Antioxidants from Natural Sources

Oxygen Derived Free Radicals

The study of radicals in the vascular wall is complicated by the fact that several different enzymes with specific sub-cellular localisations and mechanisms ofactivation can all generate oxygen-derived free radicals and contribute to the oxidative burden. These include eNOS, enzymes of the respiratory chain, some cytochrome P450 monooxygenases, xanthine oxidase and NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidases. The latter enzymes have been of particular interest given the availability of NADPH oxidase subunit knockout mice and the accumulating evidence that the generation of reactive oxygen species by NADPH oxidases triggers their release by the other enzymes, particularly from eNOS (Landmesser et al. 2003).

Effect of free radicals on actinmyosin and muscle fibres

It was shown by physiological and biochemical studies that during the death of heart muscle the acidosis inside the cell and the activation of proteolytic enzymes is resulted in the dissociation of structurally bound myosin light chains (mainly the regu latory light chain LC-2) 63-65 . The death of muscle cells caused by the irreversible damage of sarcolemma makes possible the enter of external agents into the cell and their interaction with myosin. An exogenously administered, oxygen free radical-generating system has the capacity to cause cardiac dys function 66 . The fragments of contractile proteins fall into the circulation where the concentration of cardiac myosin LC-2 is proportional to the extent of heart infarct 67 . In glycerol-extracted muscle fibres the essential -SH groups are involved in the interaction of oxygen free radicals with myosin 68 . This way the molecular dynamic state and thermal stability of muscle proteins could be a good monitor of the damage caused by the...

Accumulation of Free Radicals OxidizedNitrosylated Proteins

A role in neurotoxicity in this model. Similar results were observed when UPS function was inhibited at the level of ubiquitination (39). Several other studies have demonstrated that proteasomal inhibition could exacerbate toxicity of oxidative stressors (34, 40-42). Not always is it clear however if the increase in toxicity is solely due to the impairment of degradation of oxidatively damaged proteins or if proteasomal inhibition in itself leads to oxidative injury. In a model using primary mesencephalic cell cultures epoxomicin did not have any effect on the direct increase of ROS, but led to an elevation of oxidized protein and increased neuronal vulnerability to normally subtoxic levels of several complex-I inhibitors which induce oxidative stress. This increase in toxicity was partially abrogated by antioxidants suggesting that in this model proteasomal inhibition reduced the cellular capacity to detoxify oxidized protein (42). In contrast, in a study by Kikuchi et al. (41)...

Is CrIII an antioxidant or a prooxidant

One of the controversies surrounding the use of Cr(III)-containing nutritional supplements concerns the proposed roles of such supplements as antioxidants that reduce the diabetes-related oxidative stress 93-96 , or pro-oxidants that promote the oxidative stress through the formation of ROS 97-99 . Typical reported examples of the both actions of Cr(III) are described below. In an early report on the antioxidant action of Cr(III) 100 , pre-treatment of mice with CrCl3 (single injection of an aqueous solution, 5mgkg-1) was found to reduce the toxic effects of CCl4 (including lipid peroxidation in the liver), which are thought to be related to the formation of strongly oxidizing CCl3 radicals. Additions of CrCl3 (1-10 M, alone or in combination with 17 -estradiol) to the cell culture medium significantly reduced the levels of oxidized lipids and proteins in a human monocyte cell line treated with H2O2 or with excessive glucose concentrations 93, 101 . Synergistic action of grape seed...

Antioxidants Light Stabilizers and Thermal Stabilizers

Plastics generally age rapidly and undergo polymer degradation when exposed to UV light and in the presence of oxygen. The rate of oxidation is decreased by adding stabilizing additives, such as antioxidants or light stabilizers. These compounds stabilize the polymers by being preferentially degraded. Antioxidants can be divided into two major classes, based on their mechanisms of action primary and secondary antioxidants. The primary antioxidants are radical scavengers, hydrogen donors, or chain reaction breakers, and include hindered phenols and secondary aryl amines. The secondary antioxidants are peroxide decomposers, mainly composed of organophosphites and thioesters. To take advantage of synergistic effects, various combinations of primary and secondary antioxidants are often used. Commonly used antioxidants include Some of these antioxidants appear in the list of additives that may be used in the manufacture of plastic materials intended to come into contact with food. For...

Free radicals 111

Free radicals A highly charged, potentially destructive molecule (most commonly, a species of oxygen) that is generated naturally by breathing and by the body's response to stress. While free radicals are destructive, they have a positive role to play in the body as well. Generated by the immune system, they fend off microbes and help the digestive system break down food. In the brain, it can interact with lipids, harming the brain. While a certain amount of free radicals is necessary to maintain proper body function, high levels are toxic. Each day, the body generates thousands upon thousands of free radicals in response to

Antioxidants

Antioxidants (vitamins C and E and beta-carotene) neutralize destructive molecules called free radicals, which our bodies produce in large amounts as by-products of normal functioning. Because free radicals are prime suspects in many of the diseases and impairments that come with age, including dementia, scientists have long suspected that antioxidants might offer protection against 84 memory loss. The newest research suggests that some antioxidants A large study suggested that vitamin E, but not the other antioxidants, might help slow the rate of age-related mental decline. This study, published in the Archives of Neurology in 2002, looked at 2,889 people ages sixty-five and older who, at the outset, had normal memory and cognitive function. Researchers collected detailed nutritional profiles and asked the people which vitamin and mineral supplements they took, and then tracked their cognitive function over an average follow-up interval of three years. Cognitive function was measured...

Related titles from Woodheads food science technology and nutrition list

Antioxidants in food practical applications (ISBN 1 85573 463 X) J. Pokorny, N. Yanishlieva and M. Gordon Antioxidants are an increasingly important ingredient in food processing, as they inhibit the development of oxidative rancidity in fat-based foods, particularly meat and dairy products and fried foods. Recent research suggests that they play a role in limiting cardiovascular disease and cancers. This new book provides a review of the functional role of antioxidants and discusses how they can be effectively exploited by the food industry, focusing on naturally occurring antioxidants in response to the increasing consumer scepticism over synthetic ingredients.

