Free Radicals

Do Oxidants And Antioxidants Affect Gene Expression

It has been clearly shown that the cellular oxidant antioxidant equilibrium is a key factor in determining redox-dependent signal transduction pathways both in vitro and in vivo. Antioxidant nutrients interact with cell receptors (e.g., isofla-vones bind to estrogen receptor alpha and beta) and modulate key enzymes such as phosphatase and kinases. Changes in transcription factor activity leads to changes in mRNA and protein levels as summarized in Fig. 1.3. Furthermore, antioxidants can directly interact with enzymes (e.g., through protein-binding properties), thereby changing their activity. Molecular and cell biology has changed our understanding of how antiox-idants can mediate their biological properties. A good example is vitamin E the most important lipid-soluble antioxidant. Since its discovery, studies of the constituent tocopherols and tocotrienols have focused mainly on their antioxidant properties. In 1991, Angelo Azzi's group first described nonantioxidant, cell signaling...

Transcriptional Regulation of Cellular Antioxidant Defense Mechanisms

Reactive oxygen species (ROS) are constantly generated in human body. Enzymatic and nonenzymatic antioxidants detoxify ROS and minimize damage to biomolecules. An imbalance between the production of ROS and cellular antioxidant capacity leads to a state of oxidative stress'' that contributes to the pathogenesis of a vast variety of clinical abnormalities (1-3). The susceptibility of the target organs or cells to oxidative injury depends largely on their capability to control protective ROS scavenging systems. The primary endogenous antioxidants are present normally at low levels in human tissues and are not timely induced when exposed to oxidative stress. However, the response of certain antioxidant enzymes, constituting the critical primary defense against exogenous oxidative stress, occurs rapidly in proportion to oxidant insult. This chapter focuses on molecular aspects of adaptive cytopro-tection in response to oxidative stress.

Cellular Antioxidant Defenses

To minimize oxidative injury to major cellular components, thereby protecting cells under stress conditions, the multicel-lular organisms are endowed with distinct sets of integrated antioxidant defense mechanisms responsible for scavenging ROS or converting them to less reactive products that can be quenched by other antioxidants (11). These endogenous antioxidants comprise a co-operative network which employs a series of redox reactions. If there exists too much oxidant burden, ROS may overwhelm or attenuate inactivate the antioxidant defense system. Consequences of oxidative stress hence depend on types of cells affected and nature of ROS involved, endogenous antioxidant status, co-operation and or compensation between different antioxidant systems, and also the cellular capability to induce or potentiate the antiox-idant defense system, all of which determine the competence of the cellular defense mechanism against oxidative insult. In general, the preservation of the redox status...

Transcriptional Regulation Of Cellular Antioxidant And Detoxifying Enzymes

Oxidative stress provokes cellular responses which principally involve transcriptional activation of genes encoding proteins participating in the antioxidant defense. The eukaryotic cell contains a multitude of signal transduction pathways coupling pro-oxidative stimuli to the specific regulation of gene expression for adaptive responses. The signal transduction pathways that lead to the oxidative stress response are much less understood. In recent years, several components of the signal transduction cascades that sense oxidative injury have been identified in higher eukaryotes. These include the mitogen-activated protein (MAP) kinases and transcription factors that are subject to redox regulation. ROS can function as physiological mediators of transcrip-tional control of downstream genes encoding antioxidant enzymes and cytoprotective or stress-responsive proteins, which may lead to the adaptive responses to oxidative stress. Among the transcription factors involved in cellular...

Cycling of Antioxidants

Because free radical scavenging anti-oxidants are of great interest to us, we now look at how they participate in re-dox reactions, focusing attention on vitamin E as an example. Vitamin E is a fat-soluble antioxidant that protects fatty acids, such as those in the plasma membrane, from oxidation. To prevent the electrons of fatty acids from being lost to an oxidant or to replace them after they are lost, vitamin E sacrifices its electrons. This creates a vitamin E molecule that is now itself a free radical (i.e., it is missing an electron). Other antioxidants, commonly vitamin C, sacrifice an electron to the vitamin E radical, thus becoming free radicals themselves but regenerating vitamin E so that it can act again as an antioxidant. In a chain reaction of electron transport, the unbalance in electrons that started with the invading free radical moved first to vitamin E, then to vitamin C, and finally to NADH, the fundamental electron source within cells.a The electrons for NADH are...

Oxidative stress OS and formation of free radicals

OS occurs when the production of free radicals or their products are in excess of antioxi-dant defense mechanisms. OS, resulting from increased formation of hydrogen peroxide and oxygen-derived free radicals, can damage biological molecules and initiate a cascade of events, including dysfunction of mitochondrial respiration, excitotoxicity, and a fatal rise in cytosolic calcium, and, thus, is a major factor of the cytopathology of many neurodegenerative disorders (84). The generation of ROS during early-stage protein aggregation may be a common, fundamental molecular mechanism underlying the pathogenesis of oxidative damage, neurodegeneration and cell death in different neuro-degenerative diseases. However, it remains unclear how mitochondrial oxidative stress may induce neuronal death. In a variety of tissues, cumulative oxidative stress, disrupted mitochondrial respiration, and mitochondrial damage are associated with, and may indeed promote cell death and degeneration (84a,b)....

Sources of Free Radicals

Many of the free radicals we are concerned with are grouped under the term reactive oxygen species (ROS). As discussed in Chapter 2, these are either free radicals themselves (for example, the hydroxyl radical) or easily converted into free radicals (molecular oxygen and hydrogen peroxide). The primary source of ROS in a cell is molecular oxygen (O2), which is converted to free radicals or other ROS during cell respiration, immune activity, and redox reactions with trace metals. ROS can also be introduced from sources outside the body, such Immune cells like macrophages destroy invading pathogens and cancer cells by spitting out noxious chemicals. These chemicals include ROS such as the superoxide radical (O2* ), which is easily converted to the more damaging hydroxyl radical (OH*). (The dot signifies a free radical.) In addition, macrophages produce nitric oxide (NO *), a free radical based on nitrogen rather than oxygen. Thus the environment surrounding an activated macrophage is...

Nrf2Mediated Antioxidant Defense

ARE is a cis-acting regulatory element or enhancer sequence, which is found in promoter regions of genes coding phase II detoxification enzymes and antioxidant proteins. Okuda et al. (60) described an enhancer element which is similar to element or AP-1 site in the rat glutathione S-transferase-P gene. Subsequently, it was also found in the promoter regions of mouse glutathione S-transferase Ya (61), and human NAD(P) H qui-none oxidoreductase 1 (62) genes.

Reactive oxygen species and antioxidants

Radicals are molecules with a free (unpaired) electron that are highly reactive. Radicals are formed in all living organisms during oxidation reactions that occur as part of normal metabolism. Under certain circumstances such as environmental stress, wounding, and pathogen attack, the concentration of free radicals is increased beyond the normal levels. Radicals can do considerable damage to living organisms when left unchecked. This results in part from their reactivity, particularly towards DNA and membranes (lipids and proteins), and in part from the chain reactions they can initiate. Chain reactions occur when a radical reacts with another molecule, abstracts an electron, and thereby creates a new radical that can react with other molecules.

Ho1 Is The Most Strongly Induced Antioxidant Gene In Csexposed Cells In Vitro And In Vivo

CDNA microarray experiments, performed to study CS-induced differential gene expression on a comprehensive basis, identified HO-1 as the strongest expressed antioxidant gene, both in vitro (28) and in vivo (29). Kinetic studies in Swiss 3T3 fibroblasts exposed to subcytotoxic concentrations of aqueous extracts of CS showed an immediate strong increase in HO-1 expression resulting in a maximal 84-fold induction of this gene in comparison with untreated cells after 8 hr of exposure (28). As discussed in the section on Introduction, in order to prevent oxidative damage from the release of free iron as the result of heme degradation, transcriptional activation of HO-1 in CS-exposed cells was paralleled in an obvious, co-ordinated manner by the expression of ferritin. Apart from the paramount induction of HO-1, further results showed the transcriptional activation of other stress-related During a recent follow-up study addressing gene expression studies of CS-exposed cells in vivo,...

Antioxidants and Nutritional Support

The second category in Table 12.1 is compounds that are antioxidants or provide nutritional support. All cells need proper nutrition to function optimally, and immune cells are no exception. Although these require a variety of micro- and macronutrients, we focus here on a select few nutrients that have been extensively studied. In particular, several antioxidant vitamins appear to support immune function when their levels are low, immune function can be hampered. Animal and human studies have reported that vitamins C and E support immune function through a number of mechanisms. For example, immune cells produce various noxious compounds, including reactive oxygen species (ROS) and reactive nitrogen species antioxidants may help protect immune Antioxidants may also support immune function via their effects on intracellular glutathione levels. Glu-tathione plays an important role in immune function for three reasons. First, as a primary intracellular antioxidant, adequate glutathione is...

Antioxidants and Disease Outcome Observational Studies

Observational studies correlating potential health benefits with the consumption of antioxidants are summarized in table 1. 1 Table 1. A select list of observational studies of the role of antioxidants s, 0 - Study Study Study design Antioxidants assessed Results of study d Vitamin C and vitamin E intake determined by 24-hour recall, and plasma levels of antioxidants Food frequency questionnaire for assessment of dietary antioxidant intake Vitamin C serum levels were assayed No protective effect of antioxidant intake on diabetic retinopathy. Potential harmful effect of vitamin E and carotenoid in certain subset of diabetics Selenium and vitamin E levels were increased in those subjects with lipemia. In diabetics and hypertensive subjects the carotenoids were reduced Vitamin C intake did not seem to be associated with CVD risk among diabetics Antioxidants assessed Results of study

Antioxidants and Disease Outcome Interventional Trials

There are many small short-term interventional trials showing a highly variable effect of antioxidant supplementation on markers of oxidation, glucose disposal and vascular reactivity. Differences in study design, the type and preparation of antioxidants used and lack of information as to the oxida-tive state of the population studied may explain some of the discrepancies in the outcome of these studies. However, the true clinical role of antioxidant therapy has to be evaluated in large randomized, double-blind and placebo-controlled studies. Some of the larger interventional studies that have been published are summarized in table 2. The outcomes of these studies are not always consistent. The Cambridge Heart Antioxidant Study (CHAOS) 34 and Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study 35 found a beneficial effect of vitamin E intake. The randomization of subjects in the CHAOS trial was fraught with problems, the number of events was small and the follow-up...

