Antioxidant

Oxidative Stress and Antioxidants The Antioxidant Network aLipoic Acid and Diabetes

In this introductory chapter, oxidative stress in diabetes and implications of antioxidant treatment are considered. It is thought that free radicals may play a major role in aging and disease. Free radicals arise from radiation, environmental chemicals, cigarette smoke, and various other environmental sources. In addition, all through our life, we have a fire burning inside of us our own body metabolism, which generates free radicals. Finally, many environmental substances (as well as drugs and alcohol) are metabolized in our body, generating free radicals through cytochrome P450-mediated oxidations. Many free radicals can be cytotoxic. However, free radical reactions are also essential. They are essential for enzymes and for host defense mechanisms such as neutrophils, macrophages, and other cells of the immune system. Free radicals are important in the activation of transcription factors and in cell signal transduction and gene expression. But if free radicals are overproduced,...

Definition Of An Antioxidant

What is an antioxidant To find a definition, we went to the dictionary. Dor-land's Medical Dictionary reports (2), An antioxidant is one of many widely used synthetic or natural substances added to a product to prevent or delay deterioration by action of oxygen in the air. Examples of such products to which antioxidants may be added are rubber, paint, vegetable oils, and so on. But there are many other definitions of an antioxidant. For example, Halliwell and Gutteridge (3) defined an antioxidant as any substance that, when present at low concentrations compared to those of an oxidizable substrate, significantly delays or inhibits oxidation of that substrate. Another definition of an antioxidant (and the one I favor) is that of a metabolic antioxidant (4,5) An antioxidant is a substance which protects biological tissues from free radical damage, which is able to be recycled or regenerated by biological re-ductants. Thus, metabolic antioxidants have something similar to a catalytic...

The Antioxidant Network

The antioxidant network is composed of redox-sensitive antioxidant substances. I like to say that the hub of the antioxidant network is vitamin C. The antioxidant network usually gets activated by vitamin E (12). After vitamin E is oxidized by oxidants or lipid free radicals, then the vitamin E free radical is formed, which in turn activates vitamin C to regenerate vitamin E nonenzy-matically. Vitamin C itself becomes a radical, the vitamin C radical, in this process. Glutathione, with the aid of enzymes, can reduce the vitamin C radical (or dehydroascorbate, the completely reduced form of vitamin C). The oxidized glutathione thus produced can be reduced through enzymatic reactions that draw on cellular reducing power. There are also substances that we can obtain in our diet or that we can supplement like flavonoids, polyphenols, and lipoic acid that can also act in the antioxidant network (13,14). An example of how the antioxidant network works with respect to vitamin C, vitamin E,...

Combination Antioxidant Primary Prevention Trials

Because observational studies of antioxidants found that individuals with a higher intake of vitamin E or beta-carotene also had a higher intake of other antioxidants and micronutrients,4,21,25,57,58 it is possible that a combination of antioxidants work together as cofactors to confer a beneficial effect. For example, vitamin E alone can be oxidized to a harmful radical, while vitamin C reduces the radical back to alpha-tocopherol. Vitamin E alone can have neutral, pro-, or antioxidant effects under various cellular conditions.59 As a result, trials of a single antioxidant supplement may lead to a null result, but an appropriate combination of antioxidants may provide a clinical benefit. Several trials have tested combinations of antioxidants, and the primary prevention trials are summarized in Table 3.6. Table 3.6 Completed and ongoing randomized clinical trials of combinations of antioxidants in the primary prevention of cardiovascular disease (CVD) Table 3.6 Completed and ongoing...

Combination Antioxidant Secondary Prevention Trials

Trials testing combinations of antioxidants in secondary prevention are summarized in Table 3.7. The HDL-Atherosclerosis Treatment Study (HATS) was a trial of 160 patients with CHD, normal LDL cholesterol, and low HDL cholesterol who were randomized to a relatively high-dose combination of four antioxidants (800IU of vitamin E, 1,000mg of vitamin C, 25 mg of beta-carotene, and 100 g of selenium) and or lipid-modifying therapy (simvastatin to lower LDL and niacin to raise HDL) vs. placebo.64 After 3 years, simvastatin niacin therapy decreased both coronary stenosis (P 0.004 vs. placebo) and the event rate for a combined endpoint of death from coronary causes, MI, stroke, or revascularization (3 vs. 24 for placebo, P 0.03). The antioxidant-only group did not show a reduction in coronary stenosis (P 0.16 vs. placebo) or CVD events. While supplemental antioxidants attenuated the angiographic benefits of lipid-modifying therapy (P for interaction 0.02) and diminished the clinical benefits...

Antioxidant Enzymes

Free radical defenses of peripheral nerve are reduced relative to brain and liver, especially involving glutathione (GSH)-containing enzymes (9). Cuprozinc superoxide dismutase (SOD) is reduced in sciatic nerve of experimental diabetic neuropathy, and this reduction is improved by insulin treatment (10). Glutathione peroxidase (GSH-Px) is reported to be further reduced in experimental diabetic neuropathy in alloxan diabetic mice 7-21 days after induction of diabetes, and enzyme activity inversely regresses with glucose level (11). We recently evaluated the gene expression of the antioxidant enzymes, GSH-Px, SOD (cuprozinc czSOD and manganese mnSOD separately), and cata-lase (CAT) in L4-L6 dorsal root ganglia (DRG) and superior cervical ganglion (SCG) of rats that had been diabetic for 3 and 12 months (Kishi et al unpublished data). cDNA fragments for rat GSH-Px, czSOD, mnSOD, CAT, and cyclophilin was obtained by reverse transcriptase polymerese chain reaction of rat DRG RNA using...

Oxidative Stress And Antioxidant Treatment Effects On Neurovascular Function In Experimental Diabetes

Antioxidant protection mechanisms are compromised in nerves of diabetic rats lipid peroxidation is increased, and the levels of superoxide dismutase and reduced glutathione (GSH) are decreased, although glutathione peroxidase and reductase remain unchanged (34-37). Long-term exposure to elevated ROS, coupled with diminished endogenous antioxidant protection, could lead to cumulative neurodegenerative changes involving axonopathy and demye-lination, and damage to dorsal root ganglion cell bodies and their mitochondria has been observed (37,38). However, in the short term, ROS effects on vasa nervorum are more important, being responsible for the earliest defects in nerve function in diabetic rats. A. Antioxidant Treatment, Vascular Endothelium, and Nerve Function Defective endothelium-dependent relaxation has been found in diabetic animals and in type 1 and type 2 patients (39-47) and is an important target for antioxidant treatment. An example is shown in Figure 2, where the...

Interactions Between Antioxidants And Essential Fatty Acids

There are multiple defects of vasa nervorum endothelium and possibly smooth muscle in diabetes that cause reduced nerve blood flow and function. The NO deficit is compounded by diminished PGI2 synthesis and increases in endo-thelin-1 and angiotensin II. Recently, it was shown that relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is also affected by diabetes. In the rat mesenteric vascular bed, EDHF was 76 reduced after 8 weeks of diabetes. In common with the NO defect, the EDHF deficit was attenuated by antioxidant treatment with a-lipoic acid (89). Vasodilator prostanoid synthesis is also deleteriously affected by oxidative stress high levels of lipid peroxides inhibit cyclooxygenase (90), and a-tocopherol treatment corrected the lowering of the PGI2 thromboxane A2 ratio found in diabetic rats (91). C. Synergy Between Antioxidant and n-6 Essential Fatty Acid Treatments Low doses of an ARI or evening primrose oil (which contains GLA) had modest effects on NCV...

Antioxidant nutrients

As mentioned earlier, mutations can occur as a result of oxidative damage to DNA caused by free radicals generated as a damaging side-effect of aerobic metabolism.28 Superoxide radicals are formed by the addition of an electron to molecular oxygen. These highly reactive species can then acquire a further electron and combine with protons to form hydrogen peroxide. In the presence of transition metal ions such as Fe2+ and Cu2+, hydrogen peroxide can break down to give even more highly reactive hydroxy radicals which can damage DNA directly, or participate in self-propagating chain reactions with membrane lipids. Plant and animal cells defend themselves against these effects by deploying so-called antioxidant compounds to trap or quench free radicals and hence arrest their damaging reactions. A variety of defence systems based on both water- and lipid-soluble antioxidant species and on antioxidant enzymes are deployed throughout the intra- and extracellular environment, at the sites...

Vascular Antioxidant Defense Systems

Living organisms have evolved a number of antioxidant defense mechanisms, both enzymatic and nonenzymatic, to maintain their survival against oxidative stress.24,32,80 Major antioxidant enzymes in the vessel wall include SOD, cata-lase, and glutathione peroxidase, whereas nonenzymatic sources include small molecules and vitamins.24,80 Three mammalian SODs have been identified copper zinc SOD (SOD1), mitochondrial MnSOD (SOD2), and extracellular SOD (SOD3).24 The concentration of SOD in the extracellular fluid is lower than in the intracellular fluid. Therefore *O2- can survive longer and travel further once it gains access to the extracellular space. Arteries contain large amounts of extracellular SOD in the interstitium, suggesting a special role for this SOD isoform within the vessel wall.81,82 SOD converts *O2- to H2O2, which is hydrolyzed by catalase and glutathione peroxidase to H2O and O2. Glutathione peroxidase is the major enzyme protecting the cell membrane against lipid...

Inhibition Of Diabetic Complications By Antioxidant Treatment

In patients with diabetes mellitus, oxidative stress is increased by enhanced production of free radicals and by antioxidant depletion, resulting in an increased susceptibility to oxidative damage and possibly development of late diabetic complications. Endogenous antioxidant proteins such as superoxide dismutase, glutathione peroxidase, and metal-binding proteins may protect the body against the effect of prooxidant reactions. Multiple antioxidants, including a-lipoic acid, vitamins C and E, urate, carotenoids, flavonoids, the amino acid methionine, and protein-bound zinc and selenium, are interacting addi-tively in these biological systems. In vitro and in vivo studies using antioxidants support the concept of radical-mediated diabetic complications. Vitamin E is the most abundant antioxidant in LDL. In vitro it scavenges peroxyl radicals 10,000-fold avidly, and then these react with fatty acids. But in LDL, vitamin E is located in the more rigid outer layer of the particle, whereas...

