Publications

Protection Against Peroxynitrite-Dependent Tyrosine Nitration and α₁-Antiproteinase Inactivation by Ascorbic Acid. A Comparison with other Biological Antioxidants

Peroxynitrite, formed by reaction of superoxide and nitric oxide, appears to be an important tissue-damaging species generated at sites of inflammation. In this paper, we compare the abilities of several biological antioxidants to protect against peroxynitrite-dependent inactivation of α1-antiproteinase, and to inhibit tyrosine nitration upon addition of peroxynitrite. GSH and ascorbate protected efficiently in both systems. Uric acid inhibited tyrosine nitration but not α1-antiproteinase inactivation. The possibility that ascorbic acid is an important scavenger of reactive nitrogen species in vivo is discussed.Key Words: Peroxynitriteascorbatetyrosine nitrationα1-antiproteinasereactive nitrogen speciesrheumatoid arthritismethionineGSH

The role of iron in ascorbate-dependent deoxyribose degradation. Evidence consistent with a site-specific hydroxyl radical generation caused by iron ions bound to the deoxyribose molecule

In the presence of H2O2, ascorbate and phosphate buffer at pH 7.4, deoxyribose is degraded. Degradation is inhibited by catalase, mannitol, apotransferrin, apolactoferrin, or desferrioxamine. In the presence of sufficient apotransferrin to just inhibit deoxyribose degradation, reaction can be restored by adding more deoxyribose to the reaction mixture, but not by additional phosphate or ascorbate. It is suggested that deoxyribose degradation under our reaction conditions is achieved by a site-specific formation of hydroxyl radical using iron ions bound to the deoxyribose molecule. Spectrophotometric and kinetic evidence for the binding of iron ions to deoxyribose is presented.

Mechanism of hydrogen peroxide-induced keratinocyte migration in a scratch-wound model

Recent studies have shown that low concentrations of H2O2 are produced endogenously by nonphagocytes after wounding. We observed that H2O2 at such concentrations can stimulate proliferation as well as migration of keratinocytes in a scratch-wound assay. Both wounding and H2O2 can induce phosphorylation of ERK1/2 via EGFR, but the activation of ERK1/2 by H2O2 is more sustained and can last more than 8h. Sustained ERK1/2 activation is required for the increased proliferation and migration induced by H2O2. The p38 MAPK was also found to be phosphorylated upon treatment with H2O2 but it was not required for H2O2-induced migration or proliferation. Furthermore, it was observed that there is a cross talk between the ERK1/2 and the p38 pathways whereby inhibition of either pathway can lead to activation of the other. As a result, the motogenic effects of H2O2 were further enhanced when p38 was inhibited. Our data are consistent with the view that H2O2 may play an important signaling role in wound healing.

