Antioxidant

Lipidsoluble antioxidants

All lipid-soluble antioxidants are effective inhibitors of the propagation step of lipid peroxidation through reaction with one or more peroxyl radicals. The major lipid-soluble antioxidants are the tocopherols (vitamin E), of which a-tocopherol is the predominant form in humans (Brigelius-Flohe et al., 2002). Other potentially biologically important roles for a-tocopherol have been described (Brigelius-Flohe et al., 2002 Rimbach et al., 2002). Although the biological function of ubiquinone is not yet clear, it seems to play a pivotal role in several processes (Nohl et al., 1998). Carotenoids may quench the reactive form of oxygen, singlet oxygen (Krinsky, 1998). Bilirubin, an end product of heme metabolism, is the most potent antioxidant against lipid peroxidation known to date (Tomaro and Batlle, 2002).

Placental antioxidant status in preeclampsia

(Gulmezoglu et al., 1996), GPX enzyme activity (Knapen et al., 1999) or catalase activity (Wang and Walsh, 1996) are also raised. However, a decrease in placental antioxidant capacity is more frequently reported (Walsh, 1998 Zusterzeel et al., 2001) vitamin E levels are reported to be lower (Wang and Walsh, 1996), whereas the expression of several important enzymatic antioxidants (e.g. SOD, GPX, GSTPi and glucose-6-phosphate dehydrogenase) appear to be down-regulated (Walsh, 1998 Wang and Walsh, 1996 Zusterzeel et al., 1999).

Prophylaxis of preeclampsia using antioxidants

Despite increased understanding of the etiology of the syndrome, there is currently no accepted method of prevention of pre-eclampsia. Studies of aspirin and calcium prophylaxis have proved disappointing (Coomarasamy et al., 2003). However, the abundant evidence for oxidative stress in pre-eclampsia provides a potential avenue of hope for the development of new strategies involving antioxidant prophylaxis. The choice of antioxidant is important. Some antiox-idants, particularly vitamin E, not only detoxify free radicals, but also have other properties that may benefit women with pre-eclampsia directly (Azzi et al., 2002 Brigelius et al., 2002). Antioxidants, by altering the cell redox status, are indirectly involved in the regulation of redox-sensitive gene expression. At levels close to those found in plasma, a-tocopherol has been shown to play a role in cell signaling by the inhibition of PKC activation (Azzi et al., 2002). Via this pathway vitamin E exerts anti-proliferative...

Sources of Free Radicals

Free radicals are continuously produced from various biological processes regulated by a variety of enzymes in multiple subcellular compartments within the cell (49). Under normal physiological conditions, most of the cellular ROS are generated in the mitochondria through leakage of oxidative phosphorylation, a biological process that produces ATP, the major form of energy in cells. Nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FADH), the reduced form of coenzymes for a variety of biochemical reactions in the cell, facilitates the formation of ATP, responsible for energy-transfer reactions. In oxidative phosphorylation, the electrons from NADH or FADH flow sequentially through a mobile electron acceptor such as coenzyme Q, and through acceptors such as cytochrome c1 and cytochrome c, which form protein complexes I to IV in mitochondria. The electrons are then transferred to molecular oxygen to form water and produce a proton gradient, which is used to...

Targets of Free Radicals

Due to their reactive nature, free radicals can indiscriminately attack macromolecules such as DNA, protein, and lipid to cause damage to these molecules. Much is known about oxidative damage of these molecules caused by ROS, but less is known about damage by RNS. Lipids are the most sensitive molecules to free radicals due to the presence of bisallylic structures in polyunsaturated fatty acids. Lipid peroxidation can produce a variety of end products by chain reactions with free radicals. The end products include malonaldehyde, 4-hydroxy-2-nonenol, and F2-isoprostanes, which tend to be accumulated in the cell, especially in the membranes (48,55,56,58). F2-isoprostanes generated from the peroxidation of arachidonic acid are the biomarkers often used to determine the level of lipid peroxidation (59). b-Formation of isoprostanes is initiated by formation of peroxyl radicals, which are produced by abstraction of a bisallylic hydrogen atom and the addition of oxygen to arachidonic acid....

Transgenic Plants With Modified Antioxidant Enzyme Levels

Because of the involvement of AOS in a wide variety of environmental stresses, antioxidant enzymes are interesting molecular targets for the production of new plant varieties that can cope with these stresses. Several antioxidative stress enzymes have been genetically engineered into plants to assess their potential capacity for enhancing oxidative stress tolerance. The beneficial effects observed in some of these transgenic plants can lead to interesting agronomic applications. The following section gives an overview of the state of the art concerning transgenic plants with modified levels of antioxidant enzyme levels. The MnSOD from Nicotiana plumbaginifolia has indeed been more consistently reported to confer resistance to oxidative stress. Transgenic tobacco plants overproducing the nuclear-encoded mitochondrial MnSOD in either mitochondria or chloroplasts (by replacing the mitochondrial transit sequence with a chloroplast transit peptide) were less sensitive to MV. Overproduction...

Nitrite acts as a colorant flavorant antioxidant and antibotulinal agent in cured meat

In ancient times, meat was preserved with saline desert sands and sea salts, both of which contain nitrate 5 . The reddening effect of nitrate in preserved meat was mentioned as far back as the late Roman era, but it wasn't until the early twentieth century that the bacterial reduction product, nitrite, was identified as the agent responsible for coloring and curing meat 5 . In meat curing, nitrate functions as a reservoir for nitrite, which acts not only to color meat, but also acts as a flavorant, an antioxidant and an anti-microbial agent 14 . These days, it is generally accepted that most of these effects are due to the action of NO, which is generated by the reduction of nitrite 15 . However, in recent years the use of nitrite has faced considerable negative pressure, because its reaction with amines in meat has been shown to produce nitrosamines, which are known carcinogens and possibly mutagens 16-18 . In nitrite-cured meat, NO appears to play a crucial antioxidant role. For...

Maternal antioxidant status in preeclampsia

The total peroxyl radical-trapping ability of plasma has been found to be higher in women with pre-eclampsia (Kharb, 2000c Uotila et al., 1994), unsurprising, perhaps, since this assay includes the antioxidant uric acid, which has frequently been reported to be raised (Chappell et al., 2002 Kharb, 2000c Many et al., 1996 Zusterzeel et al., 2002). As explained above, this may reflect increased XO activity with subsequent generation of O2', rather than an elevation of functional antioxidant capacity. The oxygen radical absor-bance capacity, based on direct quenching of free radicals (Cao and Prior, 1998), is reported to be unchanged in women with mild pre-eclampsia (Zusterzeel et al., 2002), whereas studies in more severe disease have suggested that overall antiox-idant capacity, is lower (Davidge et al., 1992 Sagol et al., 1999). Overall, estimates of ''total'' anti-oxidants are unlikely to provide a good index of antioxidant capacity because of the dependency on the antioxidant...

Enzymatic antioxidants

Superoxide dismutases (SOD) provide a first line defense against free radicals through conversion of O2*, to H2O2 and oxygen (Zelko et al., 2002). The rapid cellular response to oxidative stress leads to a defensive increase in expression of SOD (Mates et al., 1999). SOD works in concordance with H2O2-removing enzymes such as glutathione peroxidase (GPX) and catalase (Mates etal., 1999). Table 8.2. Principal antioxidant pathways Antioxidant Enzymatic antioxidants Reduction of organic hydroperoxides and H2O2 Regeneration of oxidized glutathione Reduction of organic hydroperoxides Conjugation of glutathione in Phase II Conversion of O2 to H2O2 Conversion of H2O2 to H2O and O2 Regeneration of antioxidants Non-enzymatic antioxidants Scavenging of free radicals The thioredoxin system (Holmgren and Bjornstedt, 1995), although playing a lesser role in a quantitative sense, is positioned at the core of redox control and antioxidant defense, being involved in the regeneration of antioxidants...

Watersoluble antioxidants

In general, non-enzymatic antioxidants can be grouped into water- and lipid-soluble antioxidants. Glutathione is the most important water-soluble antioxidant and is widely distributed in human tissues (Hayes and McLellan, 1999 Meister, 1988). Dietary-derived ascorbic acid (vitamin C), vital for species (including man) that cannot synthesize ascorbic acid, reduces reactive nitrogen species, ROS and also the a-tocopherol radical (Nordberg and Arner, 2001). Uric acid is generally considered as a waste product of the metabolic action of XO, but shows strong antioxidant capacity toward water-soluble free radicals and stabilizes ascorbic acid at physiological concentrations. However, uric acid is ineffective against lipid-soluble radicals and forms potent radicals when oxidized (Sevanian et al., 1991). Metal-binding proteins (e.g. trans-ferrin and ferritin) as well as heme-binding proteins (e.g. haptoglobin) are also important antioxidants (Krinsky, 1998).