Nutritional Background

More recently, the complex relationship between diet and heart disease has been reviewed by Ashwell (1993). While it is acknowledged that CHD is a multifactorial disorder, it is considered that diet is one component which can be modified by everybody. The report concludes that the development of CHD can be viewed simplistically as a three-stage process starting from an initial arterial injury that is followed by atherosclerosis and the formation of a blood clot which eventually blocks the artery thus causing a heart attack. Each stage can be influenced by several physiological conditions (e.g., high blood pressure, high levels of plasma lipids, and low levels of antioxidants), and these can be affected by controllable factors, including diet. A round table model was derived to elucidate the relationships between the stages of the disease, physiological conditions, and dietary components. The level and composition of the fats consumed is shown to be of importance at all three stages,...

High Density Lipoproteins HDL

HDL is basically the opposite of LDL. Instead of having a lot of fat, HDL has a lot of protein. Instead of ferrying cholesterol around the body, HDL acts as a vacuum cleaner sucking up as much excess cholesterol as it can (see Figure 1.1). It picks up extra cholesterol from the cells and tissues and takes it back to the liver, which takes the cholesterol out of the particle and either uses it to make bile or recycles it. This action is thought to explain why high levels of HDL are associated with low risk for heart disease. HDL also contains antioxidant molecules that may prevent LDL from being changed into a lipoprotein that is even more likely to cause heart disease. Lifestyle changes affect HDL levels exercise can increase them, while obesity and smoking lower them. As for diet, in general, the high-fat diets that raise LDL also raise HDL, while low-fat diets lower both. However, by carefully choosing the right foods, you can eat a diet that lowers LDL without lowering HDL, as I'll...

Crosslinked Thermoplastics

A special case found in some modified plastics used for medical devices is that of cross-linked thermoplastics. This is where a thermoplastic is irradiated with ionizing radiation to release free radicals and induce the formation of three-dimensional cross-linked structures in a thermoplastic. This modification can have a dramatic effect on the properties and performance of the plastic material. Common applications of this process in medical devices are irradiated polyester tubing for angioplasty balloons and irradiated UHMWPE for joint implants.4

Healthrelated roles of Pcarotene

3.6.1 P-Carotene as an antioxidant The ability of carotenoids to act as antioxidants can be measured in vitro, ex vivo, or in vivo. LDL isolated from an individual who has been supplemented with carotenoids and then evaluated for its antioxidant activity is an extension of an in vivo study, i.e. ex vivo. However, when carotenoids are added to plasma and then the oxidisable value of the LDL is measured it is more like an in vitro model (Krinsky, 2001). Many studies report using the ex vivo method of measuring the oxidisability of the LDL particles after feeding increased amounts of carotene-containing foods. However, when using fruits and vegetables the outcome is variable and difficult to interpret because they also contain vitamin C, polyphenols and flavonoids, which are also potential antioxidants. One study which gave additional dietary fruits and vegetables to subjects reported an increase in the resistance of LDL to oxidation (Hininger et al, 1997) while two other studies found...

Antihemophilic factor A See factor viii

Antioxidant A substance that may prevent free radicals (chemicals with free electrons, or oxi-dants) from causing cell damage. VITAMINS A, C, and e are antioxidants. antioxidant therapy Treatment with antioxi-DANTS, substances that tend to reduce damage caused by the presence of oxidants in the blood. Renegade oxygen atoms, known as free radICALs or singlet oxygen, have been shown to damage the cellular component of the immune system. Many people living with immune deficiencies therefore attempt to reduce such damage by supplementing their diets with antioxidant nutrients

Other roles of vitamin E

Vitamin E is the most effective chain-breaking lipid-soluble antioxidant in biological membranes, where it contributes to membrane stability and protects critical cellular structures against damage from free radicals and reactive products of lipid oxidation (Burton and Ingold, 1981). There are suggestions however that it has a variety of other effects, for example on immune function, platelet and vascular functions, prevention of oxidative damage to DNA and DNA repair and modulation of signal transduction pathways (Morrissey and Sheehy, 1999). In addition to the protection provided by vitamin E against LDL oxidation, several studies have consistently reported that platelet aggregation is reduced by vitamin E supplements but amounts used to demonstrate these effects are generally in excess of 250mg a-TE d (Morrissey and Sheehy, 1999). However, a reduction in reactive oxygen species (ROS) that is promoted by vitamin E can protect against vascular cell dysfunction, preventing adhesion...

What a Heart Attack Feels Like

Although LDL is thought to be the major cholesterol-carrying culprit causing heart disease, there is still scientific controversy over the form LDL must take to cause atherosclerosis. For nearly twenty years, atherosclerosis researchers have hypothesized that LDL must change once it's in the artery wall in order to cause artery blockages. The dominant view has been that LDL must first be oxidized to a more inflammatory form in order to cause serious artery wall damage. Oxidation is the chemical reaction that causes metals to rust by changing the structure of the metals' molecules. Similarly, oxidation may change the chemical structure of LDL molecules by breaking down large fat-containing molecular chains. Although there are literally thousands of studies that have suggested a role for oxidized LDL in causing heart disease, the use of antioxidants, such as vitamin E, has not resulted in any convincing decline in atherosclerosis in humans. This isn't proof that oxidation is...