Free Radicals And Antioxidants

Free radicals are highly reactive transient chemical species characterized by the presence of unpaired electrons usually denoted by a point suffix (*). They are involved in a variety of metabolic and pathophysiological processes including both beneficial and detrimental reactions. They can be produced as by-products of normal metabolism, for example, in the mitochondrial electron transport system 15 , In biological systems, free radicals may be typically centered on oxygen, nitrogen, carbon or sulfur atoms. Biologically important free (Table 12.1). Hydrogen peroxide (H202) is an oxidizing species and potential source of free radicals, but is not are therefore conveniently classed as reactive oxygen species (ROS). In general, free radicals are continuously Cells are protected from free radical induced damage by a variety of free radical scavenging antioxidants. Antioxidants enzymes, which are capable of eliminating free radical species that cause tissue damage, include catalase,...

Role of Oxidative Stress and Antioxidants on Adhesion Molecules and Diabetic Microangiopathy

Each cell can mobilize an armory of antioxidant defense systems. Under normal metabolic conditions, the production of free radicals and the antioxidant capacity are balanced. Hyperglycemia in diabetes mellitus is associated with an increased production of free radicals. Furthermore, observational studies indicate lower levels of antioxidants like vitamin E, vitamin C, carotene, ascor-bate, and thiols in patients with diabetes mellitus (1,2). Imbalance between free radical production and the antioxidant defense system leads to oxidative stress. In diabetic patients, oxidative stress can be demonstrated by increased levels of lipid peroxidation products (3-8). There is a body of evidence that vascular and neurological complications in patients with diabetes mellitus are a consequence of oxidative stress (9-12).

Categorising natural antioxidants

Table 8.1 shows the antioxidants which constitute the defence system in vivo. As shown, there are several lines of defence. The first defence line is to inhibit the formation of active oxygen species and free radicals by sequestering metal ions, reducing hydroperoxides and hydrogen peroxide and to quench superoxide and singlet oxygen. The radical-scavenging antioxidants function as the second line defence. Vitamin E and vitamin C are major lipophilic and hydrophilic radical-scavenging antioxidants. They scavenge radicals and inhibit chain initiation or break chain propagation. Polyphe-nolic compounds may also work as important radical-scavenging antioxi- Preventive antioxidants suppress the formation of free radicals. 2. Radical-scavenging antioxidants scavenge radicals to inhibit chain initiation and break chain propagation. 4. Adaptation generate appropriate antioxidant enzymes and transfer them to the correct site at the correct time and in the correct concentration. dants. The...

Potency of natural antioxidants

As endogenous antioxidants synthesised by aerobes (e.g. SOD, catalase, GSH) do not completely prevent damage by reactive species in vivo,1 efficient repair systems are needed to reduce the damage and humans must also obtain antioxidants from the diet. There is currently a considerable amount of interest in dietary antioxidants as bioactive components of food. The physiological role of some of these, such as vitamin E and vitamin C, is well established. The interest in flavonoids has increased in recent years because of their ubiquitous presence as antioxidants in food. Flavonoids are diphenylpropanes that commonly occur in plants and are frequently components of human diet. They are consumed in relatively high quantities in our daily food. The main source of flavonoids is vegetables, fruits and beverages. For example, the content of quercetin glycoside in outer leaves of lettuce could be as high as 237 mg kg fresh weight, and the content of kaemferol glycoside in kale could be 250 mg...

Assessment of antioxidant potential of flavonoids

For measuring the antioxidant potentials of flavonoids, either the total antioxidant activity (TAA), or the trolox equivalent antioxidant activity (TEAC) has been extensively used.41-44 The TEAC method is to compare the ability of a hydrogen-donating antioxidant to scavenge a radical generated from the reaction of acid) (ABTS) with a ferrylmyoglobin radical species41-44 or potassium per-sulphate,45 with that of trolox. The value of TEAC may be considered as a stoichiometric number because TEAC for trolox was set at 1.0. To test the efficacy of a certain substance as a radical scavenger, clear evidence may come from the determination of reaction rate constants with specific radicals. Although the stoichiometric number determines the duration of the inhibition period or lag time, the rate constant can give the extent of inhibition in oxidation. Two methods including both inhibition period and extent of inhibition in oxidation are used in studying the potential of natural antioxidants...

Structural components specific groups of antioxidants

Monophenols and phenolic acids (Fig. 9.3) participate in hydrogen donating and radical scavenging reactions. Tocopherols and tocotrienols have been widely documented as having antioxidant activity, due primarily to the phenolic hydrogen at the C6 position. Also, the AOA of phenolic acids is due to the phenolic hydrogens. Pratt and Birac reported that caffeic acid was a better antioxidant than ferulic acid and p-coumaric acid.5 The presence of a second hydroxyl group enhances the AOA, mainly via intramolecular hydrogen bonding, of caffeic over p-coumaric and ferulic. The ortho methoxy substitution in ferulic acid may provide a stabilising effect on the 9.3 Monophenol (e.g. tocopherols and tocotrienols) and phenolic acids as examples of common natural antioxidants. phenoxyl radical thus explaining the better AOA of ferulic over p-coumaric acid. The presence of three hydroxyl groups gives added protection as seen by the improved AOA of trihydroxybenzoic acid (i.e. gallic acid) over...

Factors affecting antioxidants

The loss of the NAO during the processing of a commodity is of the utmost concern. Although not considered a source of NAO, soybean oil can be mixed into formulas to provide tocopherols. The loss of toco-pherol during the processing of soybean oil is an example of how processing may affect the NAO content in a product.31 The deodorisa-tion step in the process caused a 20 reduction in tocopherol content while degumming through the bleaching process resulted in a 12 reduction. In addition, the crude oil was more stable than the refined oil suggesting that the removal of the antioxidant (AO) played a key role and that processing methods should be considered when preparing or using NAO in food formulas. Other factors that influence the activity of NAO include heat, fermentation, and the presence of metals. These factors will be addressed in the sections that follow that are appropriate for the specific NAO. The usefulness of NAO will be dependent on the fractions used in the food item or...

Antioxidants from legumes nuts and oilseeds 931 Legume including pulses antioxidants

Methanol, ethanol, and acetone extracts of peanut hulls were significantly better antioxidants than chloroform and hexane extracts.37 Fractionation of the methanol extract showed that luteolin was a major component of one fraction with AOA. A total phenolic content of 1.67 mgml-1 provided the maximum protection (93-95 ) against the oxidation of linoleic acid.38 The predominant flavonoid, luteolin, was found to increase by a factor of 15 between days 74 to 144 of the growing season. However, the AOA of extracts prepared each day was not significantly dif- Tocopherols have a long tradition as being hydrogen-donating antioxi-dants. Peanut oil was found to contain between 350 and 650ppm toco-pherols.4344 Gamma (g) accounts for 55 of the tocopherols while alpha and delta make up 40 and 5 , respectively. Although not natural, roasting of peanuts enhanced the AOA due mainly to the development of Maillard browning reaction compounds.45 The combination of NAO and antioxidants developed via...

Clinical Box 51 Free Radicals and Aging

A free radical, such as the superoxide radical shown on the left, is an unstable molecule that has an unpaired electron in its outer shell. These highly reactive molecules can oxidize and damage proteins, nucleic acid and lipids, triggering oxidative stress and cell death. For example, mitochondrial damage caused by free radicals might trigger apo-ptosis. Formation of free radicals can increase for many reasons, including immune cell activation, inflammation, ischemia, infection, cancer, or simply in response to radiation from sunlight (i.e., skin damage). Antioxidants include enzymes (e.g., superoxide dismutase, SOD), cellular reducing agents (e.g., glutathione, a-lipoic acid), and nutrients (e.g., vitamin E). It has been proposed that aging results partly from accumulated damage caused by free radicals. Most of the support for this theory comes from studies of mice and rats. It has been shown that mice lacking mitochon-drial SOD survive only for a short period and that mice...

Role Of Acetaldehydeprotein Adducts And Free Radicals

The increase in malondialdehyde-acetaldehyde protein adducts supports previous suggestions that alcohol induces cardiac lipid peroxidation 83,84 concomitant with endogenous cardiac-derived acetaldehyde formation, possibly via alcohol dehydrogenase (ADH) or cytochrome P450 actions. However, although the activity of cardiac alcohol dehydrogenase is low, catalase may also generate acetaldehyde 85-88 , The importance of these studies relates to the observation that malondialdehyde-acetaldehyde adducts are cytotoxic, inducing the release ofTNF-alpha and up-regulating ICAM-1 in endothelial cells in vitro 89 , Reactive oxygen free radical species may play a prominent role in alcohol-induced heart muscle damage. Cardiac tissue from chronic alcohol misusers shows increased 'agepigments indicative of damage by reactive oxygen species 90 , Involvement of reactive oxygen species damage is also implicated by studies showing that in alcohol-fed rats, the resulting shift in fatty acid profile is...

Assessment of the Antioxidant Capacity of P indicalnfested Roots

Nourishment strategies prompted us to analyse the antioxidant status of infested roots. Ascorbate levels were consistently higher at one, two and three weeks after root infestation with P. indica, while levels of dehydroascorbate (DHA) were reduced. At the same time, activity of ascorbate recycling dehydroascorbate reductase (DHAR) increased. Concomitantly, slightly enhanced total glutathione concentrations and glutathione reductase activities were observed (Waller et al. 2005). It can be reasoned that higher antioxidant levels protect roots from cell death provoked by the root pathogens F. culmorum and C. sativus. Because production of reactive oxygen species and host cell killing is a prerequisite for successful fungal development and pathogenesis of necrotrophic fungi (Gov-rin and Levine 2000), we hypothesize that higher antioxidant capacity, such as elevated ascorbate levels, could cause the observed reduction of necrotrophic pathogens in the barley root.