Antioxidants

If oxidative damage in the immune system of aging obese individuals plays an important role in prostate cancer, then antioxidants should inhibit the process. Selenium has been suggested to reduce prostate cancer progression. Clark etal., in examining the effects of selenium in skin cancer, reported an incidental 63 decrease in prostate cancer incidence using selenium supplements in the diet.72 P-Carotene and vitamin E

Free Radicals

A free radical is a highly reactive chemical species containing an unpaired electron in its outer electron shell. Some free radicals occur naturally in the body however, additional free radicals may be derived from interactions of normal body compounds with chemical contaminants in the body or with ionizing radiation. Radiolysis is the process by which ionizing radiation breaks water, inorganic, or organic molecules into highly reactive species. For example, radiolysis of water can result in the formation of the hydroxyl (OH) and hydrogen (H-) free radicals. These free radicals can then react with other aqueous species to form other highly reactive species. Although DNA is one of the target macromolecules for these reactive species, other macromolecules can also be damaged by them. For example,

Antioxidant Systems

The presence of free radicals in the cells poses a huge dilemma to the biological systems within for the following reasons n Free radicals can randomly inflict damage to essential macromolecules this damage leads to dysfunction of physiological systems in the organism (47,58-60). n Compelling evidence indicates that free radicals play a positive physiological role in various biological processes such as immune response to pathogens (Chapter 14) and cellular signaling transduction (48,59). Cells have developed a variety of ways to balance the oxidant level by regulating production of oxidant and removal of oxidant by the antioxidant systems in order to defend themselves from oxidative stress while maintaining normal physiological functions. One antioxidant mechanism is to scavenge free radicals with various enzymes and proteins, of which one major player is superoxide dismutase (SOD), which is present in all the aerobic organisms (60). SOD is uniquely dedicated to scavenge superoxide...

Pharmaceutical Therapy

Pharmaceutical agents used to slow the progression of AD include acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galanta-mine). These agents block the breakdown of neurotransmitters in the brain and are used to lessen symptoms of mild to moderate AD. Their action extends cognitive function and improves behavioral symptoms for twelve months up to two years. Vitamin E or selegiline delays the progression of AD. Estrogen has been associated with a decreased risk of AD and enhanced cognitive functioning. Its antioxidant and anti-inflammatory effects enhance the growth of neuron processes for memory function. Ginkgo biloba has provided moderate cognitive improvement with few ill effects. Delusions and hallucinations often develop in moderately impaired patients. In the absence of agitation or combativeness, the best treatment is reassurance and distraction. Delusions and hallucinations accompanied by agitation and combativeness can be treated with low doses of...

Evening Primrose

Evening primrose, Oenothera biennis L., originally a North American species, is cultivated in the United Kingdom and Canada for the production of seeds. The seeds contain up to 25 oil rich in polyunsaturated fatty acids. The major fatty acids are linoleic acid (65-80 ), y-linolenic acid (GLA, 8-14 ), and oleic acid (6-11 ) (2). The oil also contains smaller amounts of palmitic and stearic acid (20). Traditional breeding methods have been employed in order to develop cultivars with a high oil and GLA content. The oil is obtained by cold expression. Because of its high content of unsaturated fatty acids, it is difficult to preserve and is usually incorporated in soft gelatin capsules. Antioxidants, such as vitamin E, are often added to preserve fatty oils (2).

Reactive oxygen species

Reactive oxygen species (ROS), such as the superoxide anion (O,p, are produced as a consequence of NO metabolism in the vessel wall, and suppress endothelium-dependent vasodilatation (Freeman et al., 1995). Endothelial NOS is also capable of producing oxygen free radicals from l-arginine. Superoxide anions are converted to hydrogen peroxide (H2O2) in a reaction catalyzed by the enzyme superoxide dismutase (SOD), which is an important cellular defense mechanism against free radical damage. There are three known isoenzymes of SOD - a cytosolic, mitochondrial and an extracellular form (ecSOD), the latter form of which predominates in the vessel wall. Superoxide anions react rapidly with NO to form peroxynitrite (ONOO ). Levels of ONOO in the body are usually kept low by the actions of SOD.

Molecular Targets And Candidate Prostate Cancer Prevention Agents

Existing putative prostate cancer prevention agents can be classified into those intended to inhibit ongoing cellular mechanisms, such as sex steroid signaling, differentiation or proliferation, pro-apoptosis and angiogenesis, and those intended to reverse or prevent progressive DNA damage, such as gene therapy, growth factor therapy or antioxidant therapy35 (Table 10.1). Observational data suggest that the hormonal milieu during early prostate development is an important determinant of subsequent cancer formation. Castration early in life nearly eliminates the risk of BPH and prostatic cancer in subsequent years. Additionally, because of the known hormone dependency that normal prostate epithelia and prostate cancer cells exhibit, sex steroid hormone signaling has been aggressively targeted for chemotherapeutic and chemopreventative strategies. Recent studies evaluating the role of 5a-reductase inhibition and androgen deprivation for patients with premalignant changes (PIN) are yet...

Nontransferrinbound iron

This is present in plasma in patients with gross iron overload. It is highly toxic, promoting the formation of free radicals causing peroxidation of membrane lipids. Part of the early improvement in liver and cardiac function with chelation therapy may be due to removal of this fraction, even before iron burden is substantially lowered. Its clearance by DFX is short lived as it reappears in plasma within hours of stopping an infusion. This provides a rationale for using 24-h continuous infusions in patients with iron-induced cardiomyopathy. Non-transferrin-bound iron is absent from plasma of well-chelated patients.

Function of SR Genes in Senescence

During programmed senescence, mechanisms that protect the cell from free radicals, reduced oxygen species, and other toxic by-products of senescence must be in place in order for the cell to remain viable. Transcripts that encode for catalase, an enzyme that detoxifies H2O2, show differential regulation during senescence in Nicotiana plumbagini-folia (Willekens et al., 1994). Cat1 is believed to play a principal role in scavenging photorespiratory H2O2. It is expressed at high levels throughout leaf development and increases dramatically in senescing petals. Cat2 is constitutively expressed in all tissues and is up regulated only in senescing leaves. The cat3 gene is suggested to function in the glyoxysomal process and is expressed at high basal levels in flowers and seeds but increases in abundance only during leaf senescence (Willekens et al., 1994). A number of genes encoding metallothionein-like or heavy metal binding proteins have been identified by differentially screening...

Alternative Therapies

Photodynamic therapy is based on the administration of a photosensitizing agent that is preferentially localized in neoplastic tissue. In Canada and Europe, 5-aminolevulenic acid is orally administered 122,125 . In the United States, porfirmen sodium is the only approved agent, and it is administered intravenously. On exposure to a properly tuned laser (wavelength of 630 nm) oxygen free radicals are formed 122,125 . These cause local cell death and subsequent tumor necrosis. The depth of affected tissue is less than that seen with conventional laser therapy, and therefore perforation is expected less often. Side effects include sunburn and are more commonly seen than in conventional laser treatments 122 .

Screening And Prevention

For prostate cancer, current studies are evaluating the role of micronutrients and antioxidants, such as vitamin E, selenium, lycopenes and soy products.9 In addition, the prostate cancer prevention trial testing finasteride versus placebo is now maturing with data expected in the next few years.

MT M Raijmakers and L Poston

One or more unpaired electrons) exceeds the capacity of antioxidant defense. An increasing literature has lent support to the hypothesis that oxidative stress is not only an accompaniment to the disorder of pre-eclampsia, but may also contribute to the etiology of the maternal syndrome. Supporting evidence includes reports in both placenta and maternal blood of oxidative damage to lipids, proteins and DNA, decreased total antioxidant capacity and depletion of individual antioxidants (Raijmakers et al., 2005). The diversity of the methods employed reflects the lack of a ''gold standard'' assay for oxidative stress assessment in the laboratory (Hubel, 1999) that, as this chapter will highlight, can lead to confusion and inevitably to some misinterpretation of data. Oxidative stress has been implicated in a broad spectrum of disease. This chapter provides a summary of the biochemical principles underlying oxidative stress, including the diversity of laboratory methods employed in its...

Assessment of oxidative stress

A good biomarker for oxidative stress would be one that combines the two arms that contribute to the balance of the redox state (i.e. free radical generation and antioxidant defense), is simple and inexpensive to measure, and measurement is reproducible. However, no such marker is available. Most methods only measure one aspect and therefore present a single, simplified and unbalanced view of the possible presence of oxidative stress. Many investigators have assessed total antiox-idant capacity (e.g. the oxygen radical absorbance capacity and the ferric reducing ability of plasma) (Cao and Prior, 1998), individual antioxidant levels (Krinsky, 1998) or the enzyme activity of antioxidant enzymes (Hayes and McLellan, 1999 Mates et al., 1999) as indirect evidence of oxidative stress. Most relevant assays are easy, inexpensive and generally accessible, but may be misleading. For instance, measures of ''total'' antioxidant capacity do not include all of the major antioxidants (Cao and...

Pharmaceutical Therapies

Nerve growth factor, antioxidant therapy, and other drugs are being investigated for the management of dementia. Psychotrophic medications such as carbamazepine, desipramine, haloperidol, lorazepam, and thioridazine are used to control symptoms of agitation, anxiety, confusion, delusions, depression, and hallucinations in patients with dementia. Unfortunately, some of the medications used to improve patients' quality of life may not work, may worsen memory deficits, or cause neurological effects such as irreversible tremors (tardive diskinesia).

