI). This suggests an unusual physiological feature of rheumatoid joints leads to autoimmune destruction. In this report I suggest that hypoxia, within the rheumatoid joint, leads to upregulation of the glycolytic enzyme GPI which in turn perpetuates rheumatoid arthritis.

Animals↗
PubMed2003

Novel peptoids for the detection and suppression of reactive oxygen and nitrogen species.

Novel peptoids useful for the detection and suppression of various components contributing to oxidative stress and for elucidation of the interplay between these species are presented. Oxidative stress involves redox-active metal ion activation/generation of RONS (reactive oxygen and nitrogen species). For detection of RONS, the peptoid probes consist of a conjugate designed to (1) complex redox-active and non-redox-active metal ions, and (2) differentiate between RONS based upon the reaction products following RONS attack on the probe. For suppression of RONS, subtle modifications in peptoid structure impart catalase and superoxide dismutase activities to the peptoids upon ferric or cupric ion complexation.

Nitrogen↗
PubMed2001

Drug targeting to hypoxic tissue using self-inactivating bioreductive delivery systems.

Hypoxia is a characteristic feature of a number of diseases including some cancers, rheumatoid arthritis and diabetes. Hypoxic tissue facilitates the use of bioreductive drug targeting systems as oxygen suppresses the release of the active drug. This review focuses on bioreductive delivery where accompanying intramolecular cyclisation negates adduct formation between the bioreductive and macromolecules such as DNA. To date, three systems have been reported. In the quinone lactonization system, reduction of the quinone facilitates through bond cyclisation and concomitant release of the drug. In the self-alkylating system, a nucleophile is built into the bioreductive structure to favour intramolecular cyclisation over nucleophilic attack from DNA moieties. The final system is based on vitamin E which undergoes redox mediated cyclisation between its oxidised (tocopherol quionone) and reduced (tocopherol) forms. Self-inactivating bioreductive delivery systems represent a powerful tool for extending bioreductive-based drug delivery to non-cancerous hypoxic tissues.

Animals↗
PubMed2001

EDTA bis-(ethyl phenylalaninate): a novel transition metal-ion chelating hydroxyl radical scavenger with a potential anti-inflammatory role.

Conjugation of ethylenediaminetetraacetic acid (EDTA) to ethyl phenylalaninate generates a novel radical scavenging metal-ion chelator EDTA bis-(ethyl phenylalaninate) (EBEP). The oxidation products o-, m- and p-tyrosine were isolated from hydrolysed, aqueous and aerated solutions containing EBEP, Fe(II) and H(2)O(2). Data obtained demonstrate the potential of EBEP to act as a radical scavenging, iron-ion chelating antioxidant under physiologically relevant conditions.

Anti-Inflammatory Agents↗
PubMed2001

Iron(III)-mediated intra-articular crystal deposition in arthritis: a therapeutic role for iron chelators.

Crystal deposition in arthritic diseases has attracted much interest. Many reports have established the presence of calcium pyrophosphate (CPPD), hydroxyapatite (HAP) and urate crystals throughout the range of arthritic diseases. In particular, HAP crystals have been detected in 30-60% of synovial fluid (SF) samples from patients suffering from osteoarthritis (OA) and 33% of those suffering from rheumatoid arthritis (RA). In OA, crystal deposition has been linked to greater joint deterioration. The mechanism of intra-articular calcification is unknown. Nucleation is required to transform a 'metastable' phosphate- and calcium-rich biofluid into one that generates crystals. Ferric ions have been demonstrated to induce crystallization of these stable supersaturated solutions via the process of nucleation. The inflamed arthritic joint is prone to iron loading. Microbleeding from compromised vasculature contributes to intra-articular iron loading in arthritic conditions. Low-molecular-mass redox-active iron complexes have been detected in SF in inflammatory joint diseases. These species are credited with mediating oxidative stress via interaction with peroxides and superoxide. In addition, adventitious low-molecular-mass iron complexes can cause nucleation leading to crystal growth within the joint. Decorporating agents capable of removing this misplaced iron from the arthritic joint would have the joint benefit of relieving oxidative stress and preventing crystal nucleation. Systemic side effects could be overcome by the targeting suitable chelators using bioreductive delivery systems that are activated in hypoxic inflamed synovial tissue.