Antioxidants from animal products

Peptides, amino acids, and carotenoids are three animal products that could potentially serve as NAOs. Enzymes such as glutathione peroxidase, superoxide dismutase and catalase are antioxidant enzymes present in muscle systems. However, the cost of isolating these enzymes is prohibitive, thus limiting their use as food antioxidants. Carnosine, anserine, and ophidine are histidine-containing dipeptides reported to chelate metals and scavenge radicals.156 For a complete review of the histidine-containing dipeptides, see

Antioxidants as preserving agents

Numerous reports of antimicrobial activity of phenolic antioxidants have been made. For antimicrobial activity of plant and animal antioxidants, see the review articles of Raccach,199 Fung et al.200 and Nakatani.201 Gailani and Fung found that phenolic antioxidants (e.g. BHA) had antimicrobial activity against a number of Gram positive and Gram negative bacteria.202 In addition, the phenolic antioxidants inhibited the growth of psychrotrophs, coliforms and faecal coliforms in a ground pork system. Ogunrinola et al.203 found that phenolic antioxidants were bactericidal against Escherichia coli O157 H7. These authors also noted that the combination of phenolic antioxidants acted synergistically at 4 C to inhibit E. coli O157 H7 growth a phenomenon similar to the synergism in the control of oxidation. In an attempt to promote natural antimicrobial agents, many authors have investigated the antimicrobial activity of natural antioxidants from many plant species. The following discussion...

Antioxidants from vegetables

Toes and other vegetables have been screened for antioxidant activity using different oxidation systems.3-14 In addition to the differences in methodologies, different extraction methods used to release antioxidative constituents result in variation of the antioxidant activities reported for vegetables. In early studies Pratt and Watts3 and Pratt4 found that green onion tops were twice as potent as antioxidants than potato peel, green pepper and green onion and four times more potent than potatoes in inhibiting the coupled oxidation of b-carotene and linoleic acid. Using the same oxidation model Gazzani et al.10 reported that when prepared at 2 C, most vegetable juices showed initial pro-oxidant activity. This pro-oxidant activity was very high for eggplant, tomato, and yellow bell pepper. In the cases of carrot, celery, garlic, mushroom, zucchini, tomato, and particularly eggplant juice, it was reported that the antioxidant activity of the vegetables was increased by boiling. This...

Antioxidants from fruits and berries

Data on the antioxidant activity of fruits and berries, their juices and wines vary widely partly due to the use of different oxidation systems and methods to analyse antioxidant compounds. The recent literature has focused to a large degree on the antioxidant effect of flavonoids and phenolic acids isolated from fruits and berries although ascorbic acid, 10.1 Pro-oxidant effect of lycopene and antioxidant effect of the combination of lycopene and g-tocopherol on hydroperoxide formation in rapeseed oil triacylglyc-erols oxidised under light at 25 C35 (reprinted with permission from J Agric Food carotenoids and tocopherols also contribute to the antioxidant activity of fruits and berries. By using the ORAC method, the extract of fresh strawberries had the highest total antioxidant capacity compared with the extracts of plum, orange, red grape, kiwi fruit, pink grapefruit, white grape, banana, apple, tomato, pear and honeydew melon.33 However, in lipid oxidation models (methyl...

Alcoholic Liver Disease Role Of Free Radicals

A substantial body of evidence exists to support the contention that ROS generated during ethanol metabolism may be involved in the pathogenesis of alcoholic liver disease (ALD). Decades ago, it was already emphasized by Lieber that the induction of cytochrome P450 is a critical event with respect to the development of ALD 85 , If free radical production and lipid peroxidation play a role in the development of ALD, depletion of dietary antioxidants such as vitamin E or an increase in oxidants such as non-heme iron in the liver, should enhance the ethanol induced liver damage. Indeed, a diet deficient in vitamin E has been shown to reduce hepatic vitamin E stores, increase lipid peroxidation and increase serum transaminase activities after alcohol feeding in rats 86 , Furthermore, iron supplementation in the diet increases ethanol-induced serum transaminase activities, lipid peroxidation and fibrosis 41 , In addition, a significant correlation between hepatic lipid peroxidation,...

Effect of Hypothermia on the Generation of Free Radicals

The emerging role of oxygen derived free radicals (ODFR) in tissue injury and its participation in reperfusion injury is mentioned above. Important questions that arise in the context of cold storage of tissues and organs include whether free-radical-mediated tissue injury proceeds during cold ischemia, and what effect temperature reduction has on the processes of free radical generation and the mechanisms of tissue injury. Fuller and Green and their colleagues have considered these questions their work provides a basis for the summarizing statements recorded here.143 In essence, it is recognized that cooling increases the susceptibility of cells to produce free radicals and attenuates the natural defense mechanisms by which cells normally deal with the low-level free radical production in metabolism. Due to a lower activation energy, free radical reactions are depressed less by temperature reduction than by the enzymatic processes used to scavenge them. As outlined above, the highly...

Antioxidants from microbial sources

Microorganisms are one of the most abundant and diverse species found on earth. The exploitation of microorganisms to produce food ingredients has been going on since antiquity. However, the isolation of microbial antioxidants did not become a focus of research until the early 1980s, although Forbes et al.168 and Meisinger et al.169 established a relationship between antioxidants and microorganisms. Since this early work, a vast number of compounds and microorganisms have been characterised. The intent of the following discussion is to highlight some of the studies that demonstrate the antioxidant activity of microorganisms. method.170 Extracts of two Penicillium and four Aspergillus species protected linoleic acid better than the control. One species, Aspergillus candidus CCRC 31543,protected the oil as well as BHA. In a subsequent study, Yen and Chang found that sucrose or lactose and ammonium sulphate in the culture media enhanced the A. candidus CCRC 31543 production of...

Antioxidant effects

Antioxidants in food may be defined as any substance which is capable of delaying, retarding or preventing the development in food of rancidity or other flavour deterioration due to oxidation. Antioxidants delay the development of off-flavours by extending the induction period. Addition of antioxidants after the end of this period tends to be ineffective in retarding rancidity development. Antioxidants can inhibit or retard oxidation in two ways either by scavenging free radicals, in which case the compound is described as a primary antioxidant, or by a mechanism that does not involve direct scavenging of free radicals, in which case the compound is a secondary antioxidant. Primary antioxidants include phenolic compounds such as vitamin E (a-tocopherol). These components are consumed during the induction period. Secondary antioxidants operate by a variety of mechanisms including binding of metal ions, scavenging oxygen, converting hydroperoxides to non-radical species, absorbing UV...

Antioxidants

One final target of neuroprotective therapy in acute ischemic stroke is the generation of free radicals, resulting in further release of calcium and excitatory neurotransmitters. The free radical scavenger tirilazad did not show benefit in an acute stroke trial. The drug also was investigated in subarachnoid hemorrhage and in traumatic brain injury, without convincing evidence of benefit (21). Another antioxidant with a novel, free radical-trapping mechanism is currently being evaluated in ischemic and hemorrhagic stroke. NXY-059 is the first neuroprotectant to meet the rigorous Stroke Therapy Academic Industry Roundtable (STAIR) preclinical evaluation criteria (22). Safety has been shown in clinical trials that achieve animal study plasma drug levels (23). The results of a Phase 3 NXY-059 trial SAINT I-Astra Zeneca (a double blind randomized, placebo controlled, parallel group, multicenter Phase IIb III study to assess the efficacy and safety of intravenous NXY-059 treatment in acute...

Nut antioxidants

Antioxidants from nuts are generally localised in the seed coat with lower amounts in the cotyledons. Expressed nut oil from macadamia nuts shows this trend in which the kernel oil obtained from the cotyledons had a significantly lower phenolic content (49 mgg-1) than the 838 mgg-1 in the shell.57 The phenolic compounds identified were 2,6-dihydroxybenzoic acid, 2'-hydroxy-4'-methoxyacetophenone, and 3,5-dimethoxy-4-hydroxycinnamic acid. Refining of the macadamia nut oil significantly reduced the oxidative stability of the oil. Quinn and Tang57 postulated that the cold pressing of the nuts co-extracts the phenolics and that the refining process removes important phenols. This was supported by the observed increase in oxidative stability of macadamia nut oil supplemented with the ground shell of the macadamia nut. The AOA of a refined macadamia nut oil containing 0.01 3',5'-dimethoxy-4'-hydroxyacetophenone was significantly better than the oils containing other purified antioxidants....

Other Antioxidants

B-Carotene is the plant form of vitamin A, but is a most powerful free-radical quencher. Estimates suggest that one molecule of b-carotene can cope with 1,000 free radicals. Lutein is another carotenoid which has particular value because besides being an antioxidant, it is also a powerful absorber of blue light that can damage cells quite severely. There are many other carotenoids that can also protect the skin. Pycnogenol, coenzyme Q10, a-lipoic acid, Resve-ratrol and many other chemicals are important anti-oxidants and phytonutrients that increase the general spectrum of antioxidant protection.

Free Radicals

ROS, although initially regarded primarily as potentially damaging by-products of oxidative cell metabolism, appear to be key mediators of cellular signaling and important modulators of cerebral vascular tone, particularly in endothelium-dependent responses (85). Under normal physiologic conditions, the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, when ROS production is enhanced, the overproduction of oxidants overwhelms the cellular antioxidant capacity, resulting in oxidative stress and dys-regulation of physiologic processes. Free radicals may also react with and damage cell lipids, proteins, and nucleic acids. Increasing evidence suggests that an elevation of oxidative stress and associated oxidative damage are mediators of vascular injury in various cardiovascular pathologies. Several studies indicate a pathophysiologic role of oxidative stress in cerebral vasospasm ( 55 ). A number of sources produce free radicals after SAH,...

Oilseed antioxidants

Flaxseed, sunflowers, soybean, cottonseed, and canola antioxidants typify the antioxidants from oilseeds. An important group of antioxidants not previously mentioned includes the sterols (Fig. 9.9). These compounds have been shown to prevent thermal oxidative degradation of oils.62-64 Furthermore, sterols with ethylidene side chains (e.g. D5-avenasterol) were most effective.6263 Gordon and Magos proposed that the non-lipid radicals react rapidly with the unhindered allylic carbons of the sterols.64 Subsequent electron rearrangement results in a stable allylic tertiary free radical that reacts slowly with the lipid thus disrupting the autoxidation process. Other antiox-idants common to oilseeds include tocopherols and tocotrienols (Table 9.1). Source of antioxidants Source of antioxidants The antioxidants of confectionery and oil sunflowers include phenolic acids, tocopherols and sterols while purple hulled varieties contain significant concentrations of anthocyanins.72 The average...