Obesity And Carcinogenesis

How many cancer cases would be expected to occur in a healthy population without exposure to dietary or environmental carcinogens It is theorized that perhaps 25 of tumors arise through natural biological variability in the body's normal accumulation of 'mistakes'.15 Aging plays a role by increasing the amount of free radicals, which subsequently may affect the cell's DNA causing mutations.16 As we will discuss, diet and obesity may also affect these mechanisms.

Free fatty acids oxidative stress and vascular dysfunction

The endogenous transition metals, iron (Fe) and copper (Cu) can catalyze the production of reactive oxygen species such as hydroxyl radical and thus promote oxidative stress. Albumin and ceruloplas-min are the major Cu-binding proteins in plasma. When sequestered by albumin or ceruloplasmin, Cu is usually redox-inactive (incapable of producing reactive oxygen species). However, plasma samples from at least a subset of women with pre-eclampsia (compared to normal pregnancy) display an elevated endogenous redox-cycling activity of Cu that can be inhibited by the copper (II) chelator, cuprizone I (Kagan et al., 2001). This activity may result from increased FFA in the circulation (Figure 11.4). Circulating FFAs are complexed with albumin. The molar ratio of FFA to albumin is two- to threefold greater in pre-eclampsia than normal pregnancy (Endresen et al., 1992, 1994 Vigne et al., 1997). The excess binding of fatty acids to albumin results in a conforma-tional change in the albumin...

Examples of Induction of Pathology as a Tool to Study Aging

Premature aging has been induced in a number of laboratory animals as well as in captive wild animals by various methods. One of the favorite methods is to expose the animal to stress, that is, to excessive environmental (including physical, emotional, and social) demands. Stress will activate or interfere with all major regulatory systems, that is, it will disturb neuroendocrine balance (Chapter 9), alter immunologic competence (Chapter 14), and increase the production of free radicals (93). Stress or injection of cortisol to mimic adrenocortical stimulation, in

D4 Preventive Strategies

Recently, several randomized trials have studied the role of amifostine, a radiopro-tector, in the setting of lung cancer. Amifostine (Ethyol WR-2721) is an organic thio-phosphate selected from over 4400 compounds screened by the US Army as the best radioprotective compound. Amifostine is dephosphorylated at the tissue site to its active metabolite (WR-1065) by alkaline phosphatase.51 Once inside the cell, WR-1065, the free thiol, acts as a potent scavenger of oxygen free radicals induced by ionizing radiation.52

Animal Models of Neonatal Sequelae

Studies with neonatal and fetal rats, rabbits, and sheep have provided both direct and indirect evidence of increases in the levels of oxygen free radicals in the developing brain following hypoxia-ischemia (Bagenholm et al., 1997, 1998 Hasegawa et al., 1993 Rosenberg et al., 1989). The generation of free radicals is most pronounced during the initial period of reperfusion. The type of free radical involved varies somewhat by experimental model but principally involves superoxide anion and hydrogen peroxide. In vitro and in vivo neonatal rodent models of hypoxia-ischemia have demonstrated that pre-OLs are highly susceptible to free radical attack, whereas mature OLs are resistant (Back et al., 2002). Studies with neonatal piglets subjected to hypoxia-ischemia have shown that the mechanism of pre-OL death from free radical attack is apoptosis (Yue et al., 1997). This has been confirmed in in vitro studies and has been suggested by autopsy studies of the brains of human infants born...

Aliphatic Polyamides Nylons

Exposure of aliphatic polyamides (nylons) to the environment causes discoloration and appreciable reduction in tensile strength and average molecular weight. Since the polyamide itself can absorb short-wavelength solar UV radiation, dual mechanisms of degradation initiated by sunlight have been identified in the aliphatic polyamides 36, 37 . Direct photolysis of the polyamide structure, followed by reactions of the resulting free radicals, is initiated by wavelengths as long as 340 nm absorbed by the structural components. Longer wavelengths, absorbed by impurities and defects, can only initiate photooxidation reactions. This is in contrast to other aliphatic-type polymers, such as the polyolefins, which degrade only via a photooxidation mechanism. Although the photolytic reaction is the more important weathering process 38 , the thermal history of nylon polymers has a significant effect on the impurities present, and thus on the light stability. Wavelengths extending into the visible...

Irradiance in Laboratory Weathering Tests

Exposures in laboratory weathering tests to irradiance levels much higher than those encountered under natural exposure conditions can significantly shorten test time. However, simulation of the effects of natural weathering on the materials would be compromised if the high irradiance levels alter the mechanism of degradation. Also, since all materials are not affected equally by increased irradiance, it can change the stability ranking of materials. The effect of irradi-ance level on the rate of degradation is complex. It varies with type of material, type of stabilizers present, and wavelengths responsible for the degradation. For most materials, the rate of degradation is rarely a linear function of the level of irradiance. For example, the rates of photooxidation of both polypropylene and polyethylene have been shown to be proportional to various fractional powers of the light intensity, ranging from the square root to the first power 140 . At high intensities of light, the...

Gene Profiling in the Heart by Subtractive Hybridization

Because of its fundamental function for the organism, the heart is extraordinarily receptive to variations of extracellular conditions, which are often referred to as a stress for the cardiac myocyte increased contractile performance 16 , oxygen deprivation 17, 18 , burst of free radicals 19 , endothelial dysfunction 20 , increased preload 21, 22 , cellular stretch 23 are just a few examples of the changes in extracellular conditions that directly affect the cardiac cell. All these stimuli, either physiological or deleterious, are detected by different sensors (receptors, ion channels or transmembrane proteins) 24 , relaying the information to transmitters (signaling pathways) 23 , which in turn regulate the activity of the effectors (enzymes and transcription factors) 25, 26 . The effectors are directly responsible for the adaptation of the expression of different genes in response to the initial stimulus (Fig. 5.1). In other words, the gene expression profile is the end-point of the...

Temperature in Laboratory Weathering Tests

While degradation can be accelerated by testing at temperatures higher than materials are exposed to under normal use conditions, caution must be exercised to avoid producing unrealistic test data. Often, a different degradation mechanism is triggered at high temperatures. For example, certain secondary reactions may occur only at high temperatures due to increase in rate of decomposition of hydroperoxides or in rate of diffusion of oxygen or free radicals formed in primary processes. Some reactions that take place at high temperatures will generally occur at only a very low rate, or not at all, at lower temperatures. Any change from the mechanism of degradation produced by natural weathering conditions precludes simulation of the effects of natural exposures.

Potential Mechanisms of Cardioprotection

Many of the genes implicated in cardioprotection are transcription factors which, by inducing other genes, could alter expression of many proteins and thereby lead to cardioprotection. Another major group of genes involved in cardioprotection are typically classified as stress (or heat shock) proteins. These include HSPs, GSHPx-1, SODs and HO. The antioxidant gene products could enhance protection by a reduction in reactive oxygen species, although it is likely that their protective effect is more complex than this. HSPs have been traditionally thought to be involved in regulating protein folding and degradation, although recent studies suggest that they are also involved in nuclear hormone regulation, apoptosis and other functions that could be important in protection 42 . There is also altered expression of several genes involved in growth factor signaling. Growth factors can induce cardioprotection by upregulating survival pathways such as PI3-K Akt and NF-kB. Growth factors can...

Reduced Genome Maintenance

Gene expression profiles from the liver of these mice showed that the severe genotoxic stress caused by XPF deficiency increased the expression of genes that provide antioxidant defenses and decreased the expression of genes important for insulin insulin-like growth factor-1 (IGF-1) signaling (156). The insulin IGF-1 signaling pathway is now known to be an evolutionarily conserved pathway that regulates aging modest decreases in the output of this pathway have been shown to increase the life span of nematodes, fruit flies, and mice (11,158). Notably, this pattern of gene expression was also seen in control mice subjected to chronic low-level genotoxic stress, calorie restriction, and normal aging (156). These findings suggest that damage and aging elicit a similar set of conserved metabolic responses an increase in antioxidant protection and a decrease in insulin IGF-1 signaling. These responses are similar to the effects of caloric restriction and presumably act to preserve, or...

Denis Soulet and Serge Rivest 1 Introduction

Overactivation of the excitatory amino acid (EAA) receptors (NMDA, kainate, AMPA receptors) by polyamines can lead to neuronal death via an excitotoxicity type of phenomenon. Glutamate-induced excitotoxicity is involved in central nervous system (CNS) damages and chronic neurodegenerative diseases (19,20). The prolonged calcium influx leads to a depolarization of the mitochondrial organelles (21,22), which is followed by the decoupling of the electron transport with the adenosine triphosphate production (23, 24). Then, the release of free radicals initiate the excitotoxic damages (25) that can accumulate during long periods and contribute to the apparition of neuronal atrophy and demyelinating episodes. This process may be at the origin of various neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Polyamines have also been found to play a critical role in the neuronal damage during and after cerebral ischemia (26). increase in polyamine...