Arthritis, Rheumatoid↗
PubMed1999

2-nitroimidazol-5-ylmethyl as a potential bioreductively activated prodrug system: reductively triggered release of the PARP inhibitor 5-bromoisoquinolinone.

5-Chloromethyl-1-methyl-2-nitroimidazole reacted efficiently with the anion derived from 5-bromoisoquinolin-1-one to give 5-bromo-2-((1-methyl-2-nitroimidazol-5-yl)methyl)isoquinolin -1-one. Biomimetic reduction effected release of the 5-bromoisoquinolin-1-one. The 2-nitroimidazol-5-ylmethyl unit thus has potential for development as a general prodrug system for selective drug delivery to hypoxic tissues.

Ammonium Chloride↗
PubMed1997

Multicomponent spectroscopic investigations of salivary antioxidant consumption by an oral rinse preparation containing the stable free radical species chlorine dioxide (ClO2.).

A multicomponent evaluation of the oxidative consumption of salivary biomolecules by a commercially-available oral rinse preparation containing an admixture of the stable free radical species chlorine dioxide (ClO2.) with chlorite anion (ClO2-) has been investigated using high resolution 1H NMR spectroscopy. The results obtained demonstrated that ClO2. and/or ClO2- present in this preparation effected the oxidative decarboxylation of salivary pyruvate (to acetate and CO2). Experiments conducted on chemical model systems confirmed the oxidative decarboxylation of pyruvate by this oral rinse, and also demonstrated that urate, thiocyanate anion, and the amino acids cysteine and methionine (precursors to volatile sulphur compounds responsible for oral malodour), were oxidatively consumed. The biochemical, periodontal and therapeutic significance of the results are discussed.

Absorption↗
PubMed1996

When is a radical not a radical?

It is not commonly realised that symmetrical Fe(III) complexes are expected to have EPR spectra dominated by a symmetrical narrow line close to the free-spin g-value. The aim of this note is to stress that such features can be mistakenly identified as the spectra for stable organic radicals. This situation is a particular problem in studies of animal or plant tissue samples.

Animals↗
PubMed1995

Detection and investigation of the molecular nature of low-molecular-mass copper ions in isolated rheumatoid knee-joint synovial fluid.

Low-molecular-mass copper(II) species have been detected and quantified in ultrafiltrates (n = 7) of rheumatoid synovial fluid (SF) by a highly-sensitive HPLC-based assay system with the ability to determine Cu(II) concentrations of < 10(-7) mol.dm-3. High field 1H NMR spectroscopy demonstrated that addition of Cu(II)(aq.) to isolated samples of RA SF ultrafiltrates resulted in complexation by histidine > alanine > formate > threonine > lactate > tyrosine > phenylalanine, their effectiveness in this context being in the given order. CD spectra of Cu(II)-treated samples of intact SF exhibited absorption bands typical of copper(II)-albumin complexes, in addition to a band attributable to a low-molecular-mass histidinate complex (lambda min 610 nm). Since both albumin and histidine are potent radical scavengers, these results indicate that any .OH radical generated from bound copper ions will be 'site-specifically' scavenged. Hence, low-molecular-mass copper complexes with the ability to promote the generation of .OH radical which can then escape from the metal ion co-ordination sphere (and in turn, cause damage to critical biomolecules) appear to be absent from inflammatory SF.

Adult↗
PubMed1995

Detection of aldehydes and their conjugated hydroperoxydiene precursors in thermally-stressed culinary oils and fats: investigations using high resolution proton NMR spectroscopy.

High field (400 and 600 MHz) proton NMR spectroscopy has been employed to investigate the thermally-induced autoxidation of glycerol-bound polyunsaturated fatty acids present in intact culinary frying oils and fats. Heating of these materials at 180 degrees C for periods of 30, 60 and 90 min. generated a variety of peroxidation products, notably aldehydes (alkanals, trans-2-alkenals and alka-2,4-dienals) and their conjugated hydroperoxydiene precursors. Since such aldehydes appear to be absorbed into the systemic circulation from the gut in vivo, the toxicological significance of their production during standard frying practices is discussed.