The development of oxidative rancidity in foods

Besides the development of rancid flavours, oxidative deterioration of lipids may cause the bleaching of foods due to the reaction of pigments, especially carotenoids, with the reactive intermediates, termed free radicals, which are formed during lipid oxidation. Free radicals may also lead to a reduction of nutritional quality by reaction with vitamins, especially vitamin E, which is lost from foods during its action as an antioxidant. In frying oils, the concentration of free radicals increases to a much higher level than in foods stored or processed at moderate temperatures. At the elevated temperatures used in frying, which are normally about 180 C, free radicals reach concentrations where combination to form dimers becomes significant. This causes an increase in the viscosity of the oil. Formation of free fatty acids, darkening of the oil and an increase in foaming and smoking also occur during frying. According to the recommendations of the German Society for Fat Research (DGF),...

Types and effects of rancidity

The induction period (IP) is very sensitive to small concentrations of components that shorten the IP, the pro-oxidants, or lengthen the IP, which are the antioxidants. Metal ions are the most important pro-oxidants in foods, whereas antioxidants include compounds that act by radical scavenging, metal chelation or other mechanisms. The presence of an induction period is characteristic of chemical reactions that proceed by a free-radical mechanism. The level of free radicals in oils is generally low, but in frying the rapid formation of free radicals can lead to the combination of free radicals to form triglyceride dimers. propagation reactions occur in which one lipid radical is converted into a different lipid radical. These reactions commonly involve abstraction of a hydrogen atom from a lipid molecule or addition of oxygen to an alkyl radical. The enthalpy of reaction is relatively low compared with that of the initiation reactions, so propagation reactions occur rapidly compared...

Other relevant reactions

The vitamins A, D, E and K, and chlorophyll and carotenoids are fat-soluble and loss of these food components by radical-catalysed reactions may often accompany lipid oxidation in foods containing these components. The bleaching of b-carotene in lipid solutions is sometimes used as a method of monitoring lipid oxidation. Vitamin E acts as an antioxidant and is consumed during the induction period of autoxidation.

Physicochemical state

Throughout the food and biological systems, there recur patterns of seemingly contradictory antioxidant behaviour. Prominent among these is the contrast in relative effectiveness of phenolic antioxidants in bulk vs dispersed systems, dependent on their hydrophilic lipophilic balance.241 found for Trolox C, a hydrophilic carboxylic derivative of a-tocopherol. Yanishlieva et al.243 established that the sequence of efficiencies of a-tocopherol and caffeic acid was reversed when passing from bulk phase to liposome oxidation. In the first case caffeic acid was more effective than tocopherol, while in the second case a-tocopherol showed higher efficiency than did caffeic acid. Frankel et al.244 found that the more polar rosmarinic and carnosic acids (containing a carboxy group) were most effective antiox-idants in bulk corn oil, whereas the antioxidant activity of carnosol was only limited in this oil. However, in an oil-in-water emulsion a high antioxida-tive activity was seen for...

Sources of further information and advice

Natural antioxidants are generally preferred by consumers, and may gain legislative approval more easily than synthetic additives do. However, the fact that a substance is commonly found in a food is no guarantee that it is entirely nontoxic.267 Synthetic antioxidants are tested for carcinogenic or mutagenic effects, but many natural food compounds have not yet been tested. The advantages and disadvantages of synthetic and natural antioxidants are summarised in Table 3.4.167 No rational scientific or technical argument can be given for natural antioxidants they are more acceptable to consumers mainly on emotional grounds. While it is important for manufac- Table 3.4 Advantages and disadvantages of natural and synthetic antioxidants167 Synthetic antioxidants Medium to high antioxidant activity Increasing safety concern Use banned for some of them Low water-solubility Decreasing interest Natural antioxidants Use restricted to some products Wide ranging antioxidant activity Perceived as...

Radicalscavenging methods

Radical scavenging is the main mechanism by which antioxidants act in foods. Several methods have been developed in which the antioxidant activ In the DPPH test, the scavenging of DPPH radicals is followed by monitoring the decrease in absorbance at 515nm which occurs due to reduction by the antioxidant (AH) or reaction with a radical species (R).5 Fast reaction of DPPH radicals occurs with some phenols e.g. a-tocopherol, but slow secondary reactions may cause a progressive decrease in absorbance, so that the steady state may not be reached for several hours. Most papers in which the DPPH method has been used report the scavenging after 15 or 30min reaction time. The data is commonly reported as EC50, which is the concentration of antioxidant required for 50 scavenging of DPPH radicals in the specified time period. The ABTS radical cation is more reactive than the DPPH radical, and reaction of the ABTS radical cation with an antioxidant is taken as complete within 1 min.6 The method...

Methods for measuring the current state of an oil or food sample

Some methods can be applied to assessing the current state of an oil or food sample. In order to be applied in assessment of antioxidant effectiveness, an experiment must be designed in which the antioxidant is incorporated into the food and the food is stored under controlled conditions. The principles of these methods are described below. longer fit for consumption. Consequently, any antioxidant used in the food will ultimately be evaluated by its potential for extending the time before this off-flavour can be detected. The ability of individuals to describe the nature of the aroma is useful, and the sensitivity of a trained panel to oxida-tive off-flavours may allow detection of oxidative deterioration at a stage when common chemical methods, e.g. peroxide value measurements, are unable to detect any deterioration. The main problems with sensory evaluation are that different individuals vary in their sensitivity to these off-flavours, and their performance may vary depending on...

LDL oxidation and atherogenesis

Acid dispersions, lipids, oils, and LDL.20'21 As for phenolic acids, the inhibition of oxidation by flavonoids is related to the chelation of metal ions via the ortho-dihydroxy phenolic structure, the scavenging of alkoxyl and peroxyl radicals, and the regeneration of a-tocopherol through reduction of the tocopheryl radical.20 The contribution of flavonoids and phenolic acids to the prevention and possibly to the therapy of cardiovascular disease can also be found on metabolic pathways other than the antioxidant capacity. As previously mentioned, arteriosclerosis is characterised by early cellular events and by the dysregulation of the normal cellular homeostasis.17 Molecular mechanisms, by which polyphenols may play a role either in the etiopathology or in the pathophysiology of arteriosclerosis, will be discussed here, with particular regard to the modulation of gene expression regulated by the transcription factor nuclear factor-kappa B (NF-kB), and to the induction of either...

Polyphenols and activated NFkB

The transcription factors of the nuclear factor-kB Rel family control the expression of a spectrum of different genes involved in inflammatory and proliferation responses. The typical NF-kB dimer is composed of the sub-units p50 and p65, and it is present as its inactive form in the cytosol bound to the inhibitory proteins IkB. Following activation by various stimuli, including inflammatory or hyperproliferative cytokines, ROS, oxidised LDL and bacterial wall components, the phosphorylation and proteolytic removal of IkB from the complex occurs. The activated NF-kB immediately enters the nucleus where it interacts with regulatory kB elements in the promoter and enhancer regions, thereby controlling the transcription of inducible genes.22'23 A spectrum of different genes expressed in arteriosclerosis have been shown to be regulated by NF-kB, including those encoding TNF-a, IL-1, the macrophage or granulocyte colony stimulating factor (M G-CSF), MCP-1, c-myc and the adhesion molecules...

Indirect evidence for polyphenol activity in atherogenesis

An indirect effect of flavonoids and phenolic acids on NF-kB activation, and therefore on NF-kB-driven gene expression, may be inferred from two kinds of study one addressing the modulation of NF-kB activity by other antioxidant molecules (a-tocopherol, thiolic antioxidants such as -acetyl-cysteine, lipoic acid, pyrrolidinedithiocarbamate), and others addressing the role of flavonoids and phenolic acids in the antioxidant network. a-Tocopherol and lipoic acid inhibit NF-kB in different cellular models,4 42 and several studies describe the ability of flavonoids and phenolic acids to exert a significant tocopherol and glutathione sparing effect either under basal homeostatic conditions or following oxidative challenge. Roy and co-workers demonstrated that the adhesion of lymphocyte to endothelial cells is regulated by the thiolic antioxidant a-lipoic acid and by a-tocopherol.43 Similarly, an enhancement of the endogenous levels and a protective effect on a-tocopherol after peroxynitrite...

Conclusions and future trends

Dietary consumption of polyphenols is associated with a lower risk of degenerative diseases. In particular, protection of serum lipids from oxidation, which is a major step in the development of arteriosclerosis, has been demonstrated. More recently, new avenues have been explored in the capacity of polyphenols to interact with the expression of the human genetic potential. The understanding of the interaction between this heterogeneous class of compounds and cellular responses, due either to their ability to interplay in the cellular antioxidant network or directly to affect gene expression has increased.

Conclusion the role of functional foods

In an age of convenience foods and pre-cooked meals, many consumers find a high consumption of fresh vegetables difficult to achieve. At first sight this seems to provide an excellent opportunity for the development of functional food products which could provide the protective effects of fresh vegetables without the need for greatly increased bulk or frequency of consumption. The difficulty lies in the sheer complexity of plants and the bewildering variety of diseases to which the protective effects seem to apply. There have been brave attempts to confront this problem with the development of a unifying hypothesis such as the dietary fibre model, or more recently the antioxidant theory, but attempts to prove these hypotheses have failed. Diet is inescapably complex, and food often seems to exert biological effects greater than the sum of its parts. No doubt the anti-carcinogenic mechanisms that underlie the protective effects of plant foods are susceptible to experimental...

Effect on the lipid peroxyl radical and lipid peroxidation

As hydrogen-donating antioxidants, flavonoids directly scavenge lipid peroxyl radicals.23,33 As clinical and biochemical evidence shows that low-density lipoprotein (LDL) oxidation is a crucial event in the pathogenesis of atheriosclerosis, the protective effect of flavonoids on LDL oxidation has been an interesting subject. De Whalley et al. have shown that quercetin, morin, fisetin and gossypetin with the IC50 at 1-2 mM inhibited the oxidative modification of human LDL induced by macrophages and delayed the depletion of endogenous a-tocopherol.34 It has been known that red wine contains a considerable amount of flavonoids and experimental results showed that it could inhibit porcine LDL oxidation induced by copper ion or AAPH.35 Wine diluted 1000-fold containing 10 mM total phenolics inhibited LDL oxidation significantly more than a-tocopherol.36 It was suggested that wine polyphenols seem to act by their antioxidant activity rather than by metal chelating, and it has been reported...