Cellular Mechanisms of Toxicity

Within the cell, the macromolecules described above must work in concert to allow the cell to survive and carry out its particular function. A contaminant may either damage critical macromolecules directly or may damage them indirectly by forming free radicals. Examples of cellular malfunction induced by direct interference with macromolecules are the binding of carbon monoxide to the iron in hemoglobin, thus impairing the ability of the blood to deliver oxygen to tissues, and ionizing radiation damage to DNA as a result of ionization of an atom in the DNA molecule. Indirect damage accounts for a wide array of toxic effects. For example, in addition to its direct effects, ionizing radiation can also damage DNA indirectly by the formation of free radicals, which subsequently react with and damage the DNA. Chemical contaminants are also suspected of exerting toxic or carcinogenic effects by the generation of highly reactive species. Other forms of DNA damage include strand breaks and...

Mitochondria and Oxidative Stress

Reactive molecules generated and eliminated in a balanced process in normal cells. In particular, free radicals (superoxides) are byproducts of ATP generation by the mitochondrial respiratory chain (Andreyev et al., 2005 Beyer, 1992 Raha and Robinson, 2000). Cellular energy is usually liberated from ATP molecules through the removal of single phosphate-oxygen groups, producing adenosine diphosphate (ADP). ADP is recycled in the mitochondria where it is recharged through oxidative processes to reproduce ATP. Since ROS are harmful, the balance between energy supply and energy demand is extremely critical. Any shift in this balance would introduce excess ROS to cells and would result in oxidative stress. The damaging effect of elevated levels of ROS is thought to be due to the highly reactive free electrons available to form stable chemical bonds. While H2O2 is free to escape the mitochondrion, both the superoxide anion and hydroxyl radicals have limited diffusion, and are more likely to...

Cellular Aging Free Radical Hypothesis

The free radical hypothesis of aging states that free radicals in the cell damage cell macromolecules and lead to senescence and, eventually, to cell death (44-46). Free radicals are molecules that contain unpaired and reactive electrons. Various kinds of free radicals are present in the cell and come from either endogenous or exogenous sources (45). There are two major kinds of free radicals (Table 4). One is the extensively studied reactive oxygen species (ROS), which are metabolites of molecular oxygen (O2) and are the predominant species of free radicals (46,47). Examples of ROS include weakly active superoxide radical (O2), weakly reactive nonradical hydrogen peroxide (H2O2), and highly reactive hydroxyl radical (OH). These ROS can be generated and reduced to stable water through sequential reactions of oxygen with electrons (e-) and protons. The other type of free radicals is reactive nitrogen species (RNS) (Table 4). Nitric oxide (NO) is a major RNS, which is not reactive with...

Free Radical Accumulation

Initially, the mechanistic link between metabolism and aging was unknown. However, in the mid-1950s, Harman (45) articulated the free radical theory of aging, speculating that endogenous oxygen radicals were generated in cells and resulted in a pattern of cumulative damage (47). The standard explanation for this damage is that it is the result of cellular damage caused by free radicals any number of chemical species that are highly reactive because they possess an odd number of electrons. Molecules that have unpaired electrons are thermodynamically unstable since they seek to combine with another molecule to pair off their free electron. The theory postulates that the physiological decrements characteristic of age-related changes can be ascribed to the intracellular damage done by the various free radicals (36,109). The net damage to various cell components (e.g., lipids, protein, carbohydrates, and nucleic acids) is the result of different types of free radicals present, their...

In vivo Animal Study of Vitamin Es Role in Prostate and Prostate Cancer

In spite of the constructive role of vitamin E in the development of prostate, the role of vitamin E in the incidence and progression of prostate cancer are controversial in animal models. In 3,2'-dimethyl-4-aminobiphenyl (DMBA)-initiated rat prostate carcinogenesis, the modifying effects of six naturally occurring antioxidants, including a-tocopherol, were investigated. Atypical hyperplasias and carcinomas of the prostate were observed in the ventral lobe in all groups treated with DMAB. However, the incidence of these lesions was not significantly different between carcinogen control and antioxidant-treated groups. There were also no significant increases or decreases in the incidence of tumors in any other organs.34

Lipofuscin and Melanin

Lipofuscin or age pigment, the by-product of cellular autopha-gia (self-digestion) and lipid peroxidation due to free radical accumulation, has a protein and a lipid component. It accumulates with aging in most CNS cells, both neurons and glial cells, where it follows a regional distribution (e.g., in the hippocampus, cerebellum, anterior horn of spinal cord). It increases linearly with age also in other cells of the body (e.g., cardiac and muscle cells, macrophages, interstitial cells). Lipofuscin can be visualized as autofluorescent material (Fig. 5A and B) and, with the electron microscope, as dark granules, either scattered in the cytoplasm or clustered around the nucleus (Fig. 6A and B) (50). Lipofuscin's functional significance (if any) is unclear. The claim that lipofuscin accumulation interferes with intracellular function or that reduction of brain lipofuscin through the administration of antioxidants may lead to improved neuro-psychologic behavior remains controversial.

Tissue Stores Of Nitric Oxide

NO reacts with free radicals, hemeproteins, and following reaction with molecular oxygen thiols, all of which are abundant at high concentration in mitochondria. Therefore, it comes as no surprise that NO interaction with mitochondria would have significance for cell function 111,112 . The discovery of mitochondrial NO formation in 1997 113 suggested the existence of a highly localized source of NO in the mitochondrial inner membrane 114 . The basal formation of NO in mitochondria seems to be one of the main regulators of cellular respiration, mitochondrial transmembrane potential, and transmembrane pH gradient 115 . Moreover, mitochondrially derived NO plays an important role as an antioxidant by reacting with potential harmful ROS. However, an overproduction of NO may result in the generation of RNOS (reactive oxygen and nitrogen species) that cannot be neutralized by the mitochondrial barriers, which results in oxidative stress and cell death.

Role of Neuropeptides Hormones and Metabolites

Another approach to uncovering the mechanisms at work in human memory uses imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) with radioactive tracers (e.g., 14C-labeled 2-deoxyglu-cose) to measure increases that occur in metabolic activity in response to the presentation of familiar visual clues. The distribution of the metabolic changes is compatible with the view that memory is localized in specific brain areas (e.g., the hippocampus) (Fig. 4), but the large number of neurons involved suggests that most plastic (i.e., metabolically responsive) cells participate in multiple forms of memory (89). It is still unclear whether increased activation means that neurons are being recruited to compensate for the difficulty of the task at hand (Fig. 3), or whether it simply indicates diffuse, nondifferentiated activity (90). Currently, under special conditions (e.g., administration of growth factors, antioxidants, and anti-inflammatory...

Oxidative Stress Defense Mechanisms In Plants

To limit cellular damage caused by excessive AOS levels, plants have evolved a broad variety of nonenzymatic and enzymatic protection mechanisms that efficiently scavenge AOS (19). The best-known nonenzymatic antioxidants are ascorbate, glutathione, a-tocopherol, and carotenoids. They are present in relatively high concentrations within plant cells. For a detailed overview on these components, the reader is referred to Alscher and Hess (20).

Vascular Diseases 941 Introduction

Vascular diseases are characterised by conditions that clog or weaken blood vessels. They have been widely investigated as they represent a major cause of death in industrialised countries (Minino et al. 2002 Gianazza and Sironi 2004). Vascular diseases are mainly caused by elevated levels of cholesterol and triglycerides in the blood, hypertension, hyperhomocysteinemia, diabetes and obesity, systemic inflammation and metabolic syndrome, but also a lack of physical activity, cigarette smoking, a high-fat diet, low antioxidant levels and infectious agents. Gender and age may also play a role. Vascular diseases involve many different processes. These include slow processes, such as atherosclerosis that can evolve over decades, and much more rapid events, such as infarction in the heart or the brain.

Induced Radioactivity

To understand radiation-induced effects in biological materials one has to recall that the critical molecules such as DNA, RNA, or protein in the living cell are irradiated in an aqueous environment. Damage to these molecules can be imparted either by a direct hit of the molecule or by means of an indirect mechanism by the free radicals induced in water. Therefore the study of the chemical changes induced by ionising radiation in liquid water is very important (Ferradini 1999 von Sonntag 1991). The different types of radiation interact with water by distinctly different processes but the overall result will be the formation of the ionised and excited water molecules, H2O+ and H2O*, and subexcitation electrons. These species, so-called primary products, are produced in Free radicals can be formed directly when a molecule dissociates at a covalent bond, so that one bonding electron remains with each fragment. In organic compounds bond scission tends to be almost random in straight-chain...

Monophenols and polyphenols in green tea

Plant phenols are one of the most potent groups of antioxidants. They can occur as monophenols or as clusters of monophenols, called polyphenols. The major polyphenols from green tea are epigallocatechin-3-gallate (EGCG), epigallocatechin and epicatechin-3 gallate. Together, these make up 30-40 of the solids extracted from green tea leaves during brewing. However, polyphenols are found in a wide range of plant products that also have health benefits and may make a welcome alternative to green tea. Green tea intake has been associated with a decreased risk of cancers of the prostate, colon, pancreas, skin and other organs.42-44 Seemingly, green tea prevents the damage caused by a large number of cancer-causing chemicals and even excessive sun exposure. It appears that green tea can not only prevent cancer, but is able to stop the growth or even kill human cancer cells. This ability was documented in human breast, lung, colon, pancreatic and prostate cancers in tissue culture and in...