Biochemical functions

Vitamin C can act both as an antioxidant and a pro-oxidant. AA can readily donate electrons to quench a variety of reactive free radicals and oxidant species and is easily returned to its reduced form by electron donors such as glutathione, flavonoids, tocopherol and NADPH (Zeigler et al, 1996 Xu and Wells, 1996). Vitamin C can scavenge hydroxyl, peroxyl and superoxide radicals as well as reactive peroxide, singlet oxygen and hypochlorite species (Bendich et al, 1986 Sies and Stahl, 1995). Vitamin C is believed to be of fundamental importance as an antioxidant in tissues. The evidence suggests that it protects against plasma lipid and low density lipoprotein peroxidation by scavenging peroxyl radicals from the aqueous phase before they can initiate lipid peroxidation, which it does by regenerating oxidised vitamin E to the active reduced form (Thurnham, 1994). In vitro vitamin C is rapidly lost when plasma is exposed to peroxyl radicals, cigarette smoke or activated neutrophils and...

Diseasenutrient interactions

There are also other groups within industrialised countries where there may be risks associated with elevated intakes of vitamin C. In North European communities, genetic haemochromatosis has a gene frequency of 1 in 20, such that approximately 1 in every 300 individuals are at risk of iron overload. Although they appear apparently healthy, giving vitamin C without an iron-chelating agent to such people can potentially produce serious clinical effects (Halliwell, 1994). As indicated above, iron is usually bound to transport, storage or tissue proteins and the body is therefore protected from its damaging reactions. If localised or more general breakdown of tissue integrity should occur during infection, inflammation, strenuous exercise or other traumas resulting in an acute phase response, then metal ions are potentially released into the circulation. In addition as we get older, we get sicker and in humans with advanced atherosclerotic lesions, catalytic metal ions capable of free...

Phase II Clinical Trial Material

If drug stability is identified as a potential issue, more thorough and careful drug-excip-ient compatibility studies may be necessary. On the basis of results of forced degradation and compatibility studies, a stabilization mechanism may be identified. Yoshioka and Stella46 have thoroughly reviewed drug stability and stabilization. Stabilization strategies such as incorporation of antioxidants,91 protection from moisture, or use of pH modifiers92 may be considered. If a functional excipient such as an antioxidant or a pH modifier is required, then tests to monitor its performance (i.e., consumption of the antioxidant during storage) must be developed.

Antioncogene See tumour suppressor gene

Antioxidant Any substance that inhibits oxidation, usually because it is preferentially oxidized itself. Common examples are vitamin E (a-tocopherol) and vitamin C. Important for trapping free radicals generated during the metabolic burst and possibly for inhibiting ageing.

Phytoestrogen Metabolism

Metabolism of dietary isoflavones and possesses estrogenic activity, having affinity for both ERa and ERp. Equol appears to be superior to all other isoflavones for antioxidant activity. It is the end product of the biotransformation of the phytoestrogen daidzein, one of the two main isoflavones found in abundance in soybeans and most soy foods. Once formed, equol is relatively stable however, it is not produced in all healthy adults in response to dietary challenge with soy or daidzein. Several recent dietary intervention studies examining the health effects of soy isoflavones allude to the potential importance of equol for obtaining maximal clinical responses to soy protein diets (Setchell et al., 2002b).

Folate homocysteine and cardiovascular disease CVD

Be associated with lower incidence of CVD. The consumption of fruit and vegetables has traditionally been associated with increased antioxidant intake (see sections 3.6, 3.15, 3.25) but green vegetables are also one of the main sources of folate, contributing more than 30 of total dietary folate intake.

Aspartyl protease See aspartic peptidase

Astaxanthin 3, 3'-Dihydroxy-4,4'-diketo-b-carotene A naturally occurring red carotenoid pigment with antioxidant properties. Most crustaceans are tinted red by accumulated astaxanthin, and the pink flesh of a healthy salmon is due to accumulated astaxanthin. This is added to feed in fish farms to substitute for the astaxanthin in the diet of a wild salmon.

Why paraquat is poisonous

Paraquat is also able to exist in a form called a free radical. These are normally very reactive forms of chemicals, but in the case of paraquat it is stable. Free radicals react with oxygen and convert it into a reactive form. There are high levels of oxygen in the lungs and hence paraquat is able to produce a lot of reactive oxygen. The result is that the lung cells are destroyed by this reactive oxygen and, while the lungs have a natural protection against the reactive oxygen that is always being produced in small quantities by normal processes, large amounts overwhelm the protective mechanism.

BElimination and disulfide exchange

May contribute to other degradation pathways.2 Degradation of rhM-CSF under alkaline conditions is believed to take place by a p-elimination mechanism that involves parallel cleavage and intramolecular cross-linking reactions.62 The generation of the free thiols by p-elimination may in turn catalyze disulfide interchange. Disulfide exchange may also result because of the presence of unpaired cysteine residues. These cysteine residues can react at different sites to form new disulfide bridges, resulting in proteins with incorrect disulfide linkages and nonnative conformation. The reaction is base catalyzed and promoted by mercaptoethanol, which is sometimes used as an antioxidant. It can be prevented by thiol scavengers such as p-mercuriben-zoate, N-ethylmaleimide, or copper ions.261

Betacells pancreas fiCells See B cells of pancreas

Betalain Nitrogen-containing red or yellow pigments functionally replacing anthocyanins in flowers and fruits of many Caryophyllales (ice plants, cacti, carnations). Also found in some higher fungi, where their role is obscure. Are used for food colouring, and have antioxidant and radical scavenging properties that provide protection in certain oxidative stress-related disorders

Other minerals iodine and selenium

Selenium, in the form of the unique amino acid selenocysteine, is the co-factor in several important functional metalloproteins. At physiological pH, the selenium in the selenocysteine is almost totally ionised and is an extremely efficient redox catalyst. At least 30 selenoproteins have been shown to occur in mammalian cells. Several of these have been fully characterised and their functions determined in human tissues. One group, the glutathione peroxidases, plays a role in intracellular antioxidant systems. Selenium is also an essential cofactor in the iodothyronine deiodinases, which are enzymes involved in thyroid hormone metabolism. Another important selenoenzyme is thioredoxin reductase which helps to control cell growth and division. Several other selenoproteins, including selenoprotein P and selenoprotein W, also occur in human tissues where they appear to have antioxidant and redox roles (Arthur and Beckett, 1994).