Sources of further information

Basu T K, Temple N J and Carg M L, Antioxidants in Human Health and Disease, Wallingford, CABI, 1999. Cadenas E and Packer L, Handbook of Antioxidants, New York, Marcel Dekker, 1996. Frei B, Natural Antioxidants in Human Health and Disease, San Diego, Academic Press, 1994. Packer L and Cadenas E, Handbook of Synthetic Antioxidants, New York, Marcel Dekker, 1997. Packer L and Ong A S H, Biological Oxidants and Antioxidants. Molecular Mechanisms and Health Effects, Champaign, AOCS Press, 1998. Papas A M, Antioxidant Status, Diet, Nutrition, and Health, Boca Raton, CRC Press, 1999.

Structural components general

The overall effectiveness of the NAO is dependent on the involvement of the phenolic hydrogen in radical reactions, the stability of the NAO radical formed during radical reactions, and chemical substitutions present on the structure. The substitutions on the structure are probably the most significant contribution to the ability of an NAO to participate in the control of radical reactions, and the formation of resonance stabilised NAO radicals. The effect of substituting functional groups to synthetic phenols has been known for more than 40 years since Miller and Quackenbush found that alkyl substitutions could enhance antioxidant activity (AOA).1'2 NAOs would be expected to participate in radical trapping and singlet oxygen quenching mechanisms. Radical trapping mechanisms can occur via interactions between radical species such as an antioxidant radical and lipid peroxyl radical (Fig. 9.2a). Alternatively, lipid peroxy radicals can interact with electron dense regions of a molecule....

Concluding remarks future trends and sources of further information

Similar to the concept of microbial fermentations, plant cell culturing has provided a method for producing antioxidants in a controlled environment. Rosmarinic acid production via cell cultures has been well documented.207-215 Kirikae et al.216 found that alfalfa cell cultures treated with yeast extract could produce isoflavones (daidzein) and 7,4'-dihydroxyflavone. Ferulic acid and anthocyanins production by Ajuga pyramidalis has been completed by Madhavi et al.217 Although cell culture techniques for the production of antioxidants have been around since about 1990, the industry has not fully embraced the process for food antioxidant production, which is not the case in such industries as the pharmaceutical. Reasons for this may include the value of the natural antioxidant as opposed to a pharmaceutical compound, the lack of optimal production techniques, the expense of cell culturing when compared with traditional agricultural and extraction methodologies and competition from...

Root and tuberous vegetables

Carrot (Daucus carota) has been reported to exert low antioxidant activity compared to other vegetables.5'6'9'11'13'14 Extracts of carrot leaves and peel Table 10.1 Antioxidant compounds identified in different vegetables showed antioxidant activity towards oxidation of pure methyl linoleate at 40 C while the carrot flesh was inactive.13 Boiling carrots for 30min significantly improved their antioxidant activity towards coupled oxidation of b-carotene and linoleic acid.10 In addition, the most polar fraction of carrots was found to be pro-oxidative. Potato (Solanum tuberosum) is considered a good source of antioxidants such as ascorbic acid, a-tocopherol and polyphenolic compounds. However, most studies have been focused on the antioxidant activity of phenolic compounds in potato.5'12'21'25 According to Lugasi et al.25 ethanolic extracts of potato tubers showed marked hydrogen-donating activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and had reducing power in the Fe(III) Fe (II)...

Green leafy vegetables

Contradictory results have been reported using different oxidation model systems to assess antioxidant activity of green leafy vegetables, especially spinach. The antioxidant activity of green leafy vegetables has been reported to be low spinach (Spinacia olearacea L) ranked 18th and lettuce (head) (Lactuca sativa L cv Capita) 22nd among 23 vegetables assayed for inhibition of LDL.11 Yet, according to Vinson et al.11 the phenols in spinach were able to enrich the lipoproteins by binding with them and subsequently protect them from oxidation. The ORAC activity of spinach was very high while that of leaf lettuce and iceberg lettuce was poor.6 Moderate antioxi-dant activity of spinach was reported towards oxidation of linoleic acid.9 Differently processed spinach samples were also found to inhibit formation of lipid hydroperoxides but to act as pro-oxidants in cooked meat.24 Blends of two to four vegetables including spinach increased the inhibitiory effect on lipid peroxidation, mainly...

Rosemary Rosmarinus officinalis L and sage Salvia officinalis L

Rosemary is one of the most effective spices widely used in food processing. It is the only spice commercially available for use as an antioxidant in Europe and United States. One of its main potential uses is the suppression of WOF.100 However, because of their prime use as flavouring agents, rosemary extract products are not technically listed as natural preservatives or antioxidants. The first use of an extract of rosemary leaves as an antioxidant was reported by Rac and Ostric in 1955.101 Berner and Jacobson102 obtained a patent in 1973 for production of an antioxidant extract from rosemary using oil as a solvent. Chang et al.103 reported a process for the extraction of rosemary and sage, followed by vacuum steam distillation in an edible oil or fat to obtain a colourless, odourless natural antioxidant. Bracco et al.104 described an extraction process using peanut oil, followed by micronisation, heat treatment, and molecular distillation. Inahata et al.105 obtained a patent in...

Photooxidation

In the presence of some sensitisers, such as riboflavin, type I photo-oxidation occurs. Type I photo-oxidation is characterised by hydrogen atom transfer or electron transfer between an excited triplet sensitiser and a substrate, such as a polyunsaturated fatty acid, producing free radicals or free radical ions. Autoxidation may then proceed. The mechanism for type I

Future trends

Increasing appreciation of the nutritional effects of highly unsaturated fatty acids including eicosapentaenoic acid (20 5) and docosahexaenoic acid (22 6) are likely to encourage the development of food products that are particularly susceptible to autoxidation. This is likely to increase the search for more effective antioxidant combinations, and physical methods of preventing oxidative deterioration, especially by microencapsulation, are likely to become more widely used. The careful processing of oils prior to incorporation into food in order to avoid, or minimise, the formation of hydroperoxides is also likely to become more important for highly unsatu-rated oils. Highly unsaturated hydroperoxides are relatively labile, and decomposition of these components is a ready pathway for the initiation of autoxidation.

Inhibiting oxidation

The free radical chain process of autoxidation can be retarded by two categories of inhibitors chain-breaking inhibitors (or antioxidants) and preventive inhibitors. The chain-breaking antioxidants AH scavenge the free radicals (LOO , LO ) interupting the propagation step reactions (7) and (7') in Scheme 3.5 and forming an antioxidant radical A of such a low reactivity that no further reaction with lipids can occur.

Types of inhibitors

All substances that protect foods against autoxidation should be called inhibitors of oxidation, and only substances that inhibit oxidation by reaction with free radicals should be called antioxidants.18 The preventive inhibitors acting in the first defence line suppress the formation of free radicals and active oxygen species, and the radical scavenging antioxidants are responsible in the second defence line and inhibit chain initiation and or break the chain propagation.2 3.3.1 Chain-breaking antioxidants The stoichiometric inhibition factor n (the number of kinetic chains broken per molecule of antioxidant) is normally two or fewer.73 A characteristic action of antioxidants of this type is that, at least in in vitro reactions, they produce a lag period, the so-called induction period IP, which usually is proportional in duration (or 'length') to their concentration, and which continues until about 90 of the antioxidant has been destroyed. During this lag period, lipid peroxidation...

Physical factors

A high oxygen pressure, a greater surface area with oxygen, heating or irradiation cause an acceleration of the chain initiation and propagation of the oxidation process (Section 3.1.3), and hence a decrease in the oxidation stability, or in the activity of the present or added antioxidant. The detrimental role of sunlight may be illustrated by the following results the IP of sunflower oil during oxidation at ambient temperature under sunlight had the same IP as the oil oxidised at 80 C in the dark.232 This is why, to ensure a better shelf-life, foods are often stored in light-impermeable packaging, in vacuum or in nitrogen, as well as at lower temperatures. The variation in temperature may change the mechanism of action of some antioxidants, and as a result the order of their effectiveness.89 By way of example, Figure 3.3 illustrates the oxidation kinetics of TGL in the presence of 2.4 x 10 3M a-tocopherol and ferulic acid at 100 C and at room temperature. It is to be seen that at...

Molecular biology

With the exception of certain cancers of childhood which often affect growing tissues such as the brain or bones, carcinogenesis - the development of cancer from normal cells - is usually a relatively slow process which occupies a substantial proportion of the lifetime of an individual. Tumour cells invariably contain a number of mutations affecting genes controlling the rate at which cells divide, differentiate or die, or the efficiency with which DNA damage is repaired.8'9 Such mutations may be inherited though the germ-line, and these form the basis for a number of recognised familial cancer syndromes, but most of the genetic abnormalities detectable in sporadic cancers, which are far more common, are somatic mutations acquired during carcinogenesis. Such damage may result from exposure to radiation or chemical mutagens, or through the effects of molecular species such as oxygen free radicals generated by the normal metabolism of the body.Whatever the source of the DNA damage,...

Phenolic compounds

As long ago as 1936, Rusznyak and Szent-Gyorgi63 proposed that the flavonols were an essential dietary factor contributing to the maintenance of capilliary permeability. This is no longer thought to be true, but recent interest in dietary antioxidants and metabolically active phytochemicals has focused renewed attention on the possible beneficial effects of flavonoids.64,65 Flavonoids are very effective antioxidants and it has been proposed that they protect against cardiovascular disease by reducing the oxidation of low density lipoproteins. There is some epidemiological evidence for this, but flavonoids are generally poorly absorbed from food, and their effects on the overall antioxidant capacity of the plasma remains to be established. Nevertheless, flavonoids and other phenolic substances may exert local anti-carcinogenic effects in the intestine where, in addition to acting as intraluminal antioxidants, they may induce Phase II xenobiotic

Barley

The separation of the barley kernel and subsequent processing can produce a fraction with significant concentrations of antioxidants. Hand dissection of barley kernels showed that the germ was a significant source of tocopherol and tocotrienols (i.e. Tocols) at 206mgkg-1 of germ. The whole kernel (40mgkg-1), hull (29mgkg-1), and endosperm (33mgkg-1) had dramatically lower concentrations of Tocols.104 However, a-tocotrienol accounted for 96, 83, and 63 of the Tocols in the endosperm, whole and hull, respectively. In contrast, a-tocopherol represented 90 of the total Tocols. The malting and brewing processes had a positive impact on the total Tocols. Malting caused a slight but non-significant reduction in total Tocols from 56.7mgkg-1 in the whole grain to 52mgkg-1 after malting whereas the spent grain remaining after brewing had a significantly higher Tocols content at 152.9mgkg-1.104 The tocopherol content increased from 12.8mgkg-1 in whole grain to 25.4mgkg-1 in the spent grain and...