Antioxidant Potential Of Mediterranean Diets

Interest in the antioxidant contents of Mediterranean diets has increased with the recognition that oxidative damage is an important factor in the pathogenesis of chronic and degenerative diseases.18 Fruits and vegetables are rich in natural antioxidant nutrients such as vitamin C, vitamin E, beta-carotene, lycopene (in tomatoes), organic sulfides (in garlic and onions), glucosinolates, dithiothiones, ubiquinone, and polyphenols such as quercitin, anthocyanines, procyanidines, and tannins. Their consumption has been shown to be associated with low risk for CHD.19 In the Cambridge Heart Antioxidant Study,23 2002 patients with coronary atherosclerosis were randomly assigned to receive 400 to 800 IU of vitamin E per day (or placebo). After a median follow-up of 1.4 years, a large reduction in the number of patients with nonfatal myocardial infarction was observed (relative risk 0.60). However, many other studies also reported no clear association with dietary antioxidants.24-25 In the...

Antioxidant Supplementation Pros and Cons

There are several misconceptions regarding the benefit of supplementing diet with pharmacologic doses of antioxidants. A common misconception is that overweight people are well fed and are not at risk for micronutrient deficiencies. The lay public is under the impression that since supplements are natural products, they must be safe, and since they are available over the Antioxidants and Diabetes Table 3. The arguments for and against the use of antioxidant supplementation counter, they must have the approval of the government agencies. Many also erroneously believe that antioxidant supplementation will achieve health benefits when conventional therapies fail. The arguments in favor of and against use of antioxidant supplementation are summarized in table 3. The fact that many, both in the industrialized world as well as in developing countries, do not consume a balanced diet that contains fresh fruits and vegetables, and the fact that antioxidants in small amounts appear to be safe,...

Invivo Redox Effects of Antioxidants

As with in-vitro studies, the effects an antioxidant produces in vivo are likely to be dependent on its concentration, the presence of metal ions, and the amount of other antioxidants and ROS present. In addition, the metabolism of the compound can greatly affect its redox reactivity. For example, quercetin, which shows both antioxidant and prooxidant effects in vitro, occurs in the plasma mainly in its conjugate forms (i.e., quercetin combined with glucuronic acid, a derivative of glucose). The conjugate form is less reactive than free quercetin in vitro and generally acts as a mild antioxi-dant in vivo.139-143 Similar to vitamin C, normal dietary doses of most an-tioxidants will probably have antioxidant effects in most in-vivo conditions, and one is more assured if combinations of antioxidants are used.144 For example, oral administration of a diverse group and high quantity of antioxidants produced greater protection from oxidative damage in rodents than fewer antioxidants and...

Theory on Antioxidant Effects

Data and goes beyond the simplistic argument of whether antioxidants are good or bad. Instead, we focus attention on how different conditions within various patients might alter the effects of antioxidants on cancer cell proliferation. The conclusions from this theory were summarized in Chapter 2, where we stated that depending on the circumstances, antioxidants used alone could produce beneficial, detrimental, or insignificant effects in cancer patients. When used in combination with other anticancer compounds (i.e., natural compounds or chemotherapy drugs), however, their effects are more likely to be beneficial, or at least not harmful. Lastly, we concluded that even when beneficial, the effects will probably be mild for many patients. For these reasons, we see anti-oxidants as supportive agents, best used in larger combinations of cancer-inhibiting compounds. Figure 15.3 does not reveal the role antioxidants play in oxidative stress and cancer cell proliferation. Intra-cellular...

Effects of Antioxidants on Metastasis

There are concerns that antioxidants may facilitate metastasis. That they may have this effect in some situations should not be surprising, given the above discussions. In one of the few animal studies that tested combined antioxidants, metastasis increased.192 In this study, high and very high doses of antioxidants were given in drinking water to rats with established, carcinogen-induced tumors. The high doses were about 2.4 grams of vitamin C and 1,200 I.U. of vitamin E per day (as scaled to humans). The very high doses were 10fold greater. Both groups received selenium (at 2 mg kg) and a thiol antioxidant compound (2-MPG, at 15 mg kg). The high-dose therapy was not effective in increasing life span nor was tumor size greater, but secondary metastases increased. Life span was increased 1.4fold in the very high dose group, but again secondary metastases increased equal to the high-dose group. The results suggest the antioxidants may have protected me-tastasizing cells from apoptosis....

Intrinsic Antioxidant Activity Of Resveratrol

Potent antioxidant activity of resveratrol observed in eukaryotic cells and in vivo models involves effects of resveratrol on particular redox-regulatory targets, such as the cyclooxygenases COX-1 and COX-2 (discussed in Section 18.7) and the intrinsic antioxidant activity of the polyphenol. Illustrative of the antioxidant action of resveratrol in cells, the stilbene potently suppresses the production of superoxide anion, hypochlorous acid, and nitric oxide in isolated human neutro-phils.7 The contribution of the intrinsic antioxidant activity of resveratrol to its suppression of reactive oxygen species (ROS) in cells has been inferred from the ability of the polyphenol to scavenge superoxide anion produced by the xan-thine xanthine oxidase system and hydroxyl radical, whether produced by the Fenton reaction (Fe2+ + H2O2 Fe3+ + OH + OH ) or by the transition metal Cr(VI) in the presence of NADPH and glutathione reductase.8 Resveratrol is a potent ROS scavenger in each of these...

Antioxidant Strategies In Hypercholesterolemia

By now, the reader will have gained an appreciation for the important role of oxidative stress in many of the responses observed in both acute and chronic hypercholesterolemic states. Thus, it follows that strategies targeting these oxidant-generating systems or their products could have immense therapeutic potential in the reduction of hypercho-lesterolemia-induced atherosclerosis. While animal studies have shown great promise, the use of antioxidant therapies, such as vitamins C and E, in humans has yielded disappointing results (62). Vitamins C and E have been shown to enhance antioxidant levels, prevent eNOS downregulation and improve endothelial function in several animal models (63). This may lead to reduced atherosclerotic plaque for mation (64). While there have been relatively few positive findings or mechanistic insights with vitamin therapy in humans, the use of slow-release vitamins was recently found to delay the progression of atherosclerotic lesion development (65)....

The Potential Application of Antioxidant Agents in Alzheimer Disease Therapeutics

Abstract Oxidative stress is a fundamental process contributing to the neuronal degeneration and death observed in Alzheimer disease, and many studies using markers of oxidative damage have provided evidence supporting this hypothesis. Consequently, antioxidants that prevent the detrimental consequences of oxidative stress are considered to be a promising approach to neuroprotection. While the clinical value of antioxidants for the prevention of AD is currently ambiguous, they still appear to be the most promising weapons that can be developed against disease progression.

Antioxidant Defenses Are Interlinked And Interdependent

Many of the components of antioxidant defense interact to maintain antioxidant status (1). Glutathione and the enzymes that maintain it in its reduced form are central to effective anti-oxidant status. For example, when oxidants interact with cell membranes, the oxidized form of vitamin E that results is restored to its reduced form by ascorbic acid. Dehydroascorbic acid formed in this process is reconverted to ascorbic acid by interaction with the reduced form of gluta-thione. Subsequently, oxidized glutathione formed in the reaction, is reconverted

Could Antioxidant Agents Prevent the Deleterious Consequences of Oxidative Stress

Unfortunately, no definitive therapy for the prevention or cure of AD exists. The currently approved drugs do not target any of the major mechanisms thought to cause the neuronal death loss seen in AD. Indeed, crucial to the task of preventing or potentially reducing neuronal injury in AD is the ability to elucidate the cellular mechanisms that precipitate neuronal degeneration. As discussed previously, oxidative stress is one of the primary events that occurs in AD pathophysiology. Consequently, antioxidants that prevent the detrimental consequences of oxidative stress are considered to be a promising approach to neuroprotection. Although several epidemiological clinical studies present controversial results, antioxidants constitute a major part of the panel of clinical and experimental drugs that are currently considered for AD prevention and therapy. There are various types of antioxidant compounds direct, indirect, and metabolic. Direct antioxidants have the potential to directly...

Metabolic Antioxidants

Idebenone is structurally similar to ubiquinone (CoQ), which is normally synthesized in cells as part of the mitochondria oxidative phosphorylation system. Ubiquinol, the reduced form of ubiquinone, can act as a very active antioxidant and can be absorbed through the diet. a-Lipoic acid is a coenzyme for mitochondrial pyruvate and a-ketoglutarate dehydrogenases. It is a powerful antioxidant and can recycle other antioxi-dants such as vitamins C and E and glutathione (Packer, Tritschler, & Wessel, 1997). It was reported that old rats supplemented with (R)-a-lipoic acid showed an improvement of mitochondrial function, decreased oxida-tive damage, and increased metabolic rate (Hagen et al., 1999). Accordingly, Suh and colleagues (2004) reported that old rats injected with (R)-a-lipoic acid presented an improvement in GSH redox status of both cerebral and myocardial tissues when compared with control rats. Similarly, Jesudason, Masilamoni, Jesudoss, and Jayakumar (2005) reported the...