The nutritional role of copper

Antioxidant defence Antioxidant defence Antioxidant defence and or copper sequestration Ferroxidases I and II are plasma glycoproteins. Ferroxidase I, also known as caeruloplasmin, oxidises Fe (II) to Fe (III) without formation of hydrogen peroxide (H2O2) or oxygen radicals. It is primarily this role which gives rise to caeru-loplasmin's well-known antioxidant function. It also scavenges H2O2, superoxide and hydroxyl radicals, and inhibits lipid peroxidation and DNA degradation stimulated by free iron and copper ions.4 Caeruloplasmin is also an acute-phase protein in acute response to inflammatory cues caeruloplasmin concentration rises, binding free circulating iron and limiting the amount available to participate in oxidative reactions. One molecule of caeruloplasmin contains six copper ions, of which three provide active sites for electron transfer processes, while the remaining three together form an oxygen-activating site for the enzyme's catalytic action.5 Superoxide dismutase...

Dideoxycytidine ddC See zalcitabine dideoxyinosine ddl See didanosine

Diet supplements There are many different causes for nutrient deficiencies in people living with HIV the high demand for antioxidants, the increased metabolism that begins in the earliest disease stages, malabsorption because of damage to the intestines, decreased intake of food because of mouth or throat problems, loss of appetite, loss of taste, fever, nausea, and vomiting. The resulting deficiencies are often of important nutrients critical for supporting immune function. The use of antibi

Supplementing Dietary Supplements Nutrient Boosts

One important nutrient is tocopherol (vitamin E), an antioxidant naturally synthesized only in the chloroplasts of photosynthetic organisms. The RDA for tocopherol is 7 9 mg, an amount readily obtained from a diet rich in leafy vegetables, grains, and vegetable oils. However, 10 100 times higher daily intakes of tocopherol have been associated in some scientific studies with decreased risks of various chronic disorders and degenerative diseases. Such

Inflammationdependent Oxidative Stress In The

Figure 6 presents in simplified form the rationale of why brain is considered to be susceptible to oxidative stress (12). Brain is enriched in the more easily peroxidizable fatty acids (20 4 and 22 6), consumes an excessive fraction (20 ) of the total oxygen consumption for its relatively small weight (2 ) and is not particularly enriched in antioxidant defenses. In fact, brain is low in catalase activity containing about 10 of liver catalase. Additionally, human brain has higher levels of iron (Fe) in certain regions and in general has high levels of ascorbate. Thus, if tissue organizational disruption occurs, the Fe ascorbate mixture is expected to be an abnormally potent pro-oxidant for brain membranes (12).

Oxidative Stress and Glia

Free radicals and ROS (radicals derived from oxygen) are atoms or groups of atoms that are highly reactive with other cellular molecules because they contain unpaired electrons. As ROS and other free radicals react with cellular molecules, they lead to injury and may even cause cell death. ROS and other free radicals may also trigger activation of various proteins that in turn activate the inflammatory response. The concept of ROS and free radical toxicity actually has its roots in inflammation biology (12). The secretion of reactive oxygen and nitrogen free radical species by inflammatory cells is a major mechanism for attacking a noxious or foreign agent or an injurious process (Figure 7). For example, in response to several factors including pro-inflammatory cytokines, glia (microglia and astrocytes) are capable of producing large amounts of nitric oxide due to their increased expression of inducible nitric oxide synthase (iNOS). Antioxidant Capacity oxidant peroxynitrite (ONOO)...

Box 165 Mutations Can Happen Without Any Help From Environmental Exposure

We cannot simply blame our load of mutations on exposures to things around us. A certain amount of mutation goes on no matter what we eat or drink, apparently as a simple result of the rate of errors made by the machinery of the cell as it copies the DNA. Even the most pristine lifestyle will not protect against the fact that the natural machinery by which the genetic blueprint replicates has built into it limits on how perfectly it can carry out its copying functions. As the polymerase moves along the DNA making a new copy, it must correctly read a base and put its correct complement into place, every time, over and over again, for more than a billion bases of sequence if it is going to correctly replicate the entire genome once without making any mistakes. Frankly, without any exposure to chemicals or radiation at all, sometimes the polymerase gets it wrong. At some points in the DNA, the rate at which polymerase makes errors is increased because a naturally occurring chemical...

Fosamprenavir See amprenavir

Free radicals A highly reactive molecular fragment that bears one or more unpaired electrons. For some time, it has been known that foods contain more substances than just vitamins and minerals and energy-giving nutrients. There are known nutrient antioxidants like vitamins E and C and selenium, and there are the new nonnutrient antioxidants like the carotenoids, the phytochemi-cals, and the polyphenols. These substances aid in removing molecules that attack healthy cells in the body and leave it vulnerable to cancer. The oxygen we breathe and cannot live without can become one of our worst enemies. Excess oxidation is damaging and destructive to the body. Four destructive forms of oxygen have been identified hydroxyl radical and superoxide radical (the two real free radicals) and the nonradical reactive species oxygen singlet and hydrogen peroxide. Destructive oxygen reactions have been linked to at least 50 diseases, including AIDS. oxygen reactions take place when an oxidant or...

Seminal plasma factors that affect sperm motility

Antioxidants, such as superoxide dismutase, catalase (low levels), vitamins C and E and small sulfhydryl-containing molecules (glutathione) (de Lamirande and Gagnon, 1999 Zini et al., 1993), protect spermatozoa from oxidative stress and related loss of motility (de Lamirande and Gagnon, 1992a, b de Lamirande and Gagnon, 1999 chapter by Aitken in this book). High levels of immunosuppressors, such as proteasomes, polyamines (spermine and spermidine) and transforming growth factor- , are also present in seminal plasma and protect spermatozoa from a loss of motility during infection (Kelly, 1999).