Herbal and Traditional Medicine

Integrating Traditional and Complementary Medicine into National Health Care: Learning from the International Experience. Can Traditional Medicine Coexist with Modern Medicine in the Same Health Care System? Clinical Trials for Herbal Extracts. Herbal Medicine: Criteria for Use in Health and Disease. Effects of Phytochemicals in Chinese Functional Ingredients on Gut Health. Tea and Health. Ginkgo biloba: From Traditional Medicine to Molecular Biology. Ginger. Lingzhi Polyphorous Fungus (Ganoderma lucidum). Epimedium Species. Ligusticum chuanxiong Hort. Salvia miltiorrhiza. Schisandrin B and Other Dibenzocyclooctadiene Lignans. Spirulina: An Overview. Averrhoa bilimbi. Lentinus edodes: Shiitake Mushrooms. Cruciferous Vegetables and Chemoprevention: The Mechanisms of Isothiocyanate-Mediated Chemoprotection in Humans. Pharmacological and Chemopreventive Studies of Chrysanthemum. Andrographis paniculata and the Cardiovascular System. Rosemary. Crataegus (Hawthorn). Resveratrol: The Promise Therein. Pharmacological and Physiological Effects of Ginseng. Antioxidant Activities of Prickly Pear (Opuntia ficus indica) Fruit and Its Betalains: Betanin and Indicaxanthin. Antioxidant Activity and Antigenotoxicity of Cassia tora. Sho-saiko-to. Licorice Root Flavonoid Antioxidants Reduce LDL Oxidation and Attenuate Cardiovascular Diseases. Estrogen-Like Activity of Licorice Root Extract and Its Constituents. Protection of Oxidative Brain Injury by Chinese Herbal Medicine: Shengmai San as a Model Formula for the Antioxidant-Based-Compounds Therapy of Oxidative Stress-Related Diseases. Eurycoma longifolia Jack (Tongkat Ali). The Biological and Pharmacological Properties of Cordyceps sinesis, a Traditional Chinese Medicine That Has Broad Clinical Applications. Phytochemistry, Pharmacology, and Health Effects of Brandisia hancei. Ephedra. Echinacea and Immunostimulation. Medical Attributes of St. John's Wort (Hypericum perforatum). Therapeutic Potential of Curcumin Derived from Turmeric (Curcuma longa). Extracts from the Leaves of Chromolaena odorata: A Potential Agent for Wound Healing. Medicinal Properties of Eucommia Bark and Leaves. Systemic Reviews of Herbal Medicinal Products: Doing More Good Than Harm? Use of Silicon-Based Oligonucleotide Chip in Authentication of Toxic Chinese Medicine. Traditional Chinese Medicine: Problems and Drawbacks. Review of Adverse Effects of Chinese Herbal Medicine and Herb-Drug Interactions.

Oxidants and the central nervous system: some fundamental questions. Is oxidant damage relevant to Parkinson's disease, Alzheimer's disease, traumatic injury or stroke?

Radicals are species containing one or more unpaired electrons. The oxygen radical superoxide (O2-) and the non-radical oxidant hydrogen peroxide (H2O2) are produced during normal metabolism and perform several useful functions. Excessive production of O2- and H2O2 can result in tissue damage, which often involves generation of highly-reactive hydroxyl radical (.OH) and other oxidants in the presence of "catalytic" iron ions. A major form of antioxidant defence is the storage and transport of iron ions in forms that will not catalyze formation of reactive radicals. Tissue injury, eg. by ischaemia or trauma, can cause increased iron availability and accelerate free radical reactions. This may be especially important in the brain, since areas of this organ are rich in iron and cerebrospinal fluid cannot bind released iron ions. Oxidant stress upon nervous tissue can produce damage by several interacting mechanisms, including rises in intracellular free Ca2+ and, possibly, release of excitatory amino acids. Recent suggestions that iron-dependent free radical reactions are involved in the neurotoxicity of aluminium and in damage to the substantia nigra in Parkinson's disease are reviewed. Finally, the nature of antioxidants is discussed, it being suggested that antioxidant enzymes and chelators of iron ions may be more generally-useful protective agents than chain-breaking antioxidants.

Scavenging of Hypochlorous Acid and the Myoglobin-Derived Oxidants By of Cardioprotective Agent Mercaptopropionylglycine

Mercaptopropionylglycine (MPG) has a marked cardioprotective action in several model systems of ischaemia-reoxygenation injury. Suggested mechanisms of action include scavenging of hydroxyl radical and the hypochlorous acid and reacting with an oxidant formed by reaction of myoglobin with H2O2, thereby slowing lipid peroxidation stimulated by myoglobin-H2O2 mixtures. This oxidant seems not to be singlet O2 or hydroxyl radical. Studies in vitro show that scavenging of hypochlorous acid is a feasible mechanism of cardioprotective action for MPG in vivo in ischaemia/reperfusion systems to which neutrophil-mediated injury contributes. However, the poor ability of MPG to inhibit lipid peroxidation stimulated by myoglobin/H2O2 mixtures and its ability to increase iron ion release from myoglobin in the presence of a large excess of H2O2, suggests that MPG is unlikely to protect the myocardium by interfering with oxidants produced by the myoglobin-H2O2 system.