Buckwheat

Commercially, buckwheat is used as a component in pancake mixes, noodle and pasta formulations, porridge and soups. The fact that buckwheat is already used in many products and that antioxidant activity has been found shows that a potential new source of NAO can be derived from buck-wheat.112-115 Buckwheat contains 387 and 1314mg 100g flavonoids and 47 and 77mg 100g rutin in the seeds and hulls, respectively.112 However, Dietrych-Szostak and Oleszek116 reported 18.8 and 74mg 100g total flavonoids for the seed and hull, respectively while Watanabe et al.113 reported c. 36mg 100g for the hull based on the summation of concentration of purified flavonoids. The antioxidants of corn are unique in the fact that carotenoids make up part of the antioxidants, which is not the case in most cereals. Chen and Yang reported carotene and xanthophyll levels of 2.7 and 19.9ppm respectively in yellow corn.119 Kurilich and Juvik assessed the carotenoid and tocopherol concentrations of 44 varieties of...

Millet

Millet is predominantly a cattle feed in the United States but in Japan and India millet is used as human food. Watanabe identified three phenolic antioxidants from Japanese barnyard millet (Echinochloa utilis).121 The three antioxidants are tricin, luteolin, and N-(p-coumaroyl)serotonin (NCS). All antioxidants had radical-scavenging activity with NCS being the most active, equivalent to BHA, followed by luteolin and tricin. In addition, luteolin was more active than quercetin. Sripriya et al.128 reported free-radical quenching activity of finger millet (Eleusine coracana). They noted that non-processed brown finger millet had the highest radical quenching activity and postulated that tannins and phytic acid were responsible for the activity. The phenolic content increased during the fermentation and the combined germination and fermentation processes. However, the radical scavenging activity decreased so that total phenolics did not dictate AOA. The loss of phytate and hydrolysis of...

Onions

The antioxidant activity of onion (Allium cepa) and onion scales has been studied in lipid oxidation models3'4'5'9'10'13 and in radical scavenging assays.611 Both yellow and red onion were poor antioxidants towards oxidation of methyl linoleate13 in contrast to their high antioxidant activity towards oxidation of LDL.11 Onion had also a poor antioxidant score in the ORAC activity test while garlic (Allium sativum L) gave a score that was four times higher.6 Yin and Cheng31 reported that the presence of garlic bulb, garlic greens, Chinese leek, scallion, onion bulb, and shallot bulb significantly delayed lipid oxidation of phosphatidylcholine liposomes. While allicin 4 is responsible for the antioxidant activity of garlic bulb20 compounds other than allicin are involved in determininig the antioxidant effect of other Allium members. According to Velioglu et al.12 anthocyanin-rich vegetables including red onion scales generally showed very strong activities towards oxidation of...

Citrus fruits

Grapefruit (Citrus paradisi) extracts inhibited ascorbate-iron-induced lipid peroxidation of liver microsomes in a dose-dependent way, but were less effective antioxidant towards an NADH-iron induced system.46 Naringin (naringenin 7- -neohesperidoside) 8, a major component in grapefruit, was reported not to contribute to the lipid peroxidation but to be responsible for most of the hydroxyl radical scavenging activity of grapefruit. Grapefruit was also effective towards ascorbate-iron-induced lipid per- In a study by Scarlata and Ebeler61 citrus juices from orange, tangerine and grapefruit did not have any antioxidative effect towards oxidation on lipoproteins isolated after plasma spiking. In this study, hesperetin and hesperidin, two of the major phenolic compounds in citrus fruits, did not show any activity. On the contrary, Miller and Rice-Evans43 showed that in orange juice the total antioxidant activity could be accounted for by hesperidin 9 and narirutin 10. Bocco et al.62...

Grapes and wines

Chemical Structure Narcotics

Antioxidants in grapes (Vitis vinifera) and grape juices have been recently reviewed by Frankel and Meyer.47 Both fresh grapes and commercial grape juices are a significant source of phenolic antioxidants. Extracts of fresh grapes inhibited human LDL oxidation from 22 to 60 and commercial grape juices from 68 to 75 when standardised at 10 M gallic acid equivalents (GAE).3839 The antioxidant activities of grapes and grape juices were comparable to those found for wines (Table 10.2).40 The LDL antioxidant activity correlated highly with the concentration of total pheno-lics for both grape extracts and commercial grape juices, with the level of anthocyanins and flavonols for grape extracts,with the levels of anthocyanins for Concord grape juices, and with the levels of hydroxycinnamates and flavan-3-ols with the white grape juice samples.39 Vitamin C had no significant effect on the antioxidant activity of grape juices.39 Grape extracts were also shown to inhibit formation of both...

Introduction

In the early 1980s it was recognized that excessive Ca2+ influx, presumably through voltage-gated Ca2+ channels, with a resultant increase in intracellular Ca2+, was associated with neuronal death from cerebral ischemia, hypoglycemia, and status epilepticus (Siejo 1981). Calcium activation of phospholipases, with arachidonic acid accumulation and its oxidation, generating free radicals, was thought to be a potential mechanism by which neuronal damage occurs. In cerebral ischemia and hypoglycemia, energy failure was thought to be the reason for excessive Ca2+ influx, whereas in status epilepticus it was thought that repetitive depolarizations were responsible (Siejo 1981).

Nanobiotechnology and the assembling of hemoglobin with enzymes that remove oxygen radicals

As PolyHbs can be kept at room temperature and used immediately on the spot, they can have potential for use in treating severe bleeding (hemorrhagic shock). However, the process must be carried out fast because if delay occurs, the PolyHb alone might result in the production of oxygen radicals that cause tissue injury (ischemia-reperfusion injuries). Antioxidant enzymes normally present in red blood cells are not enough to prevent this problem. We use glutaraldehyde crosslinking to assemble a nanobiotechnology complex of PolyHb-SOD-CAT by crosslinking hemoglobin, superoxide dismutase and catalase (D'Agnillo and Chang, 1998) (Fig. 2.2). In this way, one can increase the antioxidant enzymes to a much higher level than those in red blood cells.

The Role of Eicosanoids

Arachidonic acid comprises part of the membrane phospholipid pool and is released in a single-step reaction by activated phospholipase A2 (PLA2). PLA2 can be activated by various agonists, such as norepinephrine, angiotensin II, cytokines, and free radicals (107,108). Activated PLC and phospholipase D are also able to release free AA but not directly. Rather, they generate lipid products that contain AA (diacylglycerol and phosphatidic acid, respectively), which can be released subsequently by monoacylglycerol- and diacylglycerol-lipases. Once released, free AA has 3 possible fates reincorporation into phospholipids, diffusion outside the cell, and metabolism. Metabolism is carried out by 3 distinct enzyme pathways cyclooxygen-ase, lipoxygenases, and CYP. Metabolism of free AA by cyclooxygenases and lipoxygenases leads to the formation of prostaglandins, thromboxanes, and leukotrienes, with important roles in the regulation of vascular tone and inflammation (109). Cyclooxygenase- and...

Dual action nNOS inhibitors

It has been shown that a combination of a nNOS inhibitor and an antioxidant in a model of focal ischemia was synergistic in reducing neuronal damage 79 . A novel strategy for the treatment of stroke consists of designing hybrid molecules such as compound 33, which possess a NOS inhibitor pharmacophore linked to an antioxidant fragment to scavenge reactive oxygen species (ROS). This compound displayed potent nNOS inhibition (K, 0.12 p.M) and inhibition of lipid peroxidation induced by ROS (IC50 0.4 mM). Scavenging ROS and inhibiting NOS simultaneously has been shown to enhance neuronal survival after cerebral ischemia in animal models 80 . Given that NO reacts with O2_ to form peroxynitrite, it is perhaps not surprising that the two mechanisms work synergistically.

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) Edited by Lester Packer

Hemoglobin as Oxygen Carrier

As shown in Fig. 1.1, red blood cell membranes contain blood group antigens, and typing and matching are needed before red blood cells can be transfused into patients. This results in delays in emergency situations. With the standard method, red blood cells can be stored for only about 42 days. Red blood cells cannot be sterilized to remove infective agents like hepatitis viruses, HIVand other potential emerging infective agents. Thus, red blood cell substitutes are being developed (Fig. 1.1). Red blood cell (rbc) contains Hb, antioxidant enzymes and a multienzyme system to preventthe conversion of Hb to nonfunctioning metHb. As such, preparing a clinically useful complete artificial red blood cell has been a very complicated process and will be discussed in the next two chapters. In the meantime, nanobiotechnology has allowed the development of simpler oxygen carriers containing only Hb. Although the simpler oxygen carriers are not as complete as the artificial red blood cell, some...

Smallmolecule inhibitors of asynuclein aggregation

Other small-molecule inhibitors of a-synuclein have been identified in the literature such as Congo red. 80 . Polyphenolic compounds such as rifampicin, curcumin, and tetracycline are capable of inhibiting both a-synuclein 79 and Ab aggregation 82 in a concentration-dependent manner with some potency (IC50

Next Generation Cryopreservation Solution Design

With cryopreservation advancement more dependent on mitigation of the molecular-based responses to low-temperature exposure and storage, there is a growing recognition that cryopreservation solution formulation requires attention to both physical and cellular related events.33,53 The underlying principles now recognized as essential to optimization of cryopreservation processes include but are not limited to maintaining proper cold-dependent ionic ratios, control of pH at lowered temperatures, prevention of the formation of free radicals and avoidance of their detrimental effects, oncontic balance, the supply of energy substitutes, etc.6,33,53 In fact, the first attempt at addressing these issues was through the simple addition of cryoprotective agents such as DMSO to hypothermic storage solutions including ViaSpan (University of Wisconsin solution).81-83 These studies showed marginal improvement in cryopreservation outcome over classical approaches. In 1998 the first report on the...