Aldehydes↗
PubMed1994

Generation of lipid peroxidation products in culinary oils and fats during episodes of thermal stressing: a high field 1H NMR study.

The oxidative deterioration of glycerol-bound polyunsaturated fatty acids (PUFAs) in culinary oils and fats during episodes of heating associated with normal usage (30-90 min at 180 degrees C) has been monitored by high field 1H NMR spectroscopy. Thermal stressing of PUFA-rich culinary oils generated high levels of n-alkanals, trans-2-alkenals, alka-2,4-dienals and 4-hydroxy-trans-2-alkenals via decomposition of their conjugated hydroperoxydiene precursors, whereas only low concentrations of selected aldehydes were produced in oils with a low PUFA content, lard and dripping when subjected to the above heating episodes. Samples of repeatedly used, PUFA-rich culinary oils obtained from restaurants also contained high levels of each class of aldehyde. The dietary, physiological and toxicological ramifications of the results obtained are discussed.

Aldehydes↗
PubMed1994

Degradation of hyaluronate by Streptococcus intermedius strain UNS 35.

Streptococcus intermedius strain UNS 35, a brain abscess isolate, produced extracellular hyaluronidase when grown in brain heart infusion broth. Chemical assays with this enzyme indicated that hyaluronate depolymerisation resulted in the formation of carbohydrate moieties with N-acetylglucosamine at the reducing terminal and containing an unsaturated carbon-carbon double bond. The nature of the products of this hyaluronidase were investigated further by high-field (400 MHz) proton (1H) NMR spectroscopy. Treatment of hyaluronate with the enzyme resulted in a series of new, sharp resonances in spectra (acetamido methyl group singlets located at 2.03 and 2.07 ppm, sugar ring proton multiplets in the 3.5-4.2 ppm chemical shift range, and doublets at 5.16 and 5.87 ppm) characteristic of low-M(r) oligosaccharide species, predominantly those containing glucuronosyl residues with delta 4,5-carbon-carbon double bonds. Comparison of spectra acquired from hyaluronidase-treated samples with that of an authentic sample of 4-deoxy-L-threo-hex-4-enopyranosyluronic-acid-N-acetylglucosamine (delta UA GlcNAc) indicated that this disaccharide was a major product arising from the actions of this enzyme. When used in minimal media, hyaluronate supported growth of S. intermedius, with lactate as the major metabolic end-product.

Carbohydrate Sequence↗
PubMed1993

A comparative evaluation of the metabolic profiles of normal and inflammatory knee-joint synovial fluids by high resolution proton NMR spectroscopy.

High resolution 1H NMR spectroscopy has been employed to investigate the metabolic profile of healthy human knee-joint synovial fluid (SF) and the biochemical data acquired have been compared with those of matched serum, and inflammatory knee-joint SF samples. Results obtained indicate that the healthy human knee-joint has a hypoxic status (high lactate level when expressed relative to that of paired serum) that is milder than that of the inflamed human knee-joint. Moreover, normal SF differs from that of inflammatory SF in that it contains little or no NMR-detectable lipoprotein-associated fatty acids and 'acute-phase' glycoproteins, an observation reflecting the limited passage of these macromolecules from plasma into the synovial space in healthy subjects.

Acute-Phase Proteins↗
PubMed1993

An optical hydroxyl radical sensor.

A hydroxyl radical (.OH) fibre-optic sensor has been developed. An .OH radical-sensitive reagent phase (nitrophenol) was immobilized onto XAD-7 methacrylate beads. Subsequently the beads were attached to the distal end of a polymethylmethacrylate fibre optic. Nitrocatechol, generated from the attack of .OH radical on nitrophenol, exhibits a strong absorption band in the visible region of the electromagnetic spectrum (lambda max = 510 nm). Here, reflectance spectroscopy was employed to monitor the concomitant intensity decrease in the reflectance spectrum upon .OH radical attack. The sensor exhibited excellent stability and linearity of response to .OH generated by a Fenton reaction system (EDTA, Fe(II) and H2O2) with H2O2 over the concentration range of 3.6 x 10(-6)-8.0 x 10(-2) M.

Fiber Optic Technology↗