Publications

Diet-Derived Antioxidants: The Special Case of Ergothioneine

This article reviews what is presently known about the biological roles of the diet-derived compound ergothioneine (ET). ET seems important to humans because it is rapidly taken up from the diet by a transporter largely or completely specific for ET, and once taken up it is retained within the body for weeks or months. The various possible functions of ET in vivo are explored. Much emphasis has been placed on the antioxidant properties of ET, but although these are well established in vitro, the evidence that antioxidant activity is the principal function of ET in vivo is weak. ET is not unique in this: The evidence for the antioxidant roles of vitamin C and polyphenols such as the flavonoids in vivo is also weak. By contrast, α-tocopherol has demonstrated in vivo antioxidant effects in humans.

Effect of peroxynitrite on plasma extravasation, microvascular blood flow and nociception in the rat

Peroxynitrite (ONOO − ) is a cytotoxic species, formed by the reaction between nitric oxide and superoxide free radicals, that may be involved in inflammation. In this study we have investigated the effect of peroxynitrite on plasma extravasation and microvascular blood flow in the dorsal skin and on nociceptive responses in the hind paw of the rat. Male Wistar rats were anaesthetized and their dorsal skin shaved. Plasma extravasation was measured by the extravascular accumulation of 125 I‐labelled albumin over 0–45 min and 0–240 min. Blood flow was measured by laser‐Doppler flowmetry over 0–240 min. Studies in the hind paw were carried out in the conscious rat. Hind paw weight changes were determined by volume displacement and nociception by a mechanical hyperalgesia technique. Intradermal (i.d.) peroxynitrite (100–200 nmol site −1 ) produced a significant ( P <0.01) dose‐dependent increase in plasma extravasation in dorsal skin over 0–45 min which was not increased over 45–240 min. Plasma extravasation was significantly ( P <0.001) decreased in rats pretreated with the anti‐inflammatory steroid dexamethasone (1 mg kg −1 , i.v.; −180 min), but not modulated by treatment with the hydrogen peroxide deactivator catalase (2200 u site −1 ), or the superoxide scavenger superoxide dismutase (500 u site −1 ), effective doses of the tachykinin NK 1 antagonist SR140333 (1 nmol site −1 ), the cyclo‐oxygenase inhibitor indomethacin (358 μmol site −1 ), or combined pretreatment with mepyramine (histamine H 1 ‐receptor antagonist; 2.8 nmol site −1 ) and methysergide (5‐HT antagonist; 1.9 nmol site −1 ). Microvascular blood flow was significantly ( P <0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site −1 ) in dorsal skin and remained raised until the end of the recording period (240 min). The increase in blood flow was unaffected by dexamethasone (1 mg kg −1 , i.v.; −180 min) or indomethacin (10 mg kg −1 , s.c.; −30 min). Hind paw volume was significantly ( P <0.001) increased 30 min after intraplantar peroxynitrite (87.5 and 175 nmol paw −1 ) and remained raised for the duration of the experiment (360 min). By comparison, nociception was not altered by intraplantar peroxynitrite. These data indicate that peroxynitrite can cause an increase in both plasma extravasation and blood flow, suggesting that peroxynitrite could be of biological relevance to microvascular responses. These findings may be of importance in the pathology of inflammatory diseases in which peroxynitrite formation occurs. British Journal of Pharmacology (1997) 122 , 1083–1088; doi: 10.1038/sj.bjp.0701498

Phagocyte-derived reactive species: salvation or suicide?

Activated phagocytes produce ‘reactive oxygen, halogen and nitrogen species’ that help to kill some types of microorganism. How these species destroy microorganisms remains, however, an enigma: both direct oxidative damage and indirect damage (whereby reactive species promote the actions of other antibacterial agents) are involved, and no single mechanism is likely to account for the killing of all microorganisms. Phagocyte-derived reactive species are known to injure human tissues and to contribute to inflammation. Recently, however, we have learned that they can also be anti-inflammatory by modulating the immune response. These data have implications for the proposed use of antioxidants to treat inflammation.

Free Radicals in Biology and Medicine 4th ed.

No abstract is provided for this article.