Oxidative Stress in Cystic Fibrosis: Does It Occur and Does It Matter?

Cystic fibrosis (CF) is a multiorgan system disease arising from a single biochemical abnormality in a protein encoded by a gene located on chromosome 7 (band q31-32). This protein (the cystic fibrosis transmembrane conductance regulator, CFTR) appears to couple ATP hydrolysis with transmembrane chloride (Cl-) conductance across apical epithelial surfaces under the control of CAMP-dependent proteinkinaseA regulation. The defect in CF impairs the normal movement of water and electrolytes across various epithelial surfaces, most notably in the respiratory tract (RT) but also in the pancreatohepatobililary system, the gastrointestinal tract, and the sweat excretion system. There is decreased C1- secretion and an increased sodium absorption, inadequate hydration of the respiratory tract secretions. This predisposes the CF patient to impaired mucociliary clearance, chronic lung infection, and bronchiectasis. The lung infection and the ensuing inflammatory-immune responses of the lung lead to the progressive lung destruction responsible for the pulmonary morbidity and mortality of CF. The infectious inflammatory-immune processes in the lungs of CF patients cause oxidative stress and related effects on the antiprotease/protease balance. This chapter discusses the evidence that oxidative stress occurs in CF and in the lung, and assesses whether oxidative stress contributes to the disease pathology and whether antioxidants might have useful therapeutic effects. There is speculation on the potential for antioxidant therapy and dilemma of administering aerosolized thiols or ascorbic acid. This chapter has focused on the roles that oxidative stress may contribute to the pathophysiology of CF, on how the balance between reactive oxidative species and nitrogen species may interact with biomolecular constituents at RT surfaces.

Drug Antioxidant Effects

No abstract is provided for this article.

Book Reviews

Monograph on Free Radical Reactions (Environmental Health Perspectives, vol. 64, December 1985).Free Radicals, Aging, and Degenerative Diseases Modern Aging Research, Vol. 8, Eds. J.E. Johnson, Jr., R. Walford, D. Harman and J. Miquel, (Alan R. Liss, Inc., New York, 1986) 588 Pages. £93.00 p.“CRC Handbook of Methods for Oxygen Radical Research” Robert A. Greenwald, editor, CRC Press, Boca Raton, Florida, 1985. (447 pp)

Inhibition of hypochlorous acid-induced oxidative reactions by nitrite: is nitrite an antioxidant?

Consumption of flavonoids in onions and black tea: lack of effect on F2-isoprostanes and autoantibodies to oxidized LDL in healthy humans

Background: Oxidative damage to lipids in vivo may be involved in the development of atherosclerosis and cancer. Onions and black tea are foods rich in flavonoids, predominantly the flavonoid quercetin, which is a potent in vitro inhibitor of membrane lipid peroxidation and LDL oxidation. Objective: Our objective was to investigate the effects of consuming a high-flavonoid (HF) diet enriched with onions and black tea on indexes of oxidative damage in vivo compared with a low-flavonoid (LF) diet. Design: Thirty-two healthy humans were studied in a randomized crossover design. Indexes of oxidative damage used were plasma F2-isoprostanes (a biomarker of lipid peroxidation in vivo) and the titer of antibodies to malondialdehyde (MDA)-modified LDL. Results: There were no significant differences in the intake of macronutrients or assessed micronutrients, plasma F2-isoprostane concentrations, and MDA-LDL autoantibody titer between the HF and LF dietary treatments. In the men, however, plasma concentrations of the F2-isoprostane 8- epi -prostaglandin F2 α were slightly higher after the HF treatment phase than after the LF treatment [0.31 ± 0.029 nmol/L (111 ± 10.4 ng/L) compared with 0.26 ± 0.022 nmol/L (92 ± 7.8 ng/L); P = 0.041]. In all subjects, plasma quercetin concentrations were significantly higher after the HF treatment phase than after the LF treatment: 221.6 ± 37.4 nmol/L compared with less than the limit of detection of 66.2 nmol/L. Conclusion: Flavonoid consumption in onions and tea had no significant effect on plasma F2-isoprostane concentrations and MDA-LDL autoantibody titer in this study and thus does not seem to inhibit lipid peroxidation in humans.