Indirect Antioxidants

As discussed previously, it has been shown that dyshomeostasis of the redox-active metals and oxidative stress are intimately associated, contributing to the neuropathology of AD. Using an in situ detection system, we showed that NFT and senile plaques are major sites for catalytic redox reactivity. Pretreatment with DFO or diethylenetriaminepentaacetic acid abolished the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions (Smith et al., 1997 Sayre et al., 2000). Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Our findings suggest that NFT and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment. Savory and others...

Neutrophils and Free Radicals in Ischemia Reperfusion

The recruitment of neutrophils into reperfused tissue is a self-perpetuating cycle. Oxygen radicals cause endothelial activation and the upregulation of P-selectin and other neutrophil-specific integrins 4, 5 . Activated neutrophils produce more free radicals and recruit more neutrophils. The activated complement components C3a and C5a are also potent chemotactic agents. Neutrophil presence alone, however, is often not sufficient to cause reperfusion injury. Hence, in many experimental animal models, the creation of a neutrophil-free environment does not reduce injury. How It thus seems that the generation of oxygen radicals is likely to be a transient early event. The relationship between the generation of oxygen free radicals and complement activation is not well described. It is postulated that oxygen radicals are generated early and derived either from parenchymal cell xanthine oxidase or neutrophil NADPH. Either one could cause endothelial activation and cell injury, which might...

Antioxidant Effects of Isoflavones Flavones Flavonols and other Phenols

Phenolic compounds, including isoflavones, flavones, and flavonols, can act as antioxidants due to the hydrogen-donating capacity of their phenolic groups and, in some cases, their metal-chelating potential. The latter may block the generation of copper- and iron-induced free radicals. Table 19.1 ranks various phenolics and other antioxidants in comparison to vitamin C in their ability to scavenge aqueous free radicals in vitro. As seen, most flavonoids are more active than vitamins C and E. Some phenolic compounds that normally act as anti-oxidants can also act as prooxidants under the right circumstances (see Chapter 15). For example, some in-vitro conditions are adequate to auto-oxidize quercetin, and the prooxidant effect produced may account for some of quercetin's ability to cause gene mutations in vitro. In one study that tested 55 flavonoids, quercetin was the most mutagenic.74 Other flavonoids in Table 19.1 do not appear to auto-oxidize as readily or tend to be mutagenic in...

Cellular Viability In Response To Antioxidants

In order to examine whether the four antioxidants, DA, R-APO, EGCG, and melatonin, display a biphasic mode of action, NB SH-SY5Y cell viability studies were conducted with these compounds over a broad range of concentrations. The antioxidant agents demonstrated a dose-dependent effect on the viability of NB SH-SY5Y cells. At low concentrations (1-10 mM) they had no effect on cell survival, whereas at higher concentrations ( 10 mM) they induced a gradual decrease with rank order being R-APO EGCG DA melatonin (Fig. 6.1).

Antioxidant Activities Of Flavonoids

Oxidative stress and reactive oxygen species are major factors in the pathophysiology of CVD. The protective mechanism of flavonoids associated with reducing CVD is believed to be due to the potent antioxidant and free radical scavenging abilities that prevent oxidation of LDL.12 Cao et al. studied the serum antioxidant capacities of eight elderly women after intake of strawberries, spinach, red wine, and vitamin C to determine which antioxidant nutrients provided the best protection. The study indicated that the potentially important antioxidants other than vitamin C contained in the foods consumed produced over 80 of the total antioxidant capacity. Cao et al. concluded that the consumption of the rich antioxidant phenolic compounds contained in strawberries, spinach, and red wine are able to increase serum antiox-idant capacities in humans.3 High flavonoid intake is directly correlated with decreased risk of CVD. The potent antioxidant abilities of flavonoids have been demonstrated...

Depletion Of Antioxidants

Smoking and exacerbations of COPD result in decreased antioxidant capacity in plasma (22,43), in association with depleted protein sulfydryls in the plasma (22,43). The decrease in antioxidant capacity in smokers occurred transiently during smoking and resolved rapidly after smoking cessation (Fig. 9). In exacerbations of COPD, however, the decrease in antioxidant capacity remained low for several days after the onset of the exacerbation, tending to return toward normal values at the time of recovery from the exacerbation (43). The depletion of antioxidant capacity could in part be explained by the increased release of ROS from peripheral blood neutrophils, as shown by a significant negative correlation between neutrophil superoxide anion release and plasma antioxidant capacity (22). Thus, there is clear evidence that oxidants in cigarette smoke markedly decrease plasma antioxidants (42). Using an in vitro model, Eiserich et al. (62) showed that exposure of gas-phase cigarette smoke...

Other Auxiliary Antioxidants

Pacht et al. (107) demonstrated reduced levels of vitamin E in the BALF of smokers compared with nonsmokers, whereas Bui et al. (108) found a marginal increase in vitamin C in the BALF of smokers, compared to nonsmokers. Similarly, alveolar macrophages from smokers have both increased levels of ascorbic acid and augmented uptake of ascorbate (109). Increased activity of antioxidant enzymes (SOD and catalase) in alveolar macrophages from young smokers has also been reported (106). However, Kondo et al. (110) found that the increased superoxide generation by alveolar macrophages in elderly smokers was associated with decreased antioxidant enzyme activities when compared with nonsmo-kers. The activities of CuZnSOD, glutathione S-transferase, and GP are all decreased in alveolar macrophages from elderly smokers. However, this reduced activity was not associated with decreased gene expression, but was due to modification at the post-translational level (110).

Limitation of Antioxidant Therapy for Hypoxic Ischemic Injury

It has been well documented that free radicals (e.g., ROS and RNS) contribute to hy-poxic-ischemic neuronal death. Pharmacological or genetic intervention of ROS and RNS has been neuroprotective against hypoxic-ischemic injury as discussed above. However, neither tirilazad mesylate, a lipid peroxidation inhibitor, nor ebselen, a se-leno-organic compound with antioxidant activity, showed therapeutic efficacy in primary outcome measure of stroke patients. This lack of efficacy may be attributed to inappropriate administration of drugs that is insufficient to block ROS production following hypoxic ischemia. In addition, blockade of ROS neurotoxicity may result in appearance of the other death pathways, excitotoxicity, and apoptosis.

Antioxidant Therapeutic Interventions

It is now evident that oxidant antioxidant balance is altered in favor of oxidants in smokers, which play an important role in the pathogenesis of COPD. Therefore, it would be logical to propose the rationale of antioxidant therapy in ameliorating the increased inflammatory response in COPD. Furthermore, proof of concept of the role of oxidative stress in the pathogenesis of COPD will come from studies of effective antioxidant therapy. There are various options to enhance the lung anti-oxidant screen. One approach would be to use specific spin traps such as a-phenyl-N-tert-butyl nitrone to react directly with reactive oxygen and reactive nitrogen species at the site of inflammation (222). The therapeutic purposes of this drug are currently in clinical development. Inhibitors that have a double action, such as the inhibition of lipid peroxidation and quenching radicals, could be developed. Another approach could be the molecular manipulation of antioxidant genes, such as glutathione...

Statins as Antioxidants

A critical balance exists between NO and superoxide (O2-). Under physiologic conditions, NO levels are 1,000 times those of O2-, and the normal antioxidant mechanisms are able to detoxify small amounts of reactive oxygen species (ROS). During ischemia-reperfusion and inflammatory disorders, these defenses are overwhelmed and oxidant-mediated injury ensues, including peroxidation of cell membranes, impaired NO bioactivity, induction of leuko-cyte-endothelial adhesion, and thrombosis. Oxidative stress also contributes to the pathogenesis of chronic vascular diseases such as atherosclerosis, diabetes, and hypertension. The NADPH oxidase is a major source of O2- within the vascular wall, and Rac-GTPase is an important regulator of this enzyme in EC, VSMC, and phagocytes. Statins block the translocation of GTP-bound Rac to the membrane, consequently reducing transcription of critical NADPH sub-units and vascular wall production of ROS in response to various stimuli, such as angiotensin II...

Antioxidant Properties

Compounds that can scavenge radicals are also referred to as antioxidants. The best known anti-oxidants are vitamin C and vitamin E. Vitamin C is L-ascorbate (7.8), a good reducing agent that prevents oxidation of other molecules. The oxidized form of L-ascorbate is L-dehydroascorbic acid (7.9). Vitamin E is a mixture of a-, P-, y-, and S-tocopherol (7.10a-d). Of these four compounds, a-tocopherol is the most effective. Vitamin E is lipid-soluble and has the ability to disrupt the chain reaction during lipid peroxidation (see Chapter 2, Section 1.9). The effects of wine and its polyphenol constituents on early indicators of coronary heart disease such as elevated levels of plasma lipids, platelets and serum antioxidant activity were discussed in a review by Cooper et al. (2004). This review also addressed whether the polyphenols or alcohol are responsible for the beneficial effects of wine on cardio-vascular health. The authors conclude that red wine polyphenols have little effect on...

Antioxidants and Vitamins

It is generally agreed by all scientific organizations that routine supplementation of the diet with antioxidants and vitamins is not necessary. The DNSG of the EASD recommends that the consumption of foods naturally rich in dietary antioxidants (tocopherols, carotenoids, vitamin C, flavonoids, polyphenols, phytic acid), trace elements and other vitamins should be encouraged. The daily consumption of a range of vegetables and fruit is encouraged as well as regular consumption of wholegrain breads, cereal and oily fish. Salt intake is advised to be limited to

Antioxidant Micronutrients Vitamins E C carotene and Selenium

Vitamin Scheme Antioxidant

A deficiency in these important antioxidant nutrients will cause chromosomal damage and oxidative lesions to membrane structures. Outside of its crucial role as a coenzyme for copper-dependent hydroxylases and a-ketoglutarate-linked iron-containing hydroxylases, vitamin C has generalized antioxidant properties, including salvage of the spent tocopheroxyl radical back to a -tocopherol (vitamin It is worth noting that at high levels, vitamin C, as with other antioxidants such as j-carotene, may actually potentiate radical formation and compromise the integrity of genomic mechanisms (see carotenoid Figure 3.4 above) Vitamin C as a protective antioxidant Vitamin C as a prooxidant source of free radicals ascorbate + O2 + monodehydroascorbate Figure 3.5. Scheme showing antioxidant effect and salvage of vitamin C. Figure 3.5. Scheme showing antioxidant effect and salvage of vitamin C. Vitamin E protects polyunsaturated fatty acids within the cell membrane and plasma lipoproteins from lipid...