Oxidants, antioxidants, and respiratory tract lining fluids.

Respiratory tract lining fluids (RTLFs) are a heterogeneous group of substances covering the respiratory tract epithelial cells (RTECs) from nasal mucosa to alveoli. Antioxidant contained in the RTLFs can be expected to provide an initial defense against inhaled environmental toxins. The major antioxidants in RTLF include mucin, uric acid, protein (largely albumin), ascorbic acid, and reduced glutathione (GSH). RTLF antioxidants can be augmented by such processes as transudation/exudation of plasma constituents; RTEC secretory processes, including glandular mucus secretion; and cellular antioxidants derived from lysis of RTECs and of inflammatory cells. The antioxidant composition of RTLFs and their role in modulating normal and pathophysiologic RTEC functions under conditions of oxidative stress are yet to be fully characterized.

Irish neurological association

Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.

Oral zinc supplementation does not improve oxidative stress or vascular function in patients with type 2 diabetes with normal zinc levels

Objective There is considerable controversy about what constitutes optimal zinc intakes in patients with type 2 diabetes mellitus. Several studies suggest that higher zinc intakes improve vascular function and decrease oxidative damage. We aimed to assess the effects of zinc supplementation using a range of reliable biomarkers of oxidative damage and vascular function in patients with type 2 diabetes. Methods Forty male type 2 diabetic patients were supplemented either with 240mg/day of zinc as zinc gluconate (n =20) or with placebo (n =20) for 3 months. Blood and spot urine samples were taken at baseline, days 3 and 7, months 1, 2 and 3 during supplementation and 1 month after cessation. Serum zinc, reliable biomarkers of oxidative damage (F2-isoprostanes, neuroprostanes, cholesterol oxidation products, allantoin) as well as hydroxyeicosatetraenoic acid products and vascular-related indices (augmentation index, pulse wave velocity and aortic pressure) were measured. Results Despite significantly higher levels of serum zinc in the treatment group, markers of oxidative damage, levels of hydroxyeicosatetraenoic acid products and vascular indices were unchanged by zinc supplementation during the four-month study period. Conclusion Improving the zinc status in patients with type 2 diabetes with normal zinc levels did not have any impact on oxidative damage and vascular function, and such supplementation may not be generally beneficial in these individuals.

A Reassessment of the Peroxynitrite Scavenging Activity of Uric Acid

A bstract : Peroxynitrite is implicated in numerous human diseases. Hence, there is considerable interest in potential therapeutic peroxynitrite scavengers. It has been claimed that uric acid is a powerful peroxynitrite scavenger. We previously observed that uric acid is a powerful inhibitor of tyrosine nitration induced by peroxynitrite, but fails to prevent α 1 ‐antiproteinase (α 1 ‐AP) inactivation induced by peroxynitrite. However, the reactivity of peroxynitrite is significantly modified by bicarbonate and this has not been considered in evaluating the scavenging activity of uric acid and other endogenous antioxidant compounds. In the presence of bicarbonate (25 mM), the ability of uric acid, ascorbate, Trolox, and GSH to inhibit peroxynitrite‐mediated tyrosine and guanine nitration is decreased. Protection against peroxynitrite‐mediated α 1 ‐AP inactivation is also decreased by ascorbate, Trolox, and GSH, but it is enhanced by uric acid. Bicarbonate also inhibits the ability of these compounds to prevent peroxynitrite‐mediated ABTS radical cation formation. However, the abilities of these antioxidants to prevent peroxynitrite‐mediated bleaching of pyrogallol red are enhanced by bicarbonate. These results show that physiologic concentrations of bicarbonate substantially modify the ability of uric acid to prevent peroxynitrite‐mediated reactions. This study highlights the need to use several different assays in the presence of physiologically relevant concentrations of bicarbonate when assessing compounds for peroxynitrite scavenging, in order to avoid misleading results.