The measurement of free radical reactions in humans

The question as to whether free radical reactions are a major cause of tissue injury in human disease, or merely an accompaniment to such injury, is very difficult to answer because of lack of adequate experimental techniques. New techniques that are becoming available are discussed, with specific reference to their use in humans.

Book Review

Early Markers in Parkinson's and Alzheimer's Diseases New Vistas in Drug Research, Volume 1 Eds. P. Dostert, P. Riederer, M.S. Benedetti and R. Roncuczi Springer Verlag, Vienna and New York, 310pp., 1990.

Effect of nutritional supplement therapies in the prevention of Alzheimer’s disease in a transgenic mouse model

Background/Aims: The aim of this study was to examine the efficacy of diets containing (-)-epigallocatechin-3-gallate (EGCG), curcumin (Curc), DHA and a-lipoic acid (ALA) on reducing cognitive deficits and brain betaamyloid (Ab) levels in a transgenic Alzheimer’s disease (AD) mouse model. Methods: Sixty mice (age six months) were randomly assigned to one of six nutritional supplement groups (Control, Curc, Curc+EGCG+ALA, Curc+DHA+ALA, EGCG+DHA+ALA, Curc+EGCG+DHA+ALA) for 12 months. At 18 months of age, the cognitive effects of the nutritional supplements were evaluated behaviourally using the cued and contextual fear avoidance test. A commercially available assay was used for the detection and measurement of Ab levels in the brain. Difference between groups was tested using one-way ANOVA. Results: All nutritional supplement groups had lower frontal cortex Ab42 levels compared to Controls ( p p p p Conclusions: The combination nutritional supplements in this study were effective at lowering brain Ab42 levels and improving cognition. However there does not appear to be additional benefits from combinations of these nutritional components over a single nutritional supplement of Curc.

The Role of Oxygen Radicals in Human Disease, with Particular Reference to the Vascular System

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other reactive oxygen species (ROS), such as hydrogen peroxide, are formed in vivo. Imbalance between production of ROS and anti-oxidant defence can result in oxidative stress, which may arise either from deficiencies of anti-oxidants (such as glutathione, ascorbate or α-tocopherol) and/or from increased formation of ROS. Oxidative stress can result in glutathione depletion, lipid peroxidation, membrane damage and DNA strand breaks as well as activation of proteases, nucleases and protein kinases. Some degree of oxidative stress occurs in most, if not all, human diseases, and the major question to be answered is whether it makes a significant contribution to the disease pathology. In the case of atherosclerosis, evidence from studies with the chain-breaking anti-oxidant probucol and from epidemiological work suggests that oxidative damage does indeed make an important contribution to plaque development.

The behaviour of caeruloplasmin in stored human extracellular fluids in relation to ferroxidase II activity, lipid peroxidation and phenanthroline-detectable copper

No Cu(II) ion is measurable in human serum or synovial fluid by the phenanthroline assay. On storage of human serum or synovial fluid at 4 degrees C, phenanthroline-detectable copper appears, lipid peroxidation occurs, ferroxidase I activity declines and ferroxidase II activity rises, yet there is no fall in immunologically detectable caeruloplasmin. Storage of body fluids at −20 degrees C or −70 degrees C slows, but does not prevent, these deteriorative changes. It is suggested that the presence of low-molecular-mass Cu(II) ion complexes, ferroxidase II activity, ‘cytotoxic factors’ and ‘immunosuppressive factors’ in body fluids may be, in part or in whole, an artifact of the storage and handling of the fluids. A report [Blake, Blann, Bacon, Farr, Gutteridge & Halliwell (1983) Clin. Sci. 64, 551-553] that the caeruloplasmin present in rheumatoid synovial fluid is deficient in ferroxidase activity is shown to be such an artifact. It is strongly recommended that all such experiments be performed upon freshly taken fluid samples.