Antioxidants As Possible Treatment For Ms

Antioxidants are exogenous (natural or synthetic) or endogenous compounds acting to reduce or diminish the oxidative stress. The natural antioxidant system includes enzymes (i.e. superoxide dismutase (SOD), catalase, peroxidase, and some supporting enzymes), and low-molecular-weight antioxidants (LMWA), which contain ascorbic acid, lipoic acid, polyphenols, carotenoids, and vitamin E (14). The pathogenic role of oxygen and nitrogen free radicals in MS led to the recognition that antioxidants might prevent free-radical-mediated tissue damage and inhibit some of the early proinflammatory events that lead to inflammation and tissue destruction in EAE and MS. However, the main obstacle and challenge in MS treatment are to introduce substances into the brain through the BBB (14). Lehmann et al. (68) showed that administration of the oxidant-scavenger N-acetyl-L-cysteine (NAC) inhibited the induction of acute EAE in mice. The protection was associated with enhancement of the specific...

Antioxidant Protective Genes

An important effect of oxidative stress in the lungs is the upregulation of protective antioxidant genes. The antioxidant glutathione (GSH) is concentrated in epithelial lining fluid compared with plasma (101) and has an important protective role, together with its redox enzymes, in the airspaces and intracellularly in epithelial cells. Human studies have shown elevated levels of glutathione in epithelial lining fluid in chronic cigarette smokers compared with nonsmokers (26,101). However, this increase is not present immediately after acute cigarette smoking (26). stress. These events are likely to account for the increased levels of glutathione seen in the epithelial lining fluid in chronic cigarette smokers (26,101). However, the injurious effects of cigarette smoke may occur repeatedly during and immediately after cigarette smoking when the lung is depleted of antioxidants, including glutathione (26). Gilks et al. (187) have shown that rats exposed to whole cigarette smoke had...

Oxidation And Reduction Prooxidants And Antioxidants

Oxidation is defined as a loss of electrons, and reduction is a gain of electrons (87). An oxidant is a substance that is reduced by donating electrons, thus causing a reductant to be oxidized by the donated electrons. Reductant and oxidant are chemical terms, whereas antioxidant and pro-oxidant, or simply oxidant, have meaning in the context of a biological system. An antioxidant can be defined as a substance that, when present at low concentrations as compared to those of an oxidizable substrate, significantly prevents or delays a pro-oxidant-initiated oxidation of the substrate. A pro-oxidant, or simply oxidant, is a toxic substance that can cause oxidative damage to lipids, proteins, and nucleic acids, resulting in various pathologic events and diseases. Pro-oxidant is a synonym for reactive species. Chemically, a pro-oxidant is an oxidant of pathologic importance. An antioxidant is a reductant, but a reductant is not necessarily an antioxidant (88). Another definition for...

Mechanisms Of Antioxidant Defense By Flavonoids

The mechanism which has been most extensively investigated is metal chelation preventing free radical formation and secondly, the direct scavenging of oxygen and nitrogen free radicals such as hydroxyl, superoxide, and nitric oxide radicals. Most of these studies have been made in vitro or ex vivo systems. Evidence for such activity in body tissues is generally absent or inconclusive. 2. A mechanism of great importance in antioxidant defense, detoxification, and cancer prevention is the induction of phase 2 enzymes. Evidence of this important in vivo response to bioflavonoids is from cell, animal, and human studies. Figure 2 illustrates the major pathways of phase 2 enzyme induction. Phase 2 enzyme induction results in synthesis of flavonol and other conjugation enzymes. Major flavonol conjugation enzymes are Glutathione as in GSH S-tranferases Glucuronic acid as in UDP-glucuronosyltransferases Methylation as with methyl transferases Sulfation as sulfotranferases. dismuiase...

Prion Protein As An Antioxidant

Rate equivalent to one tenth of SOD-1. SOD-1 is a very potent enzyme which catalyzes the reaction at around 100 000 times the spontaneous rate of superoxide degradation 94 . It was therefore concluded that PrPc had significant superoxide dismutase activity and this was also confirmed for native protein purified from mouse brain 58 . Strict controls were used to ensure that the prion protein SOD activity was a real enzymatic activity and not simply due to Fenton chemistry arising from the copper ligation within the protein. The deletion of the specific octameric repeats of the N-terminal region abolished the SOD activity, despite there still being copper bound at the C-terminal domain 53 . In addition, a pep-tide based on the octarepeat region with copper bound to it had no SOD activity. When rPrPc was refolded without copper and the copper subsequently added to the refolded protein, the mixture did not demonstrate SOD activity to the level of the coordinated copper in the protein 53 ....

Increased Antioxidant Capacity and Genomic Stability

The traits described thus far are acquired in the course of tumor progression via alterations in the genomes of cancer cells, resulting from DNA damage. Cells are exposed to a variety of oxidizing agents, termed reactive oxygen species (ROS), coming from exogenous and endogenous sources that can damage DNA. Oxidative damage of DNA, if left unrepaired, can lead to base mutations, single and double strand breaks, DNA cross-linking, chromosomal breaks and rearrange-ments.50 An estimate of the daily rate of oxidative damage to DNA is 104 hits per cell in humans.51 Normally there is a balance between oxidizing and antiox-idizing molecules in the body and mutations in specific genes are kept in check by a number of DNA monitoring and repair systems that work to prevent and reverse alterations in specific genes.50 However, an imbalance in the system due to overproduction of free radical oxidants or an inadequacy of antioxidants, can lead to oxidative damage of large biomolecules, including...

Introduction To Free Radicals And Antioxidants

The chemical definition for free radicals (oxidants) is atoms or groups of atoms with one or more unpaired electrons.'' This property makes them very unstable and highly reactive, trying to capture the needed electron from other compounds to gain stability. When the attacked molecule loses its electron, it becomes a free radical itself, beginning a chain reaction. Some free radicals, such as the toxic oxyradical species hydroxyl radical (*OH) or the less reactive superoxide radical (O2* ), arise normally during mitochondrial oxidative metabolism. Also, the body's immune system cells purposefully generate free radicals to neutralize viruses and bacteria. Environmental factors such as pollution, radiation, cigarette smoke, and herbicides can also generate free radicals. Therefore, biological systems are continuously interacting with free radicals arising either from metabolism or from environmental sources, i.e., leading to a process called oxidation. As stated above, free radicals have...

The Molecular Mechanism Of Action Of Antioxidants

Antioxidants have neuroprotective, antioxidant anti-apoptotic activity at low concentrations, whereas at high concentrations they induce pro-oxidant and neurotoxic pro-apoptotic actions in cell cultures and in vivo models of neurodegenerative diseases. Our recent studies (10,28) provide new insights into the molecular events involved in the dose-dependent anti- and or pro-apoptotic activities of catechol-derived and indoleamine compounds at low and high concentrations. For this purpose, low neuroprotective and 50-fold higher concentrations were chosen. cDNA microarray has demonstrated a concentration-dependent homology among antioxidants R-APO, DA, melatonin, and EGCG for modulation of cell survival cell death-related gene pathways. The gene microarray analysis provides the first evidence for a selective, dose-dependent regulation of a number of mRNAs by these drugs. One important aspect of our study is the significant homology between the catechol-derived compounds and differences...

Antioxidant Network

Oxidants and antioxidants must be kept in balance to minimize molecular, cellular, and tissue damage because if the balance is upset in favor of the former oxidative stress'' occurs. The term oxidative stress'' was first coined by Helmut Sies in 1986 Ref. 5 referring to the imbalance that arises when exposure to oxidants changes the normal redox status of major tissue antioxidants, especially glutathione, the cell's primary preventative antioxidant. Glutathione is usually present in tissues in millimolar amounts in the aqueous compartments of cells and their organelles. Under normal conditions, glutathione exists primarily in its reduced form (GSH). However, upon exposure to oxidants generated during flux through the respiratory chain (cytochrome P450), electron transport reactions metabolism of foreign compounds, ligand receptor interaction, immune system activation, or exposure to environmental oxidants, GSH is oxidized to glu-tathione disulfide (GSSG), thus changing the redox...

Antioxidant Systems

Normal biological processes that make use of oxygen inevitably lead to the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide, hydroxyl radicals, nitric oxide, and peroxynitrite. While a limited amount of ROS production can serve important cell signalling and anti-microbial functions 31 , when produced in larger amounts, ROS can cause oxidant stress to the host leading to cellular and tissue injury. The mechanisms by which oxidant stress causes cellular and tissue injury include damage to genomic and mitochondrial DNA, lipid peroxidation, and protein modification 32-34 . Cell death secondary to oxidant stress can be from either necrosis or apoptosis 34 , In keeping with many biological processes that have counter-acting or counter-regulatory mechanisms, all aerobic organisms have well-developed antioxidant systems to protect cells and tissues against high levels of ROS production. Another major antioxidant mechanism in mammals is the thioredoxin...