Mechanism of Programmed Necrosis Induction

ROS family comprises different types of free radicals (i.e. species with highly reactive unpaired electrons), such as superoxide anion (O2-), nitric oxide (NO), and hydroxyl (OH) radicals, as well as other molecular species (e.g. hydrogen peroxide, H2O2, and peroxynitrite ONOO-). These reactive species generally affect unsaturated bonds in lipids yielding peroxides, hydroperoxides, and aldehydes (Kehrer 1993) and their deleterious effects are particularly important in neurons because of the high brain lipid content (Ikeda and Long 1990). ROS-mediated alterations of proteins affect their side-chains, which are oxidized to carbonyl groups (Stadtman and Oliver 1991). This structural modification often leads to the functional inactiva-tion of proteins. For example, ROS-mediated oxidation of plasma membrane proteins like Na+-K+-ATPase, renders these targets more susceptible to degradation by calpain, thus, further contributing to the intracellular ion imbalance. In the particular case of...

Induction Of Aox Enzymes

Lipid peroxidation is important in vivo for several reasons, in particular because it contributes to the development of atherosclerosis (49-51), a process known to be accelerated in diabetic patients (6). Lipid peroxides and other end products of the peroxidation process may be toxic to vascular endothelium in diabetics (6,52). Many assays are available to measure lipid peroxidation, but the simpler ones, such as the TBA test and diene conjugation, are notoriously unreliable when applied to human tissues and body fluids (reviewed in Ref. 53), although the TBA test can be improved by linking it to HPLC and adding antioxidants with the TBA reagents to prevent peroxidation during the assay procedure (54). Levels of lipid peroxides in human plasma, as measured by reliable analytical methods (54-59), seem to be low, usually

The Role of Damage Response Pathways in Stem Cell Aging

The ATM pathway effects stem cell number. (A) The normal function of the ATM pathway yields a normal stem cell number. Here, ATM detects the levels of ROS. When ROS levels reach a critical amount, p38 MAPK is activated, resulting in stem cell self-renewal and proper maintenance of the stem cell pool. (B) Mice lacking ATM cannot control the levels of ROS, leading to an increase in oxidative stress. This increase causes constitutive activation of p38 MAPK and excessive stem cell proliferation resulting in differentiation rather than self-renewal. This depletion of the stem cell pool manifests in the whole animal as stem cell aplasia. (C) Long-term treatment with antioxidants can deter the constitutive activation of p38 MAPK seen in the ATM knockout mice. With this intervention, the stem cell pool is maintained at normal levels. (D) Pharmacologic inhibition of p38 MAPK is another method of restoring normal stem cell proliferation rates and maintaining the stem cell pool in ATM...

Apoptosis of Other Cell Types in the Evolution of Fibrous Scar

The significance of elimination of noncardiomyocytes by apoptosis in MI has not been fully determined 156,157 . Inflammatory cells accumulate in the infarcted region to scavenge the necrotic tissue. The first to arrive to the site are neutrophil granulocytes, which are an essential part of the acute inflammatory response to tissue injury and are thus a first-line defense of the organism. They probably play a key role in the early stages of repair after MI 158 . However, they might contribute to myocardial damage by release of oxygen-derived free radicals, proteases, leukotriens, and activation of the complement system 158 , especially in situation in which inflammatory response is believed to be enhanced, for example, in reperfusion 159 . Furthermore, there is evidence to suggest that enhanced neutrophil infiltration might be important in the pathogenesis of the ventricular rupture after MI a more intensive interstitial neutrophil infiltration of the infarcted myocardium was found in...

Prevention And Treatment Of Vasospasm

Beyond rebleeding, vasospasm is one of the most feared consequences of aSAH because of its high rate of morbidity and mortality (14). Vasospasm occurs due to a complex cascade of parallel, yet interacting, biochemical pathways, likely including (i) endothelium-derived factors (including nitric oxide and oxygen free radicals), (ii) vascular smooth muscle-derived factors (e.g., calcium-channel activation and protein kinase C (PKC) activation), (iii) pro-inflammatory mediators (e.g., cysteines, histamine, and bradykinin), and (iv) stress-induced gene activation (e.g., heat shock proteins and heme oxygenase-1) (15). Ultimately, these pathways result in vascular constriction, vascular smooth muscle proliferation, reduced perfusion, and neuronal injury. Consequently, developing pharmacologic agents or interventions that target the underlying biochemical pathways that mediate vasospasm has become a major focus of aSAH research.

Anti Caspase Treatment

How will the body react to treatment with caspase inhibitors Caspases are responsible for several important physiological functions, besides apoptosis which removes damaged cells, they are also responsible for cytokine activation, cleaning up free radicals, and maintenance of the cytoskeleton. These functions may be adversely affected by caspase inhibitors. Long-term treatment with caspase inhibitors might therefore cause cancer, infections, and autoimmune disorders. Thus, it might be desirable to limit activation of prosurvival signaling to the heart. One possible solution would be to manipulate survival signaling pathways through local genetic or pharmacological interventions 187 .

Mediterranean Diet Effects on Oxidative Stress

Oxidative stress markers commonly used, including nonspecific in vitro assays to determine the susceptibility of lipids to oxidation (i.e. lag time, thiobarbituric acid substances, malondialdehyde, oxygen radical absorbing capacity (ORAC) or assays that measure, in vivo, end-product of oxidative damage to lipids (e.g., breath ethane or urinary isoprostanes). Formation of these oxidation products is dependant on free radical activity (i.e. metabolic rate), substrate concentration (i.e. lipids), and antioxidant activity (both endogenous and dietary). Hence, alterations in dietary patterns can give important insight into the benefit or harm of nutrients when linked to subsequent changes in markers of oxidative stress. In the DASH trial, consumption of the DASH diet reduced breath ethane exhalation (an in vivo marker of oxidized n-3 polyunsaturated acids)17 and reduced urinary isoprostanes (an in vivo degradation product of arachidonic acid). These findings provide indirect evidence for...

General considerations

A recent paradigm shift has led to efforts by neuroimmunologists to acquire deeper insight into the neurodegenerative features of chronic neuroinflammation. Recently, proteolytic enzymes, cytokines, death ligands, such as TRAIL, oxidative products, such as 7-keto-cholesterol, and free radicals have been identified as potential contributors to neuronal damage (Zipp and Aktas, 2006). It has yet to be clarified what immune cells and what mechanisms initiate neurodegeneration in in vivo animal models and the human disease. In addition, inflammation may compromise energy metabolism and cause hypoxia and cytotoxicity, making neuroprotective drugs a likely candidate for future treatment strategies. The contribution of excitotoxicity was shown by Raine and coworkers, who influenced chronic neuronal damage in the EAE model via AMPA kainate receptor antagonists (Pitt et al., 2000). Unlike ischemic or traumatic models, in which dramatic metabolic failure leads to rapid irreversible

Vitamin E In Diabetes

Vitamin E (RRR-a-tocopherol) is the most important lipid-soluble antioxidant, which protects lipoproteins and cell membrane lipids from oxidative damage. This ability is coupled to other antioxidant systems (vitamin C, glutathione, lipoic acid) that can recycle the vitamin E radical (19). In the absence of such systems, vitamin E can behave as an oxidant (20). Dietary vitamin E is transported to the liver and secreted from the liver within very-low-density lipoproteins (VLDL). It is distributed among VLDL and LDL during the transfer and metabolism of the lipoprotein lipids (21). Thermodynamic partitioning also permits some transfer into high-density lipoproteins (22). An important part of vitamin E is constituent of cell membranes where it protects the lipid moiety against peroxidation (23). Antioxidant Vitamins in Diabetics

Massimo Franchini1 Giovanni Targhert and Giuseppe Lippi

This review examines in vitro and in vivo studies, indicating that bilirubin inhibits lipid oxidation and oxygen radical formation. Experimental and epidemiological evidence is presented that suggests that bilirubin may serve as a physiological antioxidant providing protection against cardiovascular disease. Special attention is focused on large prospective studies that noted a strong, inverse relationship between serum bilirubin concentrations and cardiovascular morbidity and mortality even after adjustment for traditional risk factors. Overall, the evidence from these studies suggests that bilirubin, via its antioxidant potential, has antiatherogenic properties, and that serum bilirubin concentrations in the upper portion of the reference interval for the general population may provide some protection against cardiovascular disease, whereas concentrations in the lower portion of the reference interval indicate increased cardiovascular risk.

Molecular characterization of PolyHbCATSOD

Based on HPLC molecular weight gel filtration analysis on a BioSep Sec S-3000 column (5000-700,000 kD exclusion limits, Phenomenex, Torrance, CA). Since only trace amounts of antioxidant enzymes are used in relation to Hb, the molecular weight distribution of PolyHb-SOD-CAT is the same as that of PolyHb (Fig. 4.7). The ratio of Hb to SOD and CAT (as mg ml) is typically 1 0.009 0.0045. Only 5 of the enzyme is not crosslinked into the PolyHb-CAT-SOD (Powanda & Chang, 2002) (Table 4.1). There is no CAT or SOD enzyme activity in

Vitamin C In Diabetes

Vitamin C (ascorbic acid) is a powerful antioxidant and a cofactor in collagen biosynthesis, which affects platelet activation, prostaglandin biosynthesis, and the polyol pathway. Vitamin C acts as an antioxidant both in vitro and in vivo and protects plasma lipids and lipid membranes. It has the power to spare and to increase plasma-reduced glutathione (56). The antioxidative ability of vitamin E can be continuously restored through its recycling by other antioxidants, mainly vitamin C (18,19).

Basic Laboratory Research

Oxidative processes may play an important role in the pathogenesis of many chronic diseases, including atherosclerosis, cancer, arthritis, eye disease, and reperfusion injury during myocardial infarction (MI). Data from in vitro and in vivo studies suggest that oxidative damage to low-density lipoprotein (LDL) promotes several steps in atherogenesis,7 including endothelial cell damage,8,9 foam cell accumulation,1012 and growth13,14 and synthesis of autoantibodies.15 In addition, animal studies suggest that free radicals may directly damage arterial to prevent involvement in free radical reactions Enzymatic antioxidants (e.g., superoxide dismutase, catalase, and glutathione peroxidase) Nonenzymatic antioxidants (e.g., vitamin C, vitamin E, beta-carotene, urate, bilirubin, and ubiquinols) Several systems have evolved in aerobic organisms to minimize the damaging effects of uncontrolled oxidation (Table 3.1). Mechanisms exist to prevent the formation of unintended free radicals, and...