Antioxidants

Free radicals and other “reactive oxygen species” (ROS) are formed continuously in the human body, both deliberately and by “accidents of chemistry.” Our endogenous antioxidant defenses are inadequate to completely prevent damage by ROS. Hence, diet-derived antioxidants may be of special importance in delaying or preventing the onset of diseases in which ROS are involved, such as cardiovascular diseases, chronic inflammatory diseases, neurodegenerative diseases, and some forms of cancer. Determining the optimal intake of antioxidant nutrients is one of the greatest challenges in the nutrition/free radicals field today, but the possibility of side effects from supraoptimal doses must not be ignored.

Establishing the Significance and Optimal Intake of Dietary Antioxidants: The Biomarker Concept

Diets rich in fruits and vegetables are associated with decreased risk of cardiovascular disease and cancer. Biomarkers of oxidative DNA damage and lipid peroxidation can be used to establish the role of antioxidants in this protection and the optimal intake of those antioxidants. This concept is based on the presumptions that oxidative DNA damage is a significant contributor to the age-related development of some cancers and that lipid peroxidation plays a key role in the development of cardiovascular disease. Mass spectrometric measurements of various families of isoprostanes (F2-, F3-, and F4-isoprostanes) and of multiple DNA base oxidation products are probably the most promising biomarkers for use in human nutritional intervention studies. Biomarker studies should precede, as well as accompany, major intervention trials that measure disease incidence. The use of biomarkers provides a logical scientific basis for major intervention trials of antioxidants; such trials will, in turn, eventually validate or disprove the biomarker concept.

Nickel(II)- and cobalt(II)-dependent damage by hydrogen peroxide to the DNA bases in isolated human chromatin.

Nickel compounds are known to be carcinogenic to humans and animals. Cobalt compounds produce tumors in animals and are probably carcinogenic to humans. The mechanisms of the carcinogenicity of these metal compounds, however, have remained elusive. In the present work, we have investigated the ability of Ni(II) and Co(II) ions in the presence of H2O2 to cause chemical changes in DNA bases in chromatin extracted from cultured cells of human origin. Eleven modified DNA bases in chromatin were identified and quantitated by the use of gas chromatography-mass spectrometry. 2-Hydroxyadenine (isoguanine), which has not previously been shown to occur DNA or chromatin, was also identified. Products identified were typical hydroxyl radical-induced products of DNA bases, suggesting that the hydroxyl radical was involved in their formation. This idea was supported by partial inhibition of product formation by typical scavengers of hydroxyl radical. Partial inhibition of product formation indicated a possible "site-specific" formation of hydroxyl radical by unchelated Ni(II) and Co(II) ions bound to chromatin. Although treatment of chromatin for 1 h with Co(II)/H2O2 caused formation of significant amounts of products, treatment with Ni(II)/H2O2 required incubation times of more than 5 h and an increase in Ni(II) concentration before increases in product amounts above background levels became detectable. In both cases, ascorbic acid did not increase product yields. Glutathione at a physiologically relevant concentration had little overall effect on DNA base modification. Superoxide dismutase increased the yields of most products. Chelation of Ni(II) and Co(II) ions with EDTA almost completely inhibited product formation. Ni(II) in the presence of H2O2 produced greater base damage to the DNA in chromatin than to isolated DNA, unlike other metal ions tested. DNA damage in chromatin caused by Ni(II) and Co(II) ions in the presence of H2O2 may contribute to the established genotoxicity and carcinogenicity of these metal ions.

Proteasome inhibition by lactacystin in primary neuronal cells induces both potentially neuroprotective and pro‐apoptotic transcriptional responses: a microarray analysis

Although inhibition of the ubiquitin proteasome system has been postulated to play a key role in the pathogenesis of neurodegenerative diseases, studies have also shown that proteasome inhibition can induce increased expression of neuroprotective heat‐shock proteins (HSPs). The global gene expression of primary neurons in response to treatment with the proteasome inhibitor lactacystin was studied to identify the widest range of possible pathways affected. Our results showed changes in mRNA abundance, both at different time points after lactacystin treatment and at different lactacystin concentrations. Genes that were differentially up‐regulated at the early time point but not when most cells were undergoing apoptosis might be involved in an attempt to reverse proteasome inhibitor‐mediated apoptosis and include HSP70, HSP22 and cell cycle inhibitors. The up‐regulation of HSP70 and HSP22 appeared specific towards proteasome inhibitor‐mediated cell death. Overexpression of HSP22 was found to protect against proteasome inhibitor‐mediated loss of viability by up to 25%. Genes involved in oxidative stress and the inflammatory response were also up‐regulated. These data suggest an initial neuroprotective pathway involving HSPs, antioxidants and cell cycle inhibitors, followed by a pro‐apoptotic response possibly mediated by inflammation, oxidative stress and aberrant activation of cell cycle proteins.