Antioxidant Enzymes

Although the relatively small-sized antioxidants, vitamin C, vitamin E, and glutathione, have received the most public attention, large antioxidant enzymes in the cell also perform a vital role in neutralizing free radi-cals.a In fact, they act more efficiently than the small antioxidant compounds because they directly catalyze the conversion of free radicals to other, less harmful free radicals or to inert or useful compounds such as water and reduced glutathione. Unlike the small antioxidant compounds, antioxidant enzymes do not become free radicals that need to be regenerated. The conversion of free radicals by antioxidant enzymes is illustrated in Figure 5.2. The left side of the figure shows how oxygen (O2) loses an electron to produce the superoxide radical (O2* ). Superoxide is then converted to hydrogen peroxide by the enzyme SOD. Hydrogen peroxide is converted to harmless water (H2O) by the enzymes catalase, glutathione peroxidase, or both, with glutathione peroxi-dase...

Antioxidant Defence

The first line of defence appears to be common to all organisms with the exception of some anaerobes (Jenney et al., 1999). One or the other type of superoxide dismutase (SOD) eliminates the superoxide radical anion that arises from autoxidation processes, leakage of the respiratory chain or the respiratory burst during the innate immune response. One of the products of the SOD reaction, H2O2, has to be removed by peroxidases, since it is cytotoxic as such and may generate even more drastic oxidants such as hypochloric acid or the hydroxyl radical which destroys most of the cellular components with diffusion-limited rate constants. Nature has invented at least three distinct families of proteins for this job the heme-type peroxidases, the glutathione peroxidases (Flohe and Brigelius-Flohe, 2006), and the peroxiredoxins (Hofmann et al., 2002), and such proteins and their supply devices have been combined during evolution, with considerable complexity, to provide species-specific...

Antioxidant Effects

Another important mechanism by which estrogen may provide neuroprotection is by limiting an important component of the secondary injury cascade, free radical-induced lipid peroxidation. Lipid peroxidation is a destructive process initiated by free radicals that has been shown to produce significant damage following acute brain ischemia or traumatic injury (see references 70 and 71 for reviews). Lipid peroxidation of cell membranes is a geometrically progressing process that spreads over the surface of the membrane and on to surrounding cells. Free-radical scavengers such as superoxide dismutase69 and lipid antioxidants, such as the glucocorticoid steroid methylprednisolone,70 U-72099E,71 the 21-aminosteroid tirilazad mesylate,72 and the nonsteroidal 2-methylaminochroman U-78517F,73 have been reported to attenuate posttraumatic pathophysiology and or to promote survival and recovery in experimental head injury. Tirilazad and U-78517F have also been found protective in models of focal...

Antioxidants

In the following sections, we explore the effects of an-tioxidants in general. Many issues that applied to vitamin C apply to other antioxidants as well, and our preliminary conclusions regarding their use are the same TABLE 15.3 PROOXIDANT EFFECTS OF ANTIOXIDANTS IN VITRO In tests on a series of flavonoids, apigenin produced the greatest prooxidant effect independent of metal ions. Apparently, apigenin oxidized intracellular glutathione, and the oxidized glutathione then participated in the generation of additional free radicals.124, 125 Apigenin and luteolin acted as antioxidants at low iron concentrations but as prooxidants at high iron concentrations.126 Induced apoptosis in cancer cells through a prooxidant mechanism, and antioxidants prevented curcumin-induced apoptosis.130, 131 as those for vitamin C. In short, most antioxidants have the capacity to increase, decrease, or not effect cancer cell proliferation. To help assure an anticancer effect, they are best used as supportive...

Direct Antioxidants

Sano et al. (1997) reported that vitamin E (a chain-breaking lipid-soluble antioxidant) appeared to be beneficial in patients with moderately severe AD by delaying the time of progression to severe dementia, loss of ability to perform activities of daily living, institutionalization, or death. However, the authors also observed that cotreatment with vitamin E and selegiline (a selective monoamine oxidase type b inhibitor with antioxidant properties) had no additional benefit over that of vitamin E alone. Other studies on the effect of vitamin E supplementation in AD subjects have yielded interesting results. Those subjects supplemented with 2000 IU per day had a delayed time before they became institutionalized, but supplementation had no effect on loss of cognitive performance (Grundman, 2000). Another two studies (Engelhart et al., 2002 Morris et al., 2002) suggested that higher dietary levels of vitamin E and vitamin C can help to protect against the onset of symptoms associated...

Antioxidant Activity

Anthocyanins are highly reactive radical scavengers in various in vitro environments. Anthocyanins not only scavenge radicals, but through their ability to bind heavy metals such as iron, zinc, and copper, also prevent the formation of radicals.47 Anthocyanins may also exert antioxidant abilities through the protection or enhancement of endogenous antioxidants (i.e., sparing effect), or through the induction of antioxidant enzymes such as glutathione-S-transferase (GST) and superoxide dismutase (SOD).48,49 Also, there appears to be a synergism between anthocyanins, vitamin C, and other flavonoids which is similar to the reported recycling effect of vitamin E by vitamin C. This effect was observed in an investigation by Rossetto et al.31 where the flavonoid catechin was observed to regenerate malvidin 3-glucosides thereby increasing their antioxidant capacity in a micellar system with induced linoleic acid peroxidation. 20.2.1 Structural Characteristics Effecting Antioxidant Activity...

Why Natural Compounds

Third, we must study natural compounds because they are already being used in cancer treatment (and in the treatment of other diseases). For better or for worse, hundreds of thousands if not millions of patients around the world are experimenting with natural compounds in their efforts to heal themselves of cancer. Researchers estimate that anywhere from 10 to 80 percent of U.S., European, Australian, and Mexican cancer patients use some form of complementary medicine as part of their overall therapy.112, a For many of these patients, the use of natural compounds is an essential part of the complementary approach. For example, two studies in the United States have reported that roughly 40 to 60 percent of cancer patients who use some form of complementary medicine include the use of herbs, vitamins, antioxidant, or all three.12,13 Most of these patients are using natural compounds without the guidance of their oncologist or any real guidance from scientific studies. Because the...

Methods in Enzymology

Oxygen Radicals in Biological Systems (Part B Oxygen Radicals and Antioxidants) Volume 299. Oxidants and Antioxidants (Part A) Edited by Lester Packer Volume 300. Oxidants and Antioxidants (Part B) Edited by Lester Packer Volume 301. Nitric Oxide Biological and Antioxidant Activities (Part C)

Notes For The 2005 Downloadable Version

First, I would change Chapter 15 on vitamin C and an-tioxidants. While some of the basic information is sound, conclusions and extrapolations need to be revisited. These include conclusions on vitamin C, which requires a more thorough investigation on my part. I would completely delete the section titled A Theory on Antioxidant Effects , as it would need extensive work to make it presentable. Also, as part of my graduate work I am modeling oral clearance and toxicity, but in a more refined manner than is presented in Appendix I. Thus, the material in the appendix would need revision, as well as the dose estimates throughout the book that are based on the models presented in the appendix. Lastly, all sections of the book could be updated with information that has been published since the release of the book. In this spirit, some research updates from 2001 are available on our web site.

Contrastinduced Nephrotoxicity

Tepel et al. (37), relying on evidence (39) that reactive oxygen species may play a causative role in CIN, administered the antioxidant acetylcysteine in a prospective, placebo-controlled, randomized trial in high-risk patients and demonstrated a protective effect of the drug. In patients with chronic renal insufficiency, oral acetyl-cysteine combined with intravenous hydration was better than placebo and hydration in reducing the incidence of CIN. (Acetylcysteine is better known by its various trade names, including Mucomyst, Mucosil, Fluimucil, Genac, and many others).

Pulmonary Disease 291

Reactive Oxygen and Reactive Nitrogen Species as Surrogate Markers in Plasma and Exhaled Breath Condensate 302 Depletion of Antioxidants 309 Depletion of Glutathione 312 Other Auxiliary Antioxidants 313 Consequences of Oxidant Antioxidant Obstruction 318 Inflammation and Gene Expression 319 Antioxidant Protective Genes . . . . 325 Chromatin Remodeling (Histone Acetylation and Deacetylation) and Glucocorticoid Inefficacy 328 Inflammation and Adenoviral E1A . . . . 333 Oxidative Stress and Susceptibility to COPD 334 Antioxidant Therapeutic Interventions 335 Thiol Compounds 336 Conclusion 340

Guanylate cyclasecoupled receptors

The two forms of guanosine cyclases have different functions and follow different routes of activation. The soluble form is activated by nitric oxide (NO) and by free radicals, whereas the membrane-bound form is a part of a trans-membranous receptor. Cyclic GMP activates a specific cGMP-dependent protein kinase (PKG) and leads to a downstream activation of a 23-kDa protein (known as G substrate).

Comments On Metal Ions In Neurology

Redox-active metals (Cu, Fe, Mn) can generate radicals and reactive oxygen (ROS) and nitrogen species, by inappropriately accepting or donating electrons (a redox-active metal refers to a metal ion that can change its valence state under biological conditions). However, metal ions like Cd(II), Hg(II), Al(III), and Pb(II) can also affect redox reactions in indirect ways. Redox-active metal ions like Cu, Fe, and Mn are needed for essential biochemical activities and antioxidant defences such as cytochrome c oxidase and superoxide dismutase 1 (Cu), hemoglobin and cis-aconitase (Fe), and superoxide dismutase 2 (Mn). Because of the problem of inappropriate electron transfer from these metal ions, metalloproteins have highly structured active sites that are small and substrate-specific. Also, all cells have stringent chaperone mechanisms in place to prevent side reactions of these metals with incorrect substrates. This is probably why there is no free Cu or Fe in the cell, rather these...