Bcl2 and related genes in the regulation of apoptosis

This is supposed to be the result of deregulation of the bcl-2 Ig fusion gene. But T-cell lymphomas which do not show this translocation do express bcl-2 protein (Pezzella et al., 1990 Kondo et al., 1992), albeit at a lower level than Bcell lymphomas (Zutter et al, 1991). Therefore, there might be other mechanisms by which bcl-2 expression is deregulated. Two bcl-2 proteins, bcl-2a and bcl-2 , produced by mRNA splicing have been identified (Seto et al, 1988). The bcl-2 protein is associated with the inner and outer mitochondrial membranes (Hockenbery et al., 1990 Monaghan et al., 1992 Nakai et al., 1993 Nguyen et al, 1993a Lithgow et al., 1994). However, apoptosis can occur in human mutant cell lines that lack mitochondrial DNA and can be protected from apoptosis by an over-expression of bcl-2 protein. Apoptosis also occurs in anucleated cytoplasts and is prevented by bcl-2 overexpression (Jacobson et al., 1993, 1994). This suggests that the bcl-2 protein may occur at several...

Predicting And Testing For Genotoxic Substances

The ability to predict and test for genotoxic substances is important in preventing exposure to these substances. One way in which this is done is by the use of structure-activity relationships (see Section 7.1). Several classes of chemicals are now recognized as being potentially genotoxic (mutagenic) based on their structural features.2 These are summarized in Figure 8.4. The single most important indicator of potential mutagenicity of a compound is electrophilic functionality showing a tendency to react with nucleophilic sites on DNA bases. Steric hindrance of the elec-trophilic functionalities may reduce the likelihood of reacting with DNA bases. Some substances do not react with DNA directly, but generate species that may do so. Compounds that generate reactive free radicals fall into this category.

Treating Huntingon Disease

Current options for treating Huntington disease are very limited. Anti-dopaminergic agents are used to try to treat the choreiform movements, and antidepressants and antipsychotics help treat the psychiatric manifestations of the disease. Elevated calorie intake helps fight the typical weight loss, and physical therapy provides further assistance with movement problems. However, none of the current treatments can stop the pathologic processes of the disease itself, which advances through an inevitable progression of cell death among neurons in specific regions of the brain that affect movement and cognitive functions. Past efforts to stem disease progression through use of antioxidant therapies have failed.

Proteasome Inhibitors Delay Cell Death

To answer the question of whether the neuroprotective effects of protea-some inhibitors were correlated with the inhibition of classical markers of apop-tosis, we determined the activity of caspase-3 in CGCs deprived of potassium. These drugs were able to prevent caspase-3 activity and pro-caspase 3 activation, suggesting that proteasomes control the activation of caspase(s) (Figure 1). Accordingly, events such as calpain caspase-mediated cleavage of tau (21, 10), Reactive Oxygen Species (ROS) production, DNA laddering and the onset of a deficit of the antioxidant system normally occurring downstream of caspase activation were also prevented (22, 20) (Figure 1). Activation of caspases in CGCs occurs mainly through the intrinsic pathway, in which mitochondrial perturbation causes cytochrome c release in the cytosol to form the apoptosome, the promoter of the caspase cascade. We found that proteasome inhibitors were able to interfere with cytochrome c release (23) (Figure 1), suggesting...

How does the Proteasome Mediate the Early Steps of Neuronal Apoptosis

This drawing depicts the series of known or hypothetical events occurring in cerebellar granule cells following the apoptotic trigger. The black arrows point out the established findings underlying the role of UPS in the sequence of events leading to caspase activation, and subsequently DNA laddering, tau cleavage, ROS production, and antioxidant system failure. Gray arrows indicate the hypothesized events linked to UPS activation during the course of apoptosis and ( ) indicates that the direct or indirect involvement of UPS in the decrease of p27 during CGCs apoptosis has not been investigated. The panel visible in the central part of the figure shows an immunofluorescence analysis of cleaved, activated caspase-3 (black) in control cells (a) or in potassium-deprived cells, in the absence (b) or presence (c) of the UPS inhibitor lactacystin. Notice the presence of 3 apoptotic neurons in which the staining of activated caspase 3 is clearly visible (b) and that in the presence...

Electrode Biocompatibility

What Kind of Electrode Array and Attachment Methods Should be Used for Minimizing Any Possible Damage to Neural Tissue The biocompatibility between an implanted medical device and the host tissue is as important as its mechanical durability and functional characteristics. This includes the effects of the implant on the host and vice versa. Effects of the implant on the tissue include inflammation, sensitivity reactions, infections, and carcinogenicity. Effects of the tissue on the implant are corrosion and other types of degradation. Sources of toxic substances are antioxidants, catalysts, and contaminants from fabrication equipment.

Treatment after device placement

In the early days of weaning, the additional administration of antioxidants, enzymes (brome-laine, trypsine, rutoside), phospholipids, and fatty acids (omega-3 fatty acids) was regarded as un-proven adjuvant supplementation however, the number of articles has dramatically increased that certify favorable effects on cardiac function and oxidative stress reduction 46-62 . As heart failure per se is correlated with a high degree of oxidative stress, the use of a mechanical assist device enhances that further. According to the still preliminary experience, the nutritional supplementation reduces the number of infections and possibly the number of thromboembolic events, makes the blood cells shear stress resistant, improves the rhe-ology by cell membrane stabilization, and reduces the proinflammatory cytokines 63-65 .