Defining Oxidative Stress

The first step in addressing the role of oxidative stress (OxS) in diabetic complications is to define OxS. It is often defined as a shift in the pro-oxidant-antioxidant balance in the pro-oxidant direction. This definition of OxS is more descriptive than quantitative and chemical in nature. Philosophically, it implies a null point, a balance point at which there is no OxS OxS occurs only when the balance is shifted toward the pro-oxidant direction. There is a conceptual flaw in this definition because it fails to recognize that OxS is a constant feature of biological systems. Peroxides, superoxide, hydroxyl radicals, and other reactive oxygen species (ROS), the mediators of OxS, are being formed continuously in the body and always exist at some steady-state concentration. The resulting oxidative damage to protein, DNA, and other biomolecules is a ubiquitous and universal consequence of life under aerobic conditions. At this time it is not possible to quantify OxS, but this may...

Observational Epidemiology

While molecular mechanisms exist to explain potential benefits of antioxidants, clinical outcomes are needed to evaluate the benefit in humans. Observational studies can use information about diet and vitamin intake to identify potential protective effects of antioxidants. Results from cross-sectional, case-control, and cohort studies suggest that antioxidant consumption reduces the risk of developing heart disease and stroke19 with the strongest data in favor of vitamin E.20 Several large cohort studies have evaluated the relationship between vitamin E intake and incidence of CHD. The largest of these is the Nurses' Health Study (NHS), a cohort study of more than 87,000 U.S. female nurses aged 34-59 years with no history of CVD.21 Dietary antioxidant intake and use of antioxidant vitamin supplements were ascertained through a semiquantitative food frequency questionnaire administered at baseline in 1980 with information on antioxidant supplements updated biennially. After 8 years,...

Divalent Cation Transport

As shown in Figure 2.1, cytosolic calcium concentration is 10,000-fold lower than extracellular concentrations, and it is now postulated that enhanced or unbalanced calcium influx across the plasma membrane represents a final common pathway in cell death mediated by various conditions that share the tendency to induce an abnormal membrane permeability for calcium. For example, excessive intracellular accumulation of calcium has been implicated as playing a pivotal role in ischemia-induced neuronal death and the evolving knowledge of the mechanisms involved include the following alteration of electron transport in the respiratory chain, which leads to swelling and destruction of mitochondria the release of additional excitotoxic neurotransmitters activation of deleterious intracellular enzymes such as lipases and proteases, which break down cellular protein and lipid structures and the formation of potentially harmful oxygen and hydroxyl free radicals and cellular depolarization.109...

Rationale for Randomized Trials

Observational results suggest that antioxidants may have protective effects, but these studies have important limitations. For example, uncontrolled confounding from unknown or unmeasured confounders can be similar in magnitude to the observed health effects, and antioxidant consumption may be merely a marker for a different cardioprotective factor (e.g., exercise, diet) that is responsible for the observed health benefits. In addition, intakes of individual dietary antioxidants tend to be highly correlated with each other, making it difficult to determine the specific benefit of a particular antioxidant. Because of these limitations, randomized trials of adequate power, length of follow-up, and therapeutic dose are necessary to sort out the effects of antioxidants. By assigning subjects randomly to treatment or placebo, potential confounders should be evenly distributed between the two groups. Antioxidant vitamins are commonly used nutritional supplements, and their use is rapidly...

Vitamin E Primary Prevention Trials

Clinical trials of vitamin E have focused on alpha-tocopherol, the major component of vitamin E and the predominant antioxidant in circulating lipoproteins.28 Large randomized trials that examined vitamin E alone in the primary prevention of CVD are summarized in Table 3.2. The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study was the first large-scale randomized trial of antioxidant vitamins in a well-nourished population. This 2 x 2 factorial trial tested the effect of synthetic vitamin E (50 mg d) and beta-carotene (20 mg d) in the prevention of lung cancer among 29,133 Finnish male smokers aged 50-69 years.29 After a median of 6.1 years, vitamin E supplementation did not reduce the risk of lung cancer (the primary endpoint). There was also no clear reduction in risk of death due to ischemic heart disease (RR 0.95 95 CI, 0.85-1.05) or ischemic stroke (RR 0.84 95 CI, 0.59-1.19) although the risk of developing angina was lower among those assigned to vitamin E (RR 0.91...

Colonylevel defense

Additionally, honey bees improve their resistance to disease infections by producing antimicrobial substances in their hive products. Propolis is a resinous substance collected from tree sap or other plant sources and then mixed with wax by honey bees. Propolis has been identified to be rich in a group of biologically active antioxidants called flavonoids, which promote natural immunity and cell regeneration (Greeneway et al., 1990). It has been shown that propolis not only functions as a cement to seal nest cracks or cavities but also has antimicrobial properties that help the hive block out viruses, bacteria, and other microorganisms (Kujumgiev et al., 1999 Miorin et al., 2003). Another important feature of honey bees' natural defense is the antimicrobial activity of colony food, including honey, pollen, and royal jelly. The antibiotic agents (also called inhibin ) inhibit the development of bacteria and fungi in stored food (Burgett, 1997).

Summary And Conclusion

In the foregoing discussion we have tried to define the nature of OxS and then, using that definition, to assess the status of OxS in diabetes. Based on analysis of various biomarkers of OxS in long-lived proteins, we conclude that OxS is not overtly or systemically increased in diabetes, except at later stages in the development of complications. Metabolic derangements in diabetes lead to an increase in concentration of oxidizable substrates and compromised detoxification pathways. The resulting increase in reactive carbonyls in tissues, known as carbonyl stress, leads directly to increased chemical modification of proteins in diabetes. Efforts directed at decreasing substrate concentration (maintenance of euglycemia and normolipidemia), bolstering detoxification pathways (GSH precursors or enhancers), and trapping reactive carbonyl species (AGE inhibitors, carbonyl traps) represent reasonable therapeutic approaches for limiting the chemical modification and crosslinking of proteins...

Vitamin E Secondary Prevention Trials

Patients with established CVD may have high oxidative stress and be at a higher risk for a clinical event. As a result, antioxidant use may be most beneficial in the secondary prevention of CVD. Randomized trials of vitamin E alone in the secondary prevention of CVD are summarized in Table 3.3. Early small trials used surrogate endpoints to test the effects of supplemental vitamin E in patients with established atherosclerotic disease. In a trial of 100 patients over 4 months, 1,200 IU d of vitamin E supplementation following percutaneous transluminal coronary angioplasty led to a 30 reduction in the risk of restenosis, but this did not reach statistical significance (P 0.06).37 A study of 120 men and women with intermittent claudication randomized to antioxidants or placebo over 2 years found little improvement in lower limb function and similar rates of cardiovascular events and death,38 and the ATBC trial found that 50 mg d of vitamin E had no preventive effect on the development...

Betacarotene Secondary Prevention Trials

A meta-analysis of large antioxidant trials that evaluated beta-carotene supplementation alone or in combination with other antioxidants found a small but significant increased risk of CVD death (RR 1.10 95 CI, 1.03-1.17) and total mortality Women's Antioxidant other antioxidant0, or a combination (2 x 2 x 2 x 2 factorial design)

Mitochondrial Checkpoints of TCell Activation and Apoptosis

Overview of mitochondrial redox and metabolic checkpoints of T-cell activation and apoptosis signals. Antigen binding-initiated signaling through the T-cell receptor complex CD3 and the CD28 costimulatory molecule activate phosphatidylinositol 3-kinase (PI3K) and protein tyrosine kinases (PTK). Increased cytosolic Ca2+ concentration activates the serine threonine phosphatase calcineurin, which dephosphorylates the nuclear factor for activated T cells (NFAT). Dephospho-rylated NFAT can translocate to the nucleus, where it promotes transcription of IL-2 in concert with AP-1, NF-kB, and Oct-1. Ca2+ flux into mitochondria increases production of ROS and NF-kB activation (88-90). Mitochondrial membrane integrity is maintained by a balance of membrane-stabilizing bcl-2 and bcl-XL and pore-inducing bax and bad (34) as well as the metabolic capacity to synthesize reducing equivalents, NADPH, GSH, and TRX. Controlled increase of ROS levels activates NF-kB and promotes cell growth....

Ocular Drug Formulations

Solutions and suspensions are the most common formulation of ocular medications. Like other medications, ocular drugs contain inactive ingredients, including preservatives, agents to increase viscosity, antioxidants, wetting agents, buffers, and agents to adjust tonicity. Preservatives control growth of microorganisms that may be introduced into the solution accidentally. Some of these agents can stain contact lenses or have a high incidence of hypersensitivity reactions. Ocular ointments are ideal for prolonged contact of the drug with the eye. Ointments can cause blurry vision the patient should be informed of the possibility of a temporary decrease or blurring of vision. Drugs formulated into ocular gels also serve as vehicles for prolonged contact of the drug with the eye. Sometimes the use of multiple ocular medications is necessary, in which instance drops should be administered no less than 5 min apart to allow for adequate drug-tissue contact time and to prevent one drug from...

Nonpharmaceutical Approaches Albumin

Ginsberg's pioneering animal research has shown that albumin infusions enhance red cell perfusion and suppress thrombosis and leukocyte adhesion in the microcirculation, particularly during the early reperfusion phase.54 Albumin also improves microcirculatory flow, plasma viscosity, red cell deformability, and oxygen transport capacity. In addition, albumin has potent antioxidant and antiapoptotic effects. In experimental stroke, albumin has been shown to reduce infarct size, improve neurofunction scores, and reduce brain edema.55 In the Albumin in Acute Stroke (ALIAS) phase II trial, an open-labeled, dose-escalation, nonrandomized pilot clinical trial conducted at two centers in North America, albumin was found to be safe and effective in reducing stroke-related brain injury.56,57 Eighty-two subjects with an NIHSS 6 received 25 albumin within 16hours of stroke onset in two doses, 0.34-1.03 and 1.37-2.05 g kg. Nearly half of the patients (42) also received rt-PA. The probability of a...