Pharmacological support

Attempts to modify the inflammatory process in ARDS with pharmacological agents have met with only limited success. Agents used have included non-steroidal anti-inflammatory drugs (e.g. ibuprofen), prostaglandins (alprostadil), thromboxane synthetase inhibitors (ketoconazole), antioxidants ( -acetylcysteine), and neutrophil activator inhibitors (e.g. pentoxifylline). Corticosteroids are beneficial in animal models, but clinical trials have been disappointing. High-dose steroids have a place in the treatment of patients with significant fibroproliferation or high bronchoalveolar eosinophil counts, where sepsis is excluded. Most progress has been made in the area of inhaled vasodilators used in an attempt to improve ventilation-perfusion relationships and decrease intrapulmonary shunting. This is achieved by increasing blood flow to ventilated lung units. Reducing pulmonary vascular resistance may also decrease pulmonary edema formation and therefore increase arterial oxygenation....

Dna Rna And Gene Expression

As stated previously, RNA is the working copy of DNA from which proteins are produced. During the life of a cell, many proteins must be manufactured to perform needed functions. To take two examples, during periods of oxidant stress a cell must manufacture the proteins needed to create antioxidant enzymes, and to start proliferation a cell must manufacture proteins that initiate division. Thus the need for specific proteins changes dynamically during the life of the cell.

Methods And Applications In Nutrigenomics

There is an increasing evidence indicating that antioxidants such as vitamin E, carotenoids, ascorbic acid, lipoic acids, bioflavonoids, and ginkgo biloba as well as trace elements (e.g., Zn, Fe, Se) affect differential gene expression in Figure 1.4 Antioxidants as free-radical scavengers, metal chelators, and redox signaling molecules both prevention of oxidative damage towards lipids, proteins, and DNA as well as redox signaling contributes to their potential beneficial effects. Figure 1.4 Antioxidants as free-radical scavengers, metal chelators, and redox signaling molecules both prevention of oxidative damage towards lipids, proteins, and DNA as well as redox signaling contributes to their potential beneficial effects. Table 1.1 Studies on the Effect of Oxidants and Antioxidants on Differential Gene Expression in Cultured Cells, Laboratory Animals and in Humans Antioxidants Ascorbic acid Coenzyme Q10 Copper cultured cells, in laboratory animals, and in humans. In addition,...

Oxidative Stress as a Risk Factor

It is possible that the age-dependent progressive increases in brain oxidative stress contributes or facilitates AD lesions. This hypothesis would indicate the convenience of effective measures to prevent and treat brain oxidative stress. However, until now, there have not been conclusive studies demonstrating efficacy of vitamin C and E in arresting or significantly delaying the onset of AD. More recently, the use of agents capable of crossing the blood-brain barrier, such as lipoic or dehydroascorbic acids, has been suggested (Harman, 2006). There is a large list of antioxidant compounds that have been suggested as beneficial to prevent or delay AD including defined chemical entities or natural products such as green tea, ginkgo biloba, red wine, blueberries, etc. Some effort is being made to define the efficacy of defined extracts (e.g., from blueberries or spinach) and of assessing their effects in suitable cell and animal models (Joseph, Shukitt-Hale, & Casadesus, 2005). Although...

Neuroprotective Therapy

The first controlled, clinical trial for the purpose of evaluating medications as neuroprotective agents was the DATATOP (deprenyl and tocopherol antioxidative therapy of parkinsonism) study (20). Deprenyl (now called selegiline) is an irreversible monoamine oxidase B (MAO-B) inhibitor and thus an antioxidant. Selegiline was tested along with the antioxidant, alpha-tocopherol (vitamin E), in a 2 x 2 design. Patients were enrolled in the study early in the course of the illness and did not require symptomatic therapy. The primary endpoint was the need for dopaminergic therapy. The study showed that tocopherol had no effect in delaying parkinsonian disability, but selegiline delayed symptomatic treatment by nine months (Fig. 1). It also reduced the rate of worsening of the UPDRS by half (Table 1).

Health Benefits Not Related To Nutritional Essentiality

Associations observed subsequently between diet composition, intakes of various individual diet components, and the incidence of heart disease and cancer have implicated food constituents such as fatty acids, fiber, carotenoids, various nonnutrient substances in plants, and high intakes of some essential nutrients (especially vitamins E and C, which can function as antioxidants) as factors influencing the risk of developing these diseases ( 6) (see Chap ei Z6, Chapter.80 and Ch p.t E 1). This has led to proposals for modifying the criteria for essentiality or conditional essentiality to include dietary constituents reported to reduce the risk of chronic and degenerative diseases or to improve immune function, and for considering such effects of high intakes of essential nutrients as part of the basis for establishing RDIs (2, 3, 4, 5 and 6). Food Constituents Desirable for Health. A straightforward way of avoiding these problems is to treat food constituents that exert desirable or...

How to prevent discoloration in fruits and vegetables

And so Lemons contain ascorbic acid, or vitamin C, an antioxidant compound. Pure ascorbic acid of the kind one finds in tablet form at the pharmacy ought to be more effective than lemon juice, and experiments show that this is indeed the case. By investigating the role of oxygen in the darkening of vegetables, modern food science has been able to add to the empirical list of remedies that cooks have compiled, which includes not only the juice of certain citrus fruits (lemons, oranges, limes) but also various salty brines.

Redox Poise Across Bioenergetic Membranes

In principle, though, the mitochondria could detect ATP levels and so combine two signals 'high ATP' and 'high free radicals'. An appropriate response would now be to dissipate the proton gradient, to maintain electron flow, and there is indeed evidence that this happens (Brand et al. 2004). In contrast, if there were not enough respiratory complexes, ATP levels would decline and electrons would again accumulate in the respiratory chains. Now the signal would combine 'low ATP' with 'high free-radical leak'. This system could in theory discriminate the need for more respiratory complexes from low ATP demand. Similar signalling systems operate at a cellular level to signal apoptosis in eukaryotes ('high free radicals', 'low ATP' Zamzami et al. 1995, Richter et al. 1996 Ott et al. 2002) and homologous recombination in simple eukaryotes like Volvox carteri and S. cerevisiae ('high free radicals', 'high ATP' Brennan and Schiestl 1998 Nedelcu et al....

Discovery of R805 nimesulide

Sulphasalazine 1962

The development of nimesulide arose from investigations by Dr George (GGI) Moore (a medicinal-organic chemist Fig. 2), Dr Karl F Swingle (a pharmacologist), Dr Bob (RA) Scherrer (a medicinal chemist) and their colleagues at Riker Laboratories Inc (Northridge, California, US, later part of the 3M Company at St Paul, Minnesota, US). They had the idea that since the evidence in the late 1960s suggested that free radicals were important in chronic inflammatory diseases then drugs which scavenge these radicals might have novel anti-inflammatory mechanisms to control chronic inflammation. They undertook a detailed structure-activity analysis and determined the pharmacological properties of the sulphonamides 12 . This class of agents had previously been considered in the 1940s to have antirheumatic activity as a consequence of their antibiotic effect by Svartz and her colleagues at Pharmacia in Sweden and this culminated in the development of the sulphonamide-salicylate conjugate,...

Transcription Factors And Redox Signaling

Groups (a process involving protein phosphorylation). This process is not the only means by which signals travel within cells, however. In the last decade, researchers have discovered that signal transduction also occurs via free radicals in a process called redox (reduction-oxidation) signaling. This discovery lagged behind that of protein phosphorylation because of the inherently transient nature of free radicals and the difficulty of tracking them. It is now clear that a dynamic balance of oxidants and antioxidants exists within a healthy cell. Fluctuating concentrations of free radicals serve to switch on and off a variety of cellular activities, including enzyme activation and, via transcription factors, gene expression.1 Although more ephemeral, this form of signal transduction is as important as that of protein phosphorylation. And like signal transduction due to protein phosphorylation, redox signaling is also abnormal in cancer cells, providing them with survival advantages.

The Ljubljana Classification and WHO 2005 Classification

Up and avoidance of exposure to known risk factors is important due to the risk of malignant transformation 47, 263, 334 . Recurrences of high-risk SILs are not infrequent events, being reported in 18 of lesions that had been excised with free surgical margins 366 . If the size or other clinical obstacles make surgical treatment of oral SILs difficult, various antioxidants, such as beta-carotene and the retinoids, are most commonly used for chemoprevention 191 .

Mitochondrial Dysfunction

The elucidation of the mechanism by which MPTP produces parkinsonism in experimental animals has contributed to the understanding of the possible role of mitochon-drial dysfunction in the pathogenesis of PD. MPTP is first deaminated by MAO-B in glial cells resulting in the formation of the active moiety, the 1-methyl-4-phenylpyri-dinium ion (MPP+). MPP+ is then selectively accumulated in dopamine nerve terminals by the plasma membrane dopamine transporter. Once inside the dopam-ine nerve terminals, MPP+ generates hydrogen peroxide and other free radicals that interfere with mitochondrial respiration. MPP+ is concentrated in mitochondria, where it impairs mitochondrial respiration by inhibiting complex I of the electron transfer complex and consequently causing cell death.72 Complex I deficiency specific to the substantia nigra has been reported in human PD brains.7374 Also, selective nigral death following chronic exposure to rotenone, a well-known inhibitor of complex I, has been...

Redox Activation and Deactivation of Proteins

We have discussed what free radicals are and how they are produced and neutralized now we turn to one primary means by which free radicals activate or deactivate proteins, thus returning to turn back to the primary topic of this chapter, transcription factors. Transcription factors, being proteins, can be affected by free radicals through this mechanism. Like trace metals and antioxidants, proteins can undergo redox reactions. This is especially true for proteins containing the amino acid cysteine. Such redox reactions alter cysteine molecules in a way that activates or deactivates the protein, much as if the cysteine portion of the protein were an on-off switch. The off mode comes into play when the sulfur atom in cysteine is oxidized (i.e., loses a hydrogen atom). When oxidation occurs for two sulfur atoms in adjacent cysteine molecules, the resulting unbalanced sulfur atoms can bond with one another. This bond, aptly called a disulfide bridge, is illustrated in Figure 5.3. The...