Radiation Sensitisers And Protectors

The effects of radiation may be modified appreciably by the presence of oxygen or other compounds with sensitising or protecting properties (Schulte-Frohlinde 1995 Tomita 1997). Oxygen is in biological systems usually present in high concentrations. The presence of oxygen has an important influence on the radical induced reactions because molecular oxygen has a high affinity for free radicals. The H radical is easily transformed (1 1) into long-living reactive oxygen containing radicals HO2 and O2 and molecules H2O2. Many chemical agents have been found to alter radiation sensitivity. In general, oxidising agents are radiation sensitisers, whereas reducing agents are usually radiation protectors. The use of antioxidants, like vitamin C, vitamin E and beta-carotene, as radiation protecting agents is actually under investigation (Platzer 1998). Compounds containing sulphydryl (-SH groups) have a particular affinity for free radicals. Their presence within the cell may decrease radiation...

Experimental And Theoretical Methods For Detecting And Studying Radicals

The principal, chemically relevant information that can be obtained from an EPR spectrum is contained by the g-factor and the hyperfine tensor A. From these quantities valuable information can be gained about the structure and orientation of free radicals in single crystals as well as the distribution of the unpaired electron over the magnetic nuclei in the radical species. However, the unequivocal determination of these parameters can be seriously hampered due to the potential complex character of reallife spectra such as the ones illustrated in Fig. 2b. In principle, quantum chemical calculations allow for the theoretical determination of the main EPR spectroscopic parameters. Accurate calculations of this type are however computationally demanding. Therefore they are starting to be performed on a routine basis only since the last few years, facilitated by the ever-increasing available computer power. In this respect, the calculation of the matrix elements of the hyperfine tensor A...

C677T Polymorphism of Methylenetetrahydrofolate Reductase Gene

What could be the rationale for this association Earlier it was demonstrated that endothelium-dependant vasodilatation driven by NO release has decreased in patients with hyperhomocysteinuria 11 . Six-weeks folate consumption in 5 mg per day doses simultaneously decreased homocysteine levels in blood and increased endothelium-dependant vasodilatation in arteries of healthy volunteers 9 . This effect could be related to the decrease of homocysteine-induced oxidative stress 33 . Antioxidants like ascorbate prevented endothelial dysfunction related to a three-fold increase of homo-cystein in the blood.

Pharmacological Strategies

Despite its beneficial effects, L-dopa treatment has some contraindications such as motor complications, negative general and systemic effects such as gastrointestinal disturbances. In addition, there is a gradual loss of effectiveness after three to five years of administration, probably due to continuing loss of dopaminergic neurons and reduction of dopa-decarboxylase, with consequent deficit in DA synthesis. Because neurotoxicity from L-dopa may be due to the generation of oxidative species (79,82), it is often recommended that antioxidants (e.g., tocopherol) be coadministered to prevent or reduce accumulation of free radicals (eventually capable of destroying the dopaminergic cells). Current pharmacological therapy will remain essentially ineffectual on a long-term basis until we understand more about the cause of dopaminergic cell loss. Recent evidence from postmortem brain and animal models of the disease (87) has suggested that early depletion of the antioxidant glutathione...

Defence against oxidative stress the production of reducing power

Structure G6pd

As with all cells, but perhaps more urgently, the red blood cell needs to be protected against the effects of free radicals, hydrogen peroxide and other highly oxidative material in order to maintain the membrane integrity and functional activity. In addition, Hb has to be maintained in its functional state, and the steady production of MetHb reversed back to deoxy-haemoglobin, which is able to combine reversibly with oxygen. The major generator of reducing power within the red cell is the pentose phosphate pathway (hexose monophosphate shunt), which generates reducing power in the form of NADPH from NADP+ coupled to the oxidation of G6P to 6-phosphogluconate and the subsequent oxidation of that compound to ribose 5-phosphate, the two reactions catalysed by the enzyme G6PD and 6-phosphogluconate dehydrogenase (6PGD) (Figure 9.9). Glutathione (GSH) is important for the protection of cells from oxidative damage by these free radicals, protection against the effects of infection, the...

Endogenous Nitrates And Nitrites

In mammalian systems, nitrates and nitrites theoretically may be formed as products of the reactions of RNOS nitrates may be produced by nitrating RNOS or by the action of nitrosating and nitroxidizing RNOS nitrites may be produced by nitrosating RNOS. Nitrates and nitrites have been proposed as endogenous products of the reactions of NO, peroxynitrite, or NO2 with lipids, and other biomolecules, under oxidative and nitrosative stress. In particular, nitrite and nitrate derivatives of lipids were proposed to result from the antioxidant activity of NO towards lipid peroxyl radicals 56-59 . The capacity of NO2 to react via H atom abstraction and via radical addition underlies its reactions with olefins, including polyunsaturated fatty acids, leading to formation of nitro, nitroso (nitrite), and nitrooxy (nitrate) derivatives, under both anaerobic conditions and in the presence of O2 60-64 . Both homolytic decomposition pathways for peroxynitrite and oxidation of NO- by enzymes such as...

A potential source of placental oxidative stress in preeclampsia

The development of pre-eclampsia has been linked to abnormalities in trophoblast invasion (Figure 8.1). More recently, Jauniaux et al. (2000) found that the activity of several antioxidant enzymes in normal placental tissue was increased in parallel with the rise in oxygen tension which occurs at 10 12weeks' gestation (Jauniaux et al., 2000). The authors hypothesized that a diminished antioxidant response to this oxygenation stimulus would result in oxidative stress. This could lead to trophoblast degeneration and possibly contribute to impairment of trophoblast invasion. Indeed, in a later study, these authors reported increased staining for nitrotyrosine residues and heat shock protein 70 in placental tissue from missed miscarriage, indicating that oxidative stress may be a key factor in early pregnancy loss (Jauniaux et al., 2003).

Mechanisms of Ozoneinduced Accelerated Leaf Senescence

Ethylene And Senescence

The gene products of two SAGs induced by O3 have in common metal binding functions, namely copper chaperone (CCH) and blue copper-binding protein (BCB). These proteins may be important in the recycling of essential metals once the leaf is targeted for senescence, or may act as protectants against metal-catalyzed oxidation that leads to generation of free radicals (Weaver etal., 1997 Himelblau etal., 1998). Himelblau etal. (1998) have reported that 0.80 LL-1 O3 increased mRNA levels of CCH by 30 in 30 min. We found that CCH was induced after 6 days of the chronic exposure described above (Miller et al., 1999). CCH is a functional homologue of the Anti-oxidant 1 (ATX1) yeast gene, a gene identified for its ability to protect against oxygen toxicity in yeast lacking superoxide dismutase (Himelblau etal., 1998). The potential for other hormones to act as signals in the induction of O3 -responsive SAGs remains to be examined. Abscisic acid (ABA), for example, is known to induce ERD1 and...

How Many Dentates Of S2o3

Free radicals of a new type in yeast cells. Biofizika (Rus.) 1965 10 167-168. 11 Commoner B, Woolum JC, Senturia BH, Ternberg JL. The effects of 2-acetoaminofluorene and nitrite on free radicals and carcinogenesis in rat liver. Cancer Res. 1970 30 2091-2097.

Prediction of preeclampsia by uterine artery Doppler at 1824 weeks gestation

Uterine Artery With Gestation Age

At present, Doppler screening of uterine arteries, with the aim of reducing pre-eclampsia in screen-positive women, cannot be recommended. If the greater therapeutic benefit of antioxidants (Chappell et al., 1999) versus aspirin therapy is confirmed in large randomized trials this will need to be reviewed. With the current drive to reduce antenatal visits in ''low-risk'' women (National Collaborating Centre for Women's and Children's Health, 2003), the value of a normal uterine artery screen, also needs to be addressed.

Peroxygens 121 Hydrogen peroxide

Attention has recently been devoted to developing a plasma-activated peroxide vapour process, in which radio waves produce the plasma. This is believed to be microbicidal by virtue of the hydroxyl ions and other free radicals that are generated (Groschel, 1995 Lever & Sutton, 1996).

Complications of Encircling

Inflammation and macular pigmentary changes that could also be ascribed to the original detachment or aging. It is difficult to propose to a patient that cutting the band at a small risk of re-detachment might prevent future macular changes and ill-defined degeneration however, the intervention might prove more effective than daily antioxidants.

Consequences of oxidative stress in preeclampsia

Growth, angiogenesis, matrix remodeling, apopto-sis and cell proliferation. However, at high levels of O2* transcription factors including AP-1 and NFKB are activated, and lead to many of the facets of the inflammatory response and tissue hypertrophy. By the modulation of the (thiol) redox status of cell, oxidative stress may have an effect on redox-sensitive gene-expression, resulting in the expression of proteins with an antioxidant responsive element in the promoter region, including most of the antioxidant enzymes (Hayes and McLellan, 1999).