Prevention Of Type 2 Diabetes

Interventions have been targeted at altering a number of behavioral factors including obesity, dietary intake and physical activity. Obesity, of course, should be considered the result of behavioral, genetic and physiological factors and not simply behavioral. Pharmacological interventions have primarily used hypoglycemic or anti-hyperglycemic medication to reverse insulin resistance (biguanides, thiazolidenediones), failure of insulin secretion (sulfonylureas), or glycemic excursions (alpha-glucosidase inhibitors). Trials have attempted to alter glucose metabolism using metal supplementation (magnesium, chromium) or antioxidants (beta-carotene, vitamin E). Trials that have used

Origins of oxidative stress associated with defective sperm function

The oxidative damage detected in human spermatozoa may originate from several potential sources. Firstly, the leucocytes that contaminate every human semen sample are largely comprised of neutrophils that are commonly in an activated state. Thus the levels of spontaneous luminol-dependent chemiluminescence recorded in (unfrac-tionated) human semen samples are highly correlated with the levels of leucocyte contamination (Aitken et al., 1995a Fig. 7.5). The presence of free-radical generating leucocytes in human ejaculates might therefore create a degree of oxidative stress. Much depends on the types of leucocytes that are present, their state of activation and their origin (Aitken and Baker, 1995). If the leucocytes originate in secondary sexual organs, such as the prostate and seminal vesicles, then their ability to cause oxidative damage to the spermatozoa will be counteracted by the powerful antioxidant properties of human seminal plasma. These antioxidants include small molecular...

The physiological role of ROS

The precise nature of the ROS triggering this cascade is still uncertain. A pivotal role for H2O2 generation has been suggested by experiments demonstrating that direct addition of this oxidant to suspensions of human, hamster or bovine spermatozoa, leads to the stimulation of tyrosine phosphorylation and capacitation (Aitken et al., 1998b Bize et al., 1991 Rivlin et al., 2004). Similarly, the artificial creation of oxidizing conditions by exposing spermatozoa to extracellularly generated ROS using the glucose oxidase or xanthine oxidase systems, has been shown to stimulate capacitation and tyrosine phosphorylation in several species (man, hamster, bull and horse) via mechanisms that can be reversed by the addition of catalase (Aitken et al., 1995b Baumber et al.,2003 Bize et al., 1991 Rivlin et al.,2004). Even the incubation of spermatozoa in the presence of phorbol ester-activated leucocytes has been shown to stimulate human sperm capacitation via mechanisms that can be reversed by...

Other pharmacokineticpharmacodynamics considerations

The possibility of targeting of protein drugs to the liver nonparenchymal cells by direct succinylation has also been investigated because the liver sinusoidal cells have scavenger receptors for polyanionic macromolecules. The proteins SOD, BSA, and uricase (UC) were succinylated to get Suc-BSA (70 kDa), Suc-UC (130 kDa), and Suc-SOD (34 kDa). All succinylated proteins had pi values of less than 4.0. It seems that proteins with a molecular weight greater than 70 kDa can be targeted to the liver via direct succinyla-tion, but some sulfated polysaccharides such as dextran sulfate (DS) (8 kDa) have a large CLliver value regardless of molecular weight. Targeting of the antioxidant enzyme SOD to the liver nonparenchymal cells would be useful clinically for hepatic diseases mediated by reactive oxygen species.25

Answers and Discussion

Q1. (Answer d) Ascorbic acid is a potent reducing agent. It has been shown to convert chromium VI to chromium III in the gut and in the bloodstream. When this conversion occurs in the gut, it is beneficial because it leads to a reduction in chromium absorption. Chromium VI is absorbed 20-fold more extensively than chromium III. In the blood, chromium III binds to protein and the resulting complex is excreted in the urine. Q2. (Answer c) Some of the absorbed chromium VI is reduced to chromium III which is, in turn, excreted. There is a limited capacity for this reduction and the excess chromium VI enters cells and produces free radicals as it undergoes intracellular reduction. Lipid peroxidation, with its associated cell membrane destruction, is just one of the deleterious effects of free radical formation.

The protective effects of alcoholic drinks

It seems clear that alcohol reduces the level of 'bad' cholesterol in the blood (known as LDL) while increasing the level of 'good' cholesterol (HDL). It dilates blood vessels and lowers blood pressure (but chronic alcohol intake increases it). A decrease in colon cancer and Alzheimer's disease have also been associated with moderate drinking. There is evidence, in particular, that one or perhaps two glasses of red wine a day may be beneficial. This is the so-called 'French paradox', for the level of heart disease in France is one of the lowest in the world despite a diet traditionally rich in animal fats. The French also drink more red wine than other countries, and evidence seems to suggest that components in the grapes, polyphenols such as resveratrol, may be partly responsible for the low level of heart disease. One theory put forward is that this is due to the antioxidant effects of the polyphenols. Antioxidants such as vitamins C and E can react with and remove reactive...

Chromium Supplementation And Cardiovascular Disease Risk

The observations reported for the HPFS cohort appear to be consistent with observations reported from the European Community Multicenter Study on Antioxidants, Myocardial Infarction, and Breast Cancer (EURAMIC). The EURAMIC was an incident, population-based, case-control study conducted in eight European countries and Israel to determine whether low toenail chromium concentrations are significantly associated with increased risk for MI. The study included 684 case subjects (men with a first diagnosis of MI within 24 hours of admission to the hospital) and 724 control subjects (men with similar demographic characteristics, but without MI). Average toenail chromium was 1.10mg kg in the case subjects versus 1.30mg kg in the control subjects. Additional analysis indicated that the adjusted ORs for MI for chromium quintiles 1-5 were 1.00, 0.82, 0.68, 0.60, and 0.59, respectively 77 . The results of EURAMIC thus indicate that toenail chromium concentration has a clearly inverse relationship...