Celltocell Communication

Cell-to-cell communication is a dynamic, complex process. At least four large families of CAMs are involved, each with members that play somewhat distinct roles. In addition, several other proteins are involved in assuring cell-to-cell communication via gap junctions. Moreover, the signals generated by CAMs and the signals that control them travel to and from the nucleus via protein phosphorylation. For this reason, PTK, PKC, and other proteins involved in signal transduction, as well as free radicals, can affect CAM function and behavior. Any or all of these mediators of cell-to-cell communication can be abnormal in cancer cells. Despite the complexities, however, many natural compounds help restore normal cell-to-cell communication in such a way as to induce apoptosis or inhibit cancer cell migration, invasion, metastasis, or proliferation. For instance, PTK inhibitors can reduce the invasion of cancer cells through mechanisms related to cell-to-cell communication. Most of the...

Preventing AD and future treatments

A number of factors such as non-steroidal anti-inflammatory drugs, hormone replacement therapy, and the antioxidant vitamin E, might be of some use in strategies to prevent AD. Prevention could be primary before any signs of the disease or secondary after some manifestation of the process. Primary preventive measures would have to be directed at either the entire population or to groups at risk (identified by family history or genotype, for example), and therefore would have to be entirely benign and almost cost-free to be acceptable. Secondary prevention, possibly in those with memory impairments not amounting to dementia (minimal cognitive impairment), is a more realistic prospect rendering the determination of the very earliest signs of disease or evidence of a prodromal state a high priority. A biological marker for AD would have immense utility in both clinical practice and in clinical trials. Markers suggested have included platelet membrane fluidity and measurement of amyloid,...

Dietary Prevention Of Sudden Cardiac Death

In the absence of a generally accepted definition, SCD is usually defined as death from a cardiac cause occurring within 1 hour from the onset of symptoms.1 The magnitude of the problem is considerable because SCD is a very common, and often the first, manifestation of CHD and accounts for about 50 of cardiovascular mortality in developed countries.1 In most cases, SCD occurs outside a hospital and without prodromal symptoms. We shall now examine whether diet (more precisely, certain dietary factors) may prevent (or help prevent) SCD in patients with established CHD. We will focus our analyses on the effects of the different families of fatty acids, antioxidants, and alcohol.2 Support for the hypothesis of a clinically significant antiarrhythmic effect of n-3 PUFA in the secondary prevention of CHD, as put forward in DART,3 came from two randomized trials testing the effects of ethnic dietary patterns (instead of effects of a single food or nutrient), i.e., a Mediterranean type of...

Neuroinflammatory processes

Chronic inflammatory reactions in the CNS have been implicated as contributory factors in the pathogenesis of neurodegenerative disorders (83,127,244-246). Components related to AD neuroinflammation include microglia and astrocytes, the classic and alternate pathways of the complement system, the pentraxins, acute-phase proteins, neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferation-activated receptors (PPARs), as well as pro-inflammatory cytokines and chemokine. In animal models and human brains, both the microglia and astrocytes have been shown to generate AP, one of the main componentns of senile plaques, which, itself may act as a pro-inflammatory agent inducing the activation of glia and many of the inflammatory components (83,127,244,246). All these substances may lead to increased formation of ROS and upregulation of genes that produce toxic agents such as reactive nitrogen species (RNS). Footprints of oxygen-free radicals and peroxynitrite attack...

Introductionredox Control By Thioredoxin System

Cysteine-containing tripeptide (y-glutamyl-cysteinyl-glycine), which is a major component of cytosolic antioxidant (millimo-lar concentration). Although the amount of TRX (micromolar concentration) is less than GSH, TRX has the much stronger activity of modulating signal transduction such as transcription factors binding to target DNA than GSH (4).

Possibilities for prevention

Since the aetiopathogenesis of Lewy body and neurone loss are unknown, specific disease slowing or prevention strategies for DLB are lacking, a situation analogous to Parkinson's disease. The overlap with Alzheimer-type and vascular pathologies suggests that the range of putative neuroprotectives for these disorders, including anti-inflammatories and antioxidants, may confer some advantages in DLB. L-Deprenyl, used for disease slowing in Parkinson's disease, is prone to precipitate hallucinations and is best avoided.

Diet And Heart Failure

Been paid to nonpharmacological management. Some unidentified factors may indeed contribute to the rise in the prevalence of CHF and should be recognized and corrected if possible. For instance, CHF is now seen also as a metabolic problem with endocrine and immunological disturbances potentially contributing to its progression.3738 Only recently has it been also recognized that increased oxidative stress may contribute to the pathogenesis of CHF.39 The intimate link between diet and oxidative stress is obvious the major antioxidant defenses of the body are derived from essential nutrients.40 The vital importance of micronutrients for health and the fact that several micro-nutrients have antioxidant properties are now fully recognized. Micronutrients may function as direct antioxidants such as vitamins C and E or as components of anti-oxidant enzymes such as superoxide dismutase or glutathione peroxidase.40 It is now widely believed (but still not causally demonstrated) that...

Of Signal Transduction

Transcription by regulating NF-E2-related factor (Nrf2) through antioxidant responsive element (ARE) (19). Thioredoxin translocates from the cytosol to the nucleus upon stress, such as UV, phorbol 12-myristate acetate (PMA), tumor necrosis factor-a (TNF-a), and an anticancer drug (20-22). In the nucleus, TRX enhances DNA binding of transcription factors such as NF-kB, AP-1, and p53 (21-24). Oxidative stress induces activation of NF-kB and antioxidant such as N-acetylcysteine (NAC) suppressed the activation (25). Cytoplasmic TRX suppresses the NF-kB signaling, whereas intranuclear TRX enhances the DNA-binding activity by reducing the key cysteine residue in NF-kB (21). In co-operation with redox factor-1 (Ref-1), TRX enhances the transcriptional activity of p53, the guardian of genome,'' upregulates p53-dependent p21 expression, and affords cells to repair damaged DNA by inducing cell cycle G1 arrest (22).

DNA Variation The Provision of Biological Diversity

As living organisms are exposed to so many mutagens, life has evolved elaborate DNA repair mechanisms as a counter-measure. The mechanisms include excision-, direct-, and mismatch repair, and they are discussed at length later. This is one area where as an example, antioxidant nutrients prove useful, although they are only one form of defense in this cellular war that is continuously waged within every one of us.

Possible Membraneassociation

Apart from its antioxidant activity, the erythrocyte PrxII (at that time termed calpromotin) was shown to activate the erythrocyte membrane Ca-dependent potassium (Gardos) channels (Moore et al., 1990, 1991 Moore and Shriver, 1997 Plishker et al., 1986 1992), apparently through membrane binding. Furthermore, calpromotin was claimed to be involved with the formation of dense erythrocytes in sickle cell anaemia, where a larger quantity of calpromotin was associated with the cytoplasmic surface of the cell membrane of these cells, possibly do to the higher cytoplasmic calcium level (Moore et al., 1997). A conclusive parallel between human erythrocyte calpromotin and the antioxidant protein TSA PrxII was presented by Kristensen et al. (1999). Dimer and higher molecular weight oligomer formation by calpromotin also correlated well with the properties of TSA PrxII. Additional support for the interaction of human erythrocyte TSA PrxII with erythrocyte membranes came from the study of Cha et...

Decreased p Amyloid Production and Neurotoxicity

A number of reports94,107-111 have demonstrated that Ap toxicity is in large part due to the formation of oxygen radicals and the subsequent initiation of membrane lipid peroxidation. Behl et al.94 determined that hydrogen peroxide (H2O mediates Ap toxicity, since Ap causes the intracellular accumulation of H2O2. It has been suggested that high doses of 17p-estradiol attenuate Ap toxicity by reducing the oxida-tive stress caused by it.82,83,105 Thus, it may be that the neuroprotective effects of estrogen against Ap in stroke and AD are due in part to the antioxidant action discussed above. In addition to a direct toxic effect, Ap increases the susceptibility of neurons to excitotoxins,107,112 possibly another avenue through which estrogen may provide neuroprotection against Ap and brain injury in general.

Inhibition of Mediator Induced Macromolecular Leakage

Theless they all inhibit macromolecular leakage in postcapil-lary venules, thus emphasizing that in spite of increased blood flow and perfusion pressure in the arterioles that should favor plasma leakage from the venules, the effect of the drug localized to receptors on the endothelial cells of the postcapillary venules is the dominant factor in the regulation of plasma leakage in inflammation. Neutrophil-induced changes in vascular permeability are the result of a complex interaction between adhesive proteins expressed on the surface of leukocytes and endothelial cells, selectins, and integrins, which finally results in the firm adhesion of leukocytes in postcapillary venules. It is possible to interfere with the leukocyte-endothelial cell interaction at different steps. Monoclonal antibodies against adhesion glycopro-teins have been used to elaborate mechanisms of leukocyte rolling and adhesion. Dextran sulfate, and possibly also heparin, acts by neutralizing charged peptides...

Fetal alcohol syndrome

The basis of this pathology is a cascade of effects exerted by alcohol on the developing cell. Under normal conditions growth factors enhance the growth of cells and their differentiation, but alcohol can diminish these effects.(25) A second way of damaging the developing nerve cell is through the production of free radicals that allow calcium to accumulate in the cells 26 The induction of free-radical formation is induced by alcohol. The result of both pathogenic processes is a decrease in the overall size of the brain and a diminution in the thickness of the outer layers of the cortex, due to decreases in the total numbers of cells. Impaired nerve cell migration might also play a role in the development of the fetal alcohol syndrome. (2Z)

Protection Against Glutamate Induced Excitotoxicity

The mechanism by which estrogen reduces excitotoxicity has not been determined. There are, however, a number of hypotheses. Regan and Guo114 and Moosmann and Behl116 hypothesized that much of estrogen's beneficial effect against glutamate toxicity is mediated by its direct antioxidant activity. Indeed, the concentrations of estrogen needed to protect against glutamate-induced excitotoxicity in a cell culture are several orders of magnitude higher than those reported to saturate CNS estrogen receptors,117 making it likely that a non-genomic mechanism is involved. Moosmann and Behl116 also found significant cytoprotection against glutamate toxicity in mouse HT22 cells only when 17P-estradiol concentrations were five orders of magnitude above that needed to induce transcriptional alterations. The an-tioxidant hypothesis is also supported by the fact that concomitant treatment with the protein synthesis inhibitor, cycloheximide, or the antiestrogen, ICI 182,780, had little114 or no effect...