Stabilization of Polymers

Elastomers Stabilization with additives other than carbon black is limited to unpigmented or light-colored elastomers. Substituted salicylanilides protect natural rubber (NR) against UV by screening, and various phenols and aromatic amines inhibit hydroperoxide formation on photooxidation of polybutadiene. Combinations of phenolic antioxidants with benzotriazole UV absorbers and low-molecular-weight HALS are used for stabilization of thermoplastic rubbers (styrene block copolymers) intended for hot melt and solvent-based sealants. High loadings of a UV absorber in combinations with an antioxidant and HALS improves the light stability of a polyurethane sealant. Styrenic Polymers Stabilization of polystyrene and its copolymers is necessary for articles expected to be exposed to solar radiation or indoor fluorescent lighting. Because of the significant role played by thermal oxidation products in the effect of these sources on the polymers, thermal stabilization at the processing stage...

Methods applications and concepts of metabolite profiling Secondary metabolism

Glufosinate Metabolism

Plants manufacture a vast array of secondary metabolites natural products for protection against biotic or abiotic environmental challenges 5 . Thus, these compounds provide increased fitness due to their antimicrobial, anti-herbivory, and or alleopathic activities. These toxic chemical weapons thwart potential damage by pathogenic viruses bacteria fungi herbivores and or minimize competition with other plants. For example, select secondary metabolites produce unfavorable responses in targeted plant predators such as bloat (saponins) in cattle and infertility in sheep (isoflavones). Many natural products also have other beneficial biological functions such as flavor fragrance color attractants 13-15 , UV-protectants, antioxidants, signaling compounds associated with ecological interactions and symbiotic nodulation 16-18 , and nutraceutical pharmacological properties related to human and animal health 16-25 . In fact, natural products account for approximately 30 of all the sales of...

Radical Reactions With Biomolecules

The reactivity with free radicals in general depends to a great extent on the structure of the reactants. The selectivity is determined largely by the energetics of the processes taking place. As we will see in the next chapter, ab-initio quantum chemical calculations in combination with EPR measurements are very important to interpret these energetics and to elucidate the possible structure ofbioradicals (Lahorte 1999a,b). Also primary radiation-damage in DNA is studied through ab-initio molecular-orbital calculations (Colson 1995 Wetmore 1998a,b). LET and track structure play an important role in the production of DNA damage (Frankenburgschwager 1994 Hill 1999 McMillan 1993). The exposure of mammalian cells to 1 Gy of low-LET ionising radiation leads to the production of around 1000 tracks with 2 x 105 ion pairs per cell nucleus, roughly 2000 of which may be produced directly in the DNA itself. The same dose of high-LET radiation produces only about 4 tracks per cell nucleus, but...

Clinical and research implications of the twostage model

The concept that the interaction of maternal and fetal factors converge to generate the maternal syndrome suggests that therapy directed at this convergence point might be useful for all women destined to develop pre-eclampsia. Currently, the concept that this interaction converges to generate oxidative stress with subsequent inflammatory activation and endothelial dysfunction has directed large studies of antioxidant prophylaxis. The success of these trials is the ultimate test of the hypothesis. However, increased understanding of the steps leading to and subsequent to the convergences will also provide useful insights. Is it possible that overt pre-eclampsia which has long been considered as untreatable other than by palliative therapy and delivery could be reversed

Physiology and Biochemistry of Ozoneinduced Accelerated Leaf Senescence

Changes in activity and quantity of ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) during leaf aging parallel changes in rates of Asat. Ozone-induced accelerated senescence is associated with a more rapid loss of both activity and quantity of this key enzyme of photosynthesis (Pell et al., 1994a). Dalling (1987) proposed that the degradation of Rubisco normally occurs when free radicals in the chloroplast structurally modify the

Tetrahydrobiopterin and Vascular Disease

Pulmonary Hypertension Vascular Changes

In humans, acute BH4 administration augments NO-dependent flow-mediated vasodilatation in smokers 32 , and in patients with diabetes 32 , hypertension 14 , hypercholesterolaemia 74 or coronary artery disease 52 . Superoxide production is increased in human diabetic vessels, which is partly inhibited by a NOS inhibitor or sepiapterin 28 . However, these studies are short-term and may be confounded by non-specific antioxidant effects, given the high doses of sepiapterin used (more than hundred-fold in excess of physiological concentration). There are few data on the long-term effects of BH4 augmentation in vascular disease.

Nitric Oxide Synthesis In Plants

Iron fulfills a vital role in virtually all living organisms from bacteria to animals. Iron ability to undertake one electron oxidation-reduction reactions places this molecule in the center of key biochemical processes like oxygen transport, ATP generation and the rapid reaction with free radicals. Iron can vary its redox potential in response to different environmental conditions and place this transition metal as an important intermediate for electron-transfer reactions and thereby with essential properties for electron transport chains in respiration and photosynthesis. The fact that iron deficiency affects more than 30 of the world's population 42 confirms its relevance and places it as a subject for many research projects worldwide.

Phagocytic killing antimicrobial proteins

Membrane permeability to extracellular solutes. A mutant strain of S. typhimurium, which is resistant to BPI, has also been found to be resistant to neutrophil bactericidal activity under strict anaerobic conditions, demonstrating the importance of BPI in non-oxidative killing by neutrophils. Other neutrophil granule proteins include lactoferrin, which kills some Gram-negative bacteria by generating free radicals from iron bound to it, and lysozyme, which is involved in the digestion of killed bacteria in phagolysosomes of neutrophils. These antimicrobial proteins can also enhance the effects of other cidal mechanisms such as complement lysis and oxidative killing. Combinations of these proteins can also enhance their killing action, as seen with the combination of neutrophil lysozyme and elastase against Gramnegative bacteria. Some of the microbicidal proteins of the phagocytes have other effects at lower concentrations, such as stimulation of mast cell degranulation, release of...

Placental hyperoxia and preeclampsia

The oxygen concentration within the intervillous space will be determined by the balance of supply from the spiral arteries and extraction by the fetus and the placenta. Each spiral artery delivers its blood into the central cavity of a placental lobule and the blood disperses in a classic smoke-ring pattern, passing between the villi and exchanging respiratory gases before finally entering the uterine veins. Consequently, it was proposed that an oxygen gradient exists across a lobule (Wigglesworth, 1969), and recent data describing differences in antioxidant enzyme activity support this hypothesis (Hempstock et al., 2003a). Morphological and enzymatic differences have been reported in villi from the central compared to peripheral regions of a lobule, with those in the center appearing to be more immature (Critchley and Burton, 1987 Schuhmann et al., 1988).

Lineage Specific Differentiation

The cardiomyogenesis of ESCs can occur after EB differentiation in vitro, but such a condition is very inefficient and nonspecific. Consequently, the development of new approaches for the directed differentiation of ESCs into cardiomyocytes will facilitate the therapeutic applications of ESCs and increase our understanding of the molecular mechanism underlying cardio-myocyte differentiation and heart development. Using mESCs that are stably transfected with the cardiac-muscle-specific myosin heavy chain promoter-driven eGFP, ascorbic acid (vitamin C) was identified from a screen of known drugs that can enhance the cardiac differentiation of mESCs in the monolayer culture (Takahashi et al., 2003). Interestingly, other antioxidants (e.g., N-acetylcysteine, vitamin E) do not have a similar effect, which suggests that the cardiomyogenesis-inducing activity of ascorbic acid may be independent of its antioxidative property. A similar screening strategy has identified cardi-ogenol (a...

How Cancer Cells Respond To A Changing Tumor Microenvironment

Cancer Cell Microenvironment

And increased prostate cancer risk (88-90). Intake of anti-inflammatory drugs and antioxidants has been shown to decrease prostate cancer risk (91-94). Genetic studies revealed further supportive evidence that RNASEL, encoding an interferon-inducible ribonuclease (95,96), and MSRI, encoding subunits of the macrophage scavenger receptor (96-98), are candidates as inherited susceptibility genes for familial prostate cancer. Conversely, the loss of GSTPI, encoding a glutathione-S-trans-ferase capable of inactivating ROS and, thus, reducing genome damage, has been found to occur frequently in human prostate cancer (87,98-100). Figure 4 emphasizes the potential roles of inflammatory processes and the ways to antagonize them in prostate cancer development.

Central Nervous System

IVH generally begins with bleeding into the germinal matrix just below the lateral ventricles (i.e., a subependymal or germinal matrix hemorrhage). During the late second and early third trimesters, the subependymal germinal matrix supports the development of cortical neuronal and glial cell precursors, which migrate to the cortical layers. The germinal matrix is highly vascularized, with a rich capillary network and a relatively poor supportive matrix. Blood filling the lateral ventricles may dilate the ventricles. The incidence and severity of IVH increases with decreasing gestational age and birth weight. Factors that contribute to IVH include hypotension, hypertension, fluctuating blood pressures, poor autoregulation of cerebral blood flow, disturbances in coagulation, hyperosmolarity, and injury to the vascular endothelium by oxygen free radicals. In 10 to 15 percent of infants a germinal matrix hemorrhage will obstruct venous return and lead to venous infarction of brain tissue...

Triglycerides oxidative stress and vascular dysfunction

This discrepancy reflects methodological flaws or biology, i.e. formation of a buoyant (conceivably a unique small buoyant) LDL subtype during pregnancy that is accentuated during pre-eclampsia. LDL isolated from plasma of women with pre-eclampsia is more susceptible to oxidation upon exposure to exogenous free radicals than normal pregnancy LDL (Wakatsuki et al., 2000). This is consistent with a subtype of LDL capable of disrupting NO homeostasis and impairing endothelial cell function.