The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs

1. Hydroxyl radicals (OH) are thought to be generated at sites of inflammation and to contribute to tissue damage. All anti-inflammatory drugs tested were able to scavenge ˙ OH generated in free solution at almost diffusion-controlled rates (rate constants about 1010 M−1 s−1).2. Much ˙ OH generation in vivo occurs at specific sites, where bound metal ions (such as Fe2+) react with H2O2 to produce ˙ OH that immediately attacks the site. Only ˙ OH scavengers that have sufficient metal-binding ability to withdraw metal ions from this site can protect against site-specific damage.3. All anti-inflammatory drugs tested were able to protect against site-specific damage by ˙ OH in a simple model system in vitro. Penicillamine, diclofenac sodium, piroxicam, azathioprine, primaquine, chloroquine and hydroxychloroquine were especially effective.4. The ability of an anti-inflammatory drug to protect against ˙ OH formation in vivo depends not only on its rate constant for reaction with ˙ OH, but also on its metal-binding ability and on the geometry and redox potential of any metal complex formed.

Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Problems, resolutions and preliminary results from nutritional supplementation studies

Damage to DNA by oxygen radicals and other reactive oxygen/nitrogen/chlorine species occurs in vivo despite the presence of multiple antioxidant defence and repair systems. Such damage is thought to make a significant contribution to the age-related development of cancer. Modulation of oxidative DNA damage by diet thus constitutes a "biomarker" putatively predictive of the effect of diet on cancer incidence, provided that DNA damage can be accurately quantitated by validated methods. Current issues addressed in this article include the problems of artifactual DNA oxidation during isolation and analysis, the relative merits of different analytical methods, the advantages and disadvantages of relying on measurement of 8-hydroxy-deoxyguanosine (8OHdG, 8-oxodG) as an index of oxidative DNA damage, and the limited data that are so far available on how diet can affect "steady-state" levels of oxidative DNA damage in humans. It appears that such damage can be modulated by vegetable intake, although the effects of vegetables may be mediated by components different from the "classical" antioxidants vitamin C, α-tocopherol and β-carotene.

Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer

Review Article| January 01 1996 Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer Helen WISEMAN; Helen WISEMAN *Department of Nutrition and Dietetics, King's College London, Campden Hill Road, London W8 7AH, U.K. Search for other works by this author on: This Site PubMed Google Scholar Barry HALLIWELL Barry HALLIWELL †Pharmacology Group, King's College London, Manresa Road, London SW3 6LX, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem J (1996) 313 (1): 17–29. https://doi.org/10.1042/bj3130017 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation Helen WISEMAN, Barry HALLIWELL; Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 1 January 1996; 313 (1): 17–29. doi: https://doi.org/10.1042/bj3130017 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. The Biochemical Society, London © 19961996 Article PDF first page preview Close Modal You do not currently have access to this content.

DNA damage by nitrite and peroxynitrite: Protection by dietary phenols

SUPEROXIDE DISMUTASE, CATALASE AND GLUTATHIONE PEROXIDASE: SOLUTIONS TO THE PROBLEMS OF LIVING WITH OXYGEN

SUMMARY Recent research suggests that H 2 O 2 is a normal metabolite in both plants and animals and is not particularly cytotoxic. The impact of H 2 O 2 on cell metabolism is discussed with particular reference to photorespiration. Catalase may function by preventing the formation of excessive concentrations of H 2 O 2 and by using H 2 O 2 in the peroxidatic oxidation of compounds such as methanol and formic acid. Radicals (such as OH and O 2 ‐ ) and ‘excited’ oxygen are far more damaging to living organisms. The formation of these radicals in biological systems is described. Superoxide dismutase plays a key role in protection against such radicals, but glutathione peroxidase is also involved.