Nigrostriatal Pathway And Pd

Normal aging has also been associated with an age-related increase in tissue damage due to free radicals. The role of free radicals in apoptosis, and the aging process has received considerable attention.3 Factors that decrease free radical damage, including limiting caloric intake and the use of antioxidants, have been associated with slowing of the normal aging process and with increasing longevity.3 45-8 Iron has been implicated in the formation of free radicals via the Fenton reaction and therefore may have a role in the normal age related effects of free radicals as well as in neurodegenerative disease. MRI studies were used to determine the relationship between age and basal ganglia iron content in 20 normal individuals ranging from 24 to 79 years of age. These authors analyzed paramagnetic centers sequestered inside cellular membranes to predict local brain iron content. A strong direct relationship between age and regional iron content was found in the putamen and caudate but...

Tolerance and Dependence

Repeated and frequent exposure to organic nitrates is accompanied by the development of tissue tolerance to the drug's vasodilating effects. When nitroglycerin formulations (e.g., transdermal patches, sustained-release oral dosing, or ointments) that produce sustained plasma and tissue levels are used, tolerance may occur within 24 hours. The mechanism underlying the phenomenon of nitrate tolerance is not as yet completely understood but may be related to a nitrate-induced oxidation of sulfhydryl groups via the formation of free radicals, a decrease in the sensitivity of vascular smooth muscle soluble guanylate cyclase, or activation of the renin-angiotensin system.

Activation of MAP Kinase Pathways

Singer et al.118 have very recently suggested that, in addition to an antioxidant effect, estrogen protection against glutamate toxicity may be mediated by activation of signaling pathways similar to those used by growth factors. Mitogen-activated protein kinase (MAPK) pathways are known to play an important role in growth factor signaling and stress signaling.119 One such signaling pathway leads to expression of ERK-MAPK, which may be involved in blocking apoptosis.120

Oxidation of the phenolic hydroxyl group

Oxidation of phenols is one of the most important aspects of these compounds to the biologist. Oxidation of phenolic compounds can result in the browning of tissues. Well-known examples are the browning of fruits after they have been cut. Oxidation can also result in the formation of metabolites that are toxic to animals and plants, and that can account for spoilage of foods in processing. On the other hand, toxic compounds formed from the oxidation of phenolics can inhibit pathogenic microorganisms. Certain phenols are used as retardants or antioxidants to prevent the oxidation of fatty acids.

Inflammatory mediators and hepatocellular dysfunction

Hepatocellular dysfunction and multiple systems organ failure can occur after both sepsis and trauma without apparent infection the unifying factor in all causes is an uncontrolled systemic inflammatory response. One hypothesis has been that the initiating event is activation or priming of polymorphonuclear cells by complement polypeptide C5a, gut-derived platelet activating factor, or lipopolysaccharide. Adhesion of these cells to hepatic endothelium occurs through selectins and intercellular adhesion molecules (ICAM-1), expression of which can be upregulated by other cytokines and platelet activating factor. Subsequent events may lead to generation of reactive oxygen species, cytokines, arachidonic acid derivatives, and nitric oxide (NO). Hepatic Kupffer cells may modulate this response and act as amplifiers, transmitting effects to sinusoidal lining cells and Ito cells controlling sinusoidal perfusion. Cytokines including IL-1, IL-6, and IL-8, which are liberated in large amounts...

Experimental therapeutic strategies

A wide range of therapies have been shown to improve splanchnic blood flow in animal models of ischemia-reperfusion. These strategies have centered on inhibiting or inactivating polymorphonuclear adhesion and activation, as well as inhibiting the downstream consequences of such polymorphonuclear activation. Xanthine oxidase inactivation, phospholipase A2 inhibition, platelet activating factor antagonists, and P-selectin inhibition all inhibit polymorphonuclear sequestration in the splanchnic circulation after ischemia-reperfusion. Antibodies to IL-6 and IL-8 may also abrogate polymorphonuclear activation. The role of modulation of NO is unclear and may depend on ambient oxygen concentrations. While NO may protect the liver from lipopolysaccharide-induced injury, by acting as a vasodilator and partially reversing the effects of cytokines such as tumor necrosis factor-a, during ischemia-reperfusion No production may contribute to hepatic injury by combining with oxygen free radicals...

Transmissible Spongiform Encephalopathies And Metals

An immunoaffinity technique has been developed to isolate PrPc from brain 58 . This same technique can be applied to isolated PrP from brains of patients with CJD. This isolated protein contains both PrPc and PrPSc but the majority of the protein is in the form of PrPSc. Metal analysis of PrPSc isolated from the brain of CJD patients showed that this protein lacked significant copper binding and that substitution with manganese and zinc had occurred 111 . Other researchers have also suggested that PrP in CJD patients' brains might bind metals other than copper 93 . The SOD-like antioxidant activity associated with PrPc was lost completely from the purified PrPSc. This finding confirms the notion that prion disease causes a loss of PrPc function, which is directly related to the ability of the protein to bind copper. The SOD-like activity of PrP purified from the brains of the infected mice was also examined and compared to that prepared from control mice 90 . There was a considerable...

Genomic Vs Nongenomic Mechanisms Of Estrogen Neuroprotection

Some of the neuroprotective actions of estrogen are independent of an action on the classic cytosolic estrogen receptor (ERP). This is no doubt the case for 17P-estra-diol's chemical antioxidant effect. However, for many of the other mechanisms, the issue of the role of estrogen receptor activation is unresolved. In the vast majority of studies examining neuroprotection by estrogen, the 17P-estradiol form was used. 17P-estradiol is the traditional estrogen and is responsible for many of the reproductive effects associated with estrogen. The classical mechanism by which 17P-estradiol exerts its effects is by binding to the cytosolic receptor, causing either stimulation or repression of gene transcription. Therefore, any effects associated with it, including neuroprotection, theoretically could be mediated via this mechanism. This is not the only mechanism by which 17P-estradiol can act, however.131-136 For example, nonclassic membrane receptor actions of estrogen also exist,135 such as...

Neurological Disorders and Neurodegenerative Diseases

The excitotoxic effect is related to the massive entry of Ca2+ into the cells as a consequence of the sustained activation of glutamate receptors. An excessive raise in intracellular Ca2+ accounts for multiple cytotoxic damage to the neurons such as perturbation of cytoskeletal proteins and activation of proteases and phospholipases. In addition to their proteolytic and lipolytic acitivity these enzymes result in the formation of free radicals which damage the cells. It is generally believed that the most important mechanism mediating the toxic influx of Ca2+ into neurons, is the ionotropic channel of the NMDA receptors. The following arguments support this view

Novel substratesfuture or present

The underlying disturbance of trauma or sepsis is viewed as a metabolic 'set' which is driven by catabolic hormone and cytokine release. This results in tissue catabolism and mobilization of amino acids from skeletal muscle protein, supplying amino acids for acute-phase protein synthesis and gluconeogenisis (e.g. brain and kidney metabolism) and glutamine for the maintenance of the intestine and immune system functions. In addition, other substrates derived from glutamine (e.g. glutathione) are necessary for maintaining antioxidant defenses. The intestine is viewed as an 'infected wound' whose barrier function, once impaired, will lead to movement of bacteria across the mucosa and into the systemic circulation. Mobilization of lipid provides precursors for prostaglandin and leukotriene synthesis, thus mediating the inflammatory response, and the intensity of this may be modulated by varying the ratio of n-3 to n-6 polyunsaturated fatty acids in the lipid...

Vitamins minerals and water

Dose and frequency of administration has not been defined in detail in critically ill patients. The need to provide increased amounts of zinc (large intestinal losses), magnesium, and vitamin E to prevent acute deficiencies and to maximize antioxidant potential has been stressed

Materials and methods

SH-SY5Y cells were cultured as reported (Shamoto-Nagai et al., 2004). Transfectant with a proteasome sensor vector was established using a pZsProSensor-1 eukaryotic expression vector, designed to express ZsGFP fused to the degradation domain of mouse or-nithine decarboxylase, a specific substrate for 26S proteasome, by lipofection technique as reported previously (Shamoto-Nagai et al., 2004). The culture medium was changed with the medium containing L-Cyst-DMSO solution without (control) or with NM and the cells were cultured for 3 days. In addition, the cells transfected with proteasome sensor vector was incubated with various concentrations of iron in the presence or absence of 25 mM DFX or antioxidants for 20 h. The fluorescence of ZsGFP in the living cells was measured as described before (Shamoto-Nagai et al., 2004), and the fluorescence intensity of the cells was expressed as arbitrary fluorescence unit mg protein. The protein amount was measured according to Bradford (1976)....

General Dietetic Advice For Pregnancy

Once pregnancy has been confirmed the diet should be reviewed to ensure the recommended vitamin and mineral intakes, including folate and iron, for pregnancy are met. Ensuring adequate amounts of antioxidants in the diet may help to lessen the risk of pre-eclampsia and congenital malformation. Recently dietary supplementation with the antioxidant vitamins C and E have been shown to reduce the incidence of pre-eclampsia in high-risk women (15). Animal, but so far not human, studies have shown that these vitamins also protect embryos from the teratogenic effects of hyperglycaemia (16).