Axons of Mammalian Spinal Cord

Second, undamaged neurons become overexcited, releasing excess amounts of the neurotransmitter, glutamate. Glutamate kills undamaged neurons by opening membrane channels that allow the influx of toxic amounts of calcium, a phenomenon called glutamate toxicity. A further source of toxicity is the production of free radicals by lipid peroxidation.

Oxidative stress in normal pregnancy

Normal pregnancy is a mild state of oxidative stress. Despite the presence of antioxidant systems such as SOD, catalase, GPX and GSTPi, and the co-factors glutathione and cysteine that are present from early pregnancy onwards (Jauniaux et al., 2000 Raijmakers et al., 2001a), a low level of oxidative modification occurs in placental tissue of uncomplicated pregnancies (Qanungo et al., 1999 Raijmakers et al., 2002). Also maternal factors lead to increased generation of O2* and other ROS during pregnancy (Luppi et al., 2002). Indeed, physiological pregnancy is characterized by a transient increase of ROS production that is partially counteracted by an induction of antiox-idant defense mechanisms (Chappell et al., 2002 Cikot et al., 2001 Little and Gladen, 1999). After delivery, both the level of oxidative damage and antioxidants return to pre-conception values (Cikot et al., 2001 Uotila et al., 1991). Normal vaginal delivery is associated with increased oxidative stress when compared...

Schizophrenia And Other Cognitive Disorders

An interesting emerging direction is the study of the use of potential neuroprotective agents. Damage from free radicals and oxidative stress has been proposed as a cause of tardive dyskinesia. A recent study in rats 36 investigated whether neuroleptic medications may affect the motor system through the creation of free radicals, and whether structural brain changes related to oxidative damage may disrupt normal striatal function. The study showed that rats treated chronically with fluphenazine had significantly lower striatal cholinergic neuron densities than those that did not receive antioxidants. Rats exposed to a diet consisting of antioxidants had significantly higher neuron densities in each of the three regions tested than did those that did not receive antioxidants. Clinical trials of the antioxidant vitamin E for reducing the severity of symptoms of tardive dyskinesia have had mixed results 37 , but it may be that irreversible neuronal loss had already occurred and that...

Neonatal Lung Disease

The premature lung is particularly susceptible to free radical-induced injury because of the delay in the development and the reactivities of antioxidant defenses (Bracci, 1997 Saugstad, 1990). Oxygen-induced injury is caused by the overproduction of free radicals, such as superoxide, hydrogen peroxide, and perhydroxyl. The presence of free radicals overwhelms the immature antioxidant system, leading to the oxidation of enzymes, the inhibition of proteins and DNA synthesis, decreased surfactant production, and lipid peroxidation, all of which play a role in lung injury. Multiple pathways of ROS generation have been found both in humans and in animal models. These include ischemia-reperfusion and hypoxanthine oxidase reactions, the metabolism of catecholamines, the arachidonic acid cascade, and mitochondrial metabolism. An additional source of free radicals in the lungs is thought to be phagocyte activation. The increases in phagocyte numbers and interleukin concentrations and the...

Damage To The Endoplasmic Reticulum

As the smooth endoplasmic reticulum is the site for the oxidative metabolism of many foreign compounds, it is vulnerable to damage from reactive metabolites such as epoxides and free radicals. Short-lived, reactive intermediates with only a narrow radius of action will obviously damage the immediate vicinity. Thus, with carbon tetrachloride, damage to both smooth and rough endoplasmic reticulum occurs leading to disruption of functions, such as metabolism and protein synthesis, of the whole organelle. One particular function of the endoplasmic reticulum which is important in terms of cellular homeostasis is calcium sequestration. Compounds which damage the endoplasmic reticulum such as carbon tetrachloride are known to inhibit this function of sequestrating calcium.

Covalent Binding To Macromolecules

As well as free radicals, other reactive intermediates, usually electrophilic species, may be produced by metabolism. These reactive intermediates can interact with proteins and other macromolecules and bind covalently to them. Studies have shown that there is a correlation between both the amount and site of binding and tissue damage. Therefore it was suggested that covalent binding to critical macromolecules was a possible cause of the cellular injury. While this may be true with regard to mutations and tumour induction where the target macromolecule, DNA, is known, with other types of toxic response the target molecule and the mechanism is less clear. Rather, it may simply be that covalent binding to macromolecules is an indication of the production of a reactive intermediate which is also a necessary step in the mechanism of cytotoxicity. Studies with paracetamol have shown that treatments which protect against cytotoxicity do not alter covalent binding in hepatocytes, and that...

Side Effects Of Selenium And Vitamin E

Vitamin E, when combined with blood thinners of all types, may increase the risk of internal bleeding.38 It is notable that smokers in the ATBC trial had an increased risk of hemorrhagic stroke at only 50 mg of vitamin E daily. Other clinical studies have demonstrated that obtaining over 1000mg of supplemental vitamin E daily may be harmful.63-65 For example, it can reduce the body's absorption of other antioxidants (like vitamin C) and may act as a pro-oxidant at these levels rather than an antioxidant, especially if you are not a smoker.66 It seems that, if any of these supplements have an impact on health, then they do so within a certain window period. Too little does not do anything and too much has either a negative or no impact. This will be a real challenge for future supplement trials deciding on the right supplement, at the right dosage, and which can give maximal efficacy and minimal side effects.

The Molecules that Cause Oxidative Stress

Oxidative stress is caused by a group of extremely reactive molecules comprising free radicals of oxygen, singlet oxygen, and hydrogen peroxide these are collectively known as active oxygen species (AOS). Singlet oxygen (*O2) is formed when the two unpaired electrons of molecular oxygen become paired, thus increasing the reactivity by making O2 amenable to donation of electrons in different spin configurations. Addition of electrons to molecular oxygen forms free radicals see Fig. 13-1 also reviewed in Halliwell and Gutteridge (1985), Cadenas (1989) and Wojtaszek (1997) . Transfer of a single electron, often catalyzed by transition metals such as Fe and Cu, to O2 forms the superoxide radical, O2 . In aqueous solutions, O2 disproportionates to hydrogen peroxide, H2O2. The decomposition of H2O2 can form the extremely reactive hydroxyl radical, OH indeed, this is one of the main sources of H2O2 toxicity (Cadenas, 1989). The reactivity of free radicals causes them to either abstract H+...

Coagulation and fibrinolytic systems in preeclampsia

In pre-eclampsia, PAI-1 activity is significantly increased (Estelles et al., 1991) and may be another marker for endothelial dysfunction (Caron et al., 1991). The ratio of PAI-1 PAI-2 has been used to test the efficacy of treatment with antioxidants on endothelial and placental function in a recent trial (Chappell et al., 2002).

Altered Autoregulation Of Cerebral Blood Flow In Hypoxia

Abstract Acute mountain sickness (AMS) is a syndrome of headache, anorexia, nausea and fatigue, which commonly occurs with rapid ascent to high altitudes. The pathogenesis of AMS remains incompletely understood. A leading theory has been that AMS could be an early stage manifestation of high altitude cerebral edema, which sometimes complicates AMS and is of poor prognosis. There has indeed been recent reports of magnetic resonance imaging (MRI) evidence of hypoxia-induced reversible brain edema in healthy volunteers. Interestingly, in these studies, brain edema was both vasogenic and cytotoxic but with only the MRI cytotoxicity signals correlated to AMS symptomatology. Studies in volunteers exposed to normobaric or hypobaric hypoxic conditions have disclosed a hypoxia-induced alteration of the autoregulation of cerebral blood flow in proportion to the severity of oxygen deprivation and to AMS symptoms. The alteration of cerebral autoregulation contributes to breathing instability...

Stabilization Of Plastics

In the 1960s and 1970s antioxidants and UV absorbers provided basic levels of protection against thermal and UV degradation. During the 1980s, hindered amine light stabilizers (HALS) extended the service lifetime of a range of polyolefin-based applications. Even during the past 10 years development has continued in the area of new structures of HALS, their performance, controlling the negative

Frank Van Breusegem and Dirk Inze

A variety of environmental stresses (such as chilling, ozone, high light, drought, and heat) can severely damage crop plants with consequent high yield losses. A common factor in all these adverse conditions is the occurrence of oxidative stress. Oxidative stress can be defined as the enhanced accumulation of active oxygen species (AOS) within several subcellular compartments of the plant. The AOS can react very rapidly with DNA, lipids, and proteins, with cellular damage as a result. Under normal growth conditions, AOS are efficiently scavenged by both enzymatic and nonen-zymatic detoxification mechanisms. Nevertheless, during prolonged stress conditions, this defense system becomes saturated and cellular damage is inevitable. The key players in the defense system are superoxide dismutases, ascorbate peroxidase, and catalases. These antioxidant enzymes directly eliminate AOS. This chapter gives an overview of transgenic plants with modulated antioxidant enzyme levels (focusing on...