Metabolic transit and in vivo effects of Maillard reaction products

11.6.2 Antioxidant activity An important primary effect of browning is the formation of antioxidants, compounds that are able to delay or prevent oxidation processes, typically involving lipids. Such antioxidants greatly affect the shelf-life of foods but may also benefit health (Halliwel, 1996), especially in the prevention of cancer (Kim and Mason, 1996), cardiovascular disease (Maxwell and Lip, 1997) and ageing (Deschamps et al, 2001). The formation of antioxidants in browning has been observed in several different systems, for example sugar amino acids model systems (Lignert and Eriksson, 1981), model melanoidins (Hayase et al, 1990), and honey lysine model systems (Antony et al, 2000). They have also been seen in heated or roasted foods, such as coffee brews (Nicoli et al, 1997). However, the processing conditions should be chosen very carefully in coffee, for example, the antioxidant activity increases with roasting up to the medium-dark roasted stage, then decreases with...

Formation of toxic compounds

AIAs are also referred to as thermic mutagens because they are formed at temperatures used during ordinary cooking and were first isolated from cooked meat and fish. Since they are very mutagenic, much attention has been applied to their determination in foods. They are characterised by the presence of a 2-amino-imidazo group, indispensable for genotoxic mutagenic activity, and derive from the condensation of creatine with an aldehyde, coming from the Strecker degradation, and a pyrazine or pyridine. There are indications that free radicals may be involved (Pearson et al, 1992). Phenylalanine and creatine are the precursors of PhIP (Felton and Knize, 1991).

In Vivo Nonenzymatic Chemical Modification

Oxidation of proteins occurs in vivo with generally unfavorable consequences. For example, the oxidation of the active-site methionine residue in alpha-1-antitrypsin (alpha-1-antiprotease inhibitor) results in pulmonary damage.157-159 Methionine is quite susceptible to oxidation, first to the sulfoxide, a reversible reaction, and to the sulfone (Figure 2.35).160161 A wide spectrum of oxidizing agents exists including free radicals such as hydroxyl radical,162163 organic peroxides164 and hypochlorites (Figure 2.2).165 Organic peroxides are most notable as lipid peroxides observed in oxidative stress.166167 Hypochlorites can be formed by the action of myeloperoxidase and may be responsible for protein oxidation in atherosclerosis and Alzheimer's disease.168169 Oxidative covalent modifications of proteins are also suggested to be signals for degradation.170

Free Radical Formation

The energy demands of cardiac pumping require that oxidative phosphorylation supplies most of the needed energy. Utilization of molecular oxygen leads to the formation of highly reactive oxygen-derived free radicals. There are mechanisms in place that inactivate many of the free radicals produced by metabolism and, thus, protect cells from oxidative injury. Components of the antioxidant defense system include glu-tathione-glutathione peroxidase, superoxide dismutase, catalase, ascorbic acid (vitamin C), and alpha-tocopherol (vitamin E). It is beyond the scope of the present discussion to expand on the actions of each of these antioxidant mechanisms however, one must emphasize that some cardiotoxins act at the level of interference in this normal method for oxidant removal. Again, specific examples are discussed below.

Improvement of endothelial function

Endothelial dysfunction leads to defects in insulin-mediated glucose uptake. Blockade of vascular nitric oxide synthesis with L-arginine analogue also impairs endothelial dependent va-sodilation. Endothelial function improves with exercise, a low-fat, low-carbohydrate diet, and with use of statins and ACE inhibitors (Table 5) 29,59,67 . Angiotensin I blockade has not shown any improvement of endothelial dysfunction, but benefit has been noted with peroxisome pro-liferator activated receptor gamma (PPAR-y) stimulator, antioxidants, hormone replacement therapy, and L-arginine 66,68,69 . In addition, the ACE inhibitor quinapril significantly improved endothelial function in multiple studies, both in normotensive volunteers and in subjects with coronary artery disease 70-77 .

Sources of further information and advice

To technology', Food Rev Int, 9, 629-55 andrieux c and sacQuet e (1984), 'Effects of Maillard's reaction products on apparent mineral absorption in different parts of the digestive tract. The role of microflora', Reprod Nutr Develop, 24, 379-82 andrieux c, sacQuet e and gueguen l (1980), 'Interactions between Maillard's reaction products, the microflora of the digestive tract and mineral metabolism', Reprod Nutr Develop, 20, 1061-9 anese m, manzocco l, nicoLi m c and Lerici c r (1999), 'Antioxidant activity of tomato FuRth A j (1997), 'Glycated proteins in diabetes', Brit J Biomed Sci, 54, 192-200 geRmond j e, phiLippossiAn g, RichLi u, bRAcco i and ARnAud m j (1987), 'Rapid and complete urinary elimination of 14C -5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats', J Environm Health, 22, 79-89 gRosch w (1987), 'Reaction of hydroperoxides - products of low molecular weight', in Chang H W-S, Autoxidation of Unsaturated Lipids, London, Academic Press, 95-140...

Ischemia Reperfusion Injury

Tissue ischemia and reperfusion involve complex mechanisms that have not yet been completely identified or understood. However, reperfusing tissues after acute ischemia initiates changes in local vascular tone, coagulation, and biochemical, molecular, and cellular alterations that are collectively called ischemia-reperfusion injury. 18,19 The activation of neutrophil granulocytes by oxygen-free radicals and consecutive endothelial injury are the central processes in ischemia-reperfusion injury.20,21 Neutrophil activation and up-regulation of corresponding receptors in the postcapillary venules leads to adhesions between white cells and endothelium, which can be visualized by in-vivo microscopy as leukocyte sticking and rolling. Segmental vessel occlusion occurs as a result of this leukocyte-endothelium interaction, leading to leukocyte migration into tissue, increased production of oxygen-free radicals, and tissue-damaging enzymes. The lack of venous reflow occurs in tissues after...

Regulated Induction of Peroxisomal Proliferation

Enlarged and usually elongated peroxisomes may be formed from preexisting peroxisomes in several organisms, including plants, under regulated induced conditions such as changes in cell culture medium and density, growth factors, increased irradiance, ureide production, hypolipidemic drugs, fatty acids, increased free radicals (hydrogen peroxide, ozone) (black arrow, Fig. 1). Isoforms of Pex11 proteins and various types of dynamin-like proteins are involved in these induction pathways (Koch et al. 2004 Thoms and Erdmann 2005). Schrader et al. (1998) concluded that certain Pex11 forms promote elongations in the induction pathways, whereas other Pex11 forms stimulate elongation in the constitutive pathway. Although Pex11 proteins induce peroxisomal elongation prior to peroxisomal division, they are themselves not mechanically involved in the peroxisomal fission process.