Recent imaging studies in hypoxic volunteers

Most recently, Bailey et al. combined molecular and neuroimaging techniques to investigate whether hypoxia-induced release of oxygen free radicals might account for vasogenic edema and increased intracranial pressure in AMS 2 . Twenty-two subjects were exposed for 18 hours to 12 oxygen breathing, with sampling of blood and spinal fluid for oxygen free radicals measurements, lumbar puncture to estimate intracranial pressure, and MRI at the end of the hypoxic exposure. A clinical AMS was diagnosed in 50 of the subjects. Electron paramagnetic resonance spectroscopy identified a clear increase in blood and spinal fluid oxygen free radicals. Intracranial pressure remained normal. There was a slight increase in brain volume, by an average of 7 ml (0.6 ) with no evidence of edema. There was tendency for greater increase in brain volume in the sickest subjects, without relationship to oxidative stress or intracranial pressure.

Causes

Estrogen use has been associated with a decreased risk of AD and enhanced cognitive functioning. Its antioxidant and anti-inflammatory effects enhance the growth of processes of neurons for memory function. This has created intense interest in the relationship between estrogen, memory, and cognitive function in humans.

Endoperoxides

Artemesinin is an endoperoxide-containing ses-quiterpene lactone and was identified in 1972 as the active component of qinghaosu. Artemesinin (tablet and suppository formulations) and two derivatives, artesunate (tablet, suppository and parenteral formulation) and artemether (tablet and parenteral formulations), are effective in the treatment of multidrug-resistant P. falciparum malaria. These agents are converted into free radicals, which react with and damage specific malaria membrane-associated proteins. They are most active against late-stage ring parasites and trophozoites and are gametocytocidal (Mesh-nick et al., 1996). Artemesinin has been given to millions of patients in China and IndoChina and no serious toxicity has been reported (Hien and White, 1993). Artemesinin given as rectal suppositories appeared to be as effective as parenteral agents in one study (Hien et al., 1992). Artesunate is the most rapidly acting of the available compounds, possibly because it is...

Mechanisms of Injury

Host soluble mediators have been implicated in the injury resulting from Babesia infection. Clark postulated that endotoxin was involved in injury and death during babesiosis and acute malaria (Clark, 1978). He noted that babesiosis has effects similar to 'endotoxin shock'. Since these studies have been performed, it has become clear that much of endotoxin shock is mediated by the release of cytokines (Dinarello et al., 1993). It is possible that Babesia also elicits the production of cytokines by host cells and that cytokines might be responsible for some of the observed injury, in much the same manner as postulated for malaria (Harpaz et al., 1992 Urquhart, 1994). Other potential mediators of injury in Babesia infection have been postulated, including oxygen-derived free radicals (Clark et al., 1986).

Confounders

An important question is whether isolated vitamin, mineral and antioxidant supplements are as effective as those naturally present in fruits and vegetables. There are increasing reports that the interaction of the natural vitamins and antioxidants make them more effective compared to the isolated com-pounds.79 Thus, there has been an increased awareness of the benefits of eating fruits and vegetables to prevent or hinder cancer progression. However, there is also an increasing awareness of the relationships between the use of pesticides and the etiology of certain tumors, such as bladder cancer.80,81 Thus, a nationwide effort was established to decrease the use of DDT and other toxic pesticides known to be carcinogenic. Unfortunately, approximately 50 of all the fruit and vegetable produced in the USA is imported from countries that do not have restrictions on pesticides.

Carotenoids

These are a group of complex unsaturated hydrocarbons occurring as pigments in plants, for example, carrots. Some carotenoids are precursors of vitamin A, whereas others, such as lycopene, have a different structure and are not convertible to vitamin A. These compounds have been shown to have antioxidant potential, which is particularly marked with lycopene.12'13 A population-based case-control study carried out in Auckland, New Zealand, in 1996-1997 and recruiting 317 prostate cancer cases and 480 controls investigated associations between prostate cancer risk and dietary intake of the carotenoids P-carotene and lycopene and their major plant food sources, including carrots, green leafy vegetables and tomato-based foods. Dietary intake of P-carotene and its main vegetable sources was largely unassociated with prostate cancer risk, whereas intake of lycopene and tomato-based foods was weakly associated with a reduced risk.14 A prospective study was designed to examine the relationship...

Vitamin C

Vitamin C is a water-soluble antioxidant obtained from fruits and vegetables in food. Most recent cohort and case-control studies showed no significant association between vitamin C intake and risk of prostate cancer.17,18 The lack of activity of vitamin C, which is known to be a powerful antioxidant, underlines the complexity of prostate cancer biology and prevention.

Selenium

Differences in bioavailability of selenium reflect large geographical dietary intake variations. Selenium enters the food chain through plants.31,32 Commercial sources of selenium come from copper ores refinement. Selenium is a key component of a number of functional selenoproteins required for normal health, such as glutathione peroxidase enzymes, which are antioxidants that remove hydrogen peroxide and damaging lipid and phospholipid hydroperoxides generated in vivo by free radicals. A clinical double-blind study on 974 men in the USA showed that selenium reduced overall cancer incidence by 37 and that of prostate cancer by 50 .33

Recent Updates

During the time of this chapter's publication, several laboratory and clinical studies have provided some updates that seem relevant to the topic of antioxidant use and prostate cancer. Some of these findings include the following. A 3-year, double-blind trial of 160 patients with heart disease, low high-density lipoprotein (HDL) cholesterol levels, and normal low-density lipoprotein (LDL) cholesterol levels were randomly assigned to receive one of four treatments statin cholesterol-lowering drug plus niacin, antioxidants, the combination or placebo.116 The clinical end-points of the study were arteriographic evidence of any change in coronary blockage and the occurrence of any first cardiovascular event that included death, myocardial infarction, stroke or revascular-ization. The antioxidant supplements utilized in this study were 800IU vitamin E day plus 100 g selenium day plus 1000 mg of vitamin C day, and 25mg day of P-carotene. Interestingly, numerous findings were found that may...

NonACC Pathway

Although ethylene production in most instances occurs via induction of ACC synthase, alternative ethylene synthesis pathways also exist during certain stresses and other situations. For example, ACC does not appear to serve as a precursor of ethylene in aquatic ferns, some aquatic angiosperms, in Ceratocystis-infected sweet potato root tissue, or acid-stressed Norway spruce needles (see Mattoo and White, 1991). In several of these examples, oxygen free radicals interact with fatty acids or methionine to generate ethylene. Since free radical generation is intimately associated with PCD (Chapter 13), it is possible that in some of these processes ethylene is produced via a non-ACC pathway to allow for relatively quick death of infected or damaged cells.

Concluding remarks

Bilodeau, J.-F. and Hubel, C. (2003). Current concepts in the use of antioxidants for the treatment of preeclamp-sia. J. Obstet. Gynecol. Can, 25, 742-50. Bourdon, E., Loreau, N. and Blache, D. (1999). Glucose and free radicals impair the antioxidant properties of serum albumin. FASEB J, 13, 233-44. Plotnick, G.D., Corretti, M.C. and Vogel, R.A. (1997). Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. J. Am. Med. Ass., 278, 1682-6. Walsh, S. W. (1998). Maternal-placental interactions of oxidative stress and antioxidants in preeclampsia. Semin. Reprod. Endocrinol., 16, 93-104.

Oxygen

Oxygen enhances the effect of solar radiation in a number of ways (1) It forms a complex with conjugated unsaturated hydrocarbons that strongly absorbs UV radiation, thus increasing the amount of solar radiation absorbed. (2) It reacts with the carbon-centered free radicals produced by solar radiation to form peroxy

Apoptosis

Trxn is a ubiquitous protein whose activity has been linked to cell growth, transcription factor regulation, DNA synthesis, protein binding 43 45 , detoxi cation of free radicals 33 , and regeneration of antioxidant compounds (ascorbic acid, selenium-containing substances, and ubiquinones) 46 . Trxn isozymes of all organisms contain a conserved Cys-Gly-Pro-Cys- active site that is essential for the function of this class of proteins as general protein disul de reductases 43,44 , Trxn-(SH)2 regulates the activity of thiol-containing proteins via reduction of their S S bonds to protein-(SH)2 at the expense of its own oxidation to Trxn-(S)2. Trxn is maintained in its active, reduced form by thioredoxin reductase (TrxnR) that uses NADPH to reduce its S S bridge between Cysteines 32 and 35, respectively. Haendeler et al. reported that overexpression of Trxn in endothelial cells activates eNOS, increases basal levels of endogenous S-nitrosothiols, and inhibits TNF-a-induced apoptosis 47 ....

Conclusions

Altogether, these results are compatible with brain edema as a common determinant to AMS and high altitude cerebral edema. Disturbed cerebral autoregulation could be the cause of the vasogenic component of cerebral edema in severe AMS. Since head trauma with cerebral edema is known to be associated with an alteration in cerebral autoregulation, and since oxygen free radicals are a cause of abnormal vasoreactivity, there would be a vicious circle as illustrated in figure 5, where increased blood pressure with exposure to cold and or exercise would understandably intervene as aggravating factors. Oxygen free radicals The cause of both cytotoxic edema and abnormal CBF regulation could be the hypoxia-induced release of oxygen free radicals.