Mechanism Of The Effect Of Diet On Carcinogenesis

Studies performed to address these questions have provided conflicting results. In the rat PC model, like the mammary cancer model,15-17 voluntary exercise reduced the growth rate of induced lesions,16,18 whereas in the hamster-BOP (N-nitrosobis-2(oxopropyl)amine) model exercise had no effects on tumor yield.19 Several studies in the rat PC model examined the role of an HF diet on lipid peroxidation and the generation of free radicals. In the rat model, feeding high levels of Vitamin C, p-carotene, and selenium reduced the incidence of pancreatic tumors, whereas, Vitamin E was ineffective.20 In the hamster model, dietary supplementation of Vitamin C, p-carotene, Vitamin E, or selenium, either alone or in combination, had no effects in the hamster.21 The results contrasted with another study showing a significant inhibitory effect of Vitamin A and Vitamin C22 and a promoting effect of high doses of selenium on tumorigenesis in the hamster model.23 Also, the effect of...

The Role of Nitric Oxide in Preconditioning

The above studies confirm the results of other authors, although Oshima's conclusion was highly speculative. Moreover, NO is involved in the natural defense against ischemia reperfusion injury but not in inducing it. Other studies report a possible cytotoxic action for NO because it damages hydroxyl-free radicals in models of

Dietary CrIii And Free Radical Scavenging Ability

Earlier studies have demonstrated perturbed glucose insulin metabolism is associated with augmented formation of free radicals 67 . Free radicals have the ability to attack vital cell components, injure cell membranes, inactivate enzymes, and damage the genetic material in the cell nucleus 67 . Augmented free-radical formation and enhanced lipid peroxidation are not uncommon in diabetes mellitus 45, 67 . Chromium(III) has been postulated to be an antioxidant, beneficial in the treatment of hypertension. Chromium(III) therapies influencing the glucose insulin system and age-related hypertension have been shown to also lower free radical formation 45 . In spontaneously hypertensive rats, niacin-bound chromium supplementation decreased lipid peroxidation by altering free-radical formation measured, determined by thiobarbi-turic acid reactive substances (TBARS) 45, 46 . Preuss et al in 1997 examined several chromium compounds to determine their efficacy in regulating blood pressure of...

Nutrient deficiency 345

Nutrient deficiency There are many causes of nutrient deficiency in people living with HIV, including malabsorption because of damage to the intestines (by HIV or other infections) the high demand for antioxidants the increased metabolism that begins in the earliest disease stages and decreased intake of food because of mouth or throat problems, loss of appetite, loss of taste, fever, nausea, and vomiting. The resulting serious deficiency of nutrients critical for supporting immune function, and malnutrition, are common among people with HIV and frequently contribute to the development of opportunistic infections and general deterioration that are the immediate causes of death.

The effects of irradiation on food

The interaction of ionising radiation with matter takes place by means of a cascade of secondary electrons carrying enough kinetic energy to cause ionisation of atoms and molecules and the formation of free radicals. Besides these direct effects and primary chemical reactions chain reactions of secondary and indirect transitions take place. In systems as complex as food and for biological systems usually high in water content most primary reactive species are formed by the radiolysis of water and the pathways of further reactions largely depend on composition, temperature, dose rate and relative reactivities. Only for a few very simple single-component models have the full pathways of reactions been identified for highly complex systems a complete picture has not yet been achieved. Nevertheless, some aspects of the picture are beginning to emerge, especially with regard to the main components, i.e. carbohydrates, lipids and proteins. The effects of radiation on micronutrients, in...

Health Impairing Oxidation Products 1331 Oxidized Lipids

Lipids are the food components that are most prone to oxidation. In food systems, oxidation of lipids starts as autoxidation, photooxidation, or lipoxygenase-catalyzed reactions, depending on the properties of the product and conditions of storage or processing (Kolakowska, 2002). The factors that affect the rate of oxidation of lipids in foods are high temperature, light, and the presence of oxygen and prooxidants. Polyenoic fatty acids oxidize at a very much higher rate than monoenoic fatty acids. Natural and added antioxidants, acting through various mechanisms, decrease the rate of reaction.

Protein Oxidation Products

Oxidative changes also contribute to the loss of sensory and nutritional quality of protein-rich foods. During processing and prolonged frozen storage, the food proteins may be oxidized due to the activity of singlet oxygen (1O2), superoxide anion radical (O2 '), and hydoxyl radical (' OH). These reactive oxygen species are formed by enzymatic processes and catalytic action of cations, light, and ionizing radiation. Lipid radicals and lipid oxidation products also have an important impact. In some foods, the residues from H2O2 used in processing may oxidize the proteins. Polyphenols are readily oxidized to quinones by oxygen at neutral and alkaline pH. The quinones act as strong oxidizing agents in different products. The rate of change in proteins is controlled by the activity of the oxidizing agents and inhibitors, the presence of sensitizers, e.g., chlorophyll, methylene blue, erythrosine, and riboflavin, different prooxidants and antioxidants, temperature, and the sensitivity of...

The safety of microwaveheated food

Prejudice and lack of technical understanding are causes of unfounded allegations that food heated by microwave might become toxic and exotic chemical compounds could be formed. However, microwave radiation cannot break chemical bonds and cannot cause ionisation nor create free radicals. Here there is an essential difference from ionising radiation which has a quantum or photon energy that is larger by several orders of magnitude. For this reason the possibility of induced chemical reactions other than thermal ones is nonexistent. This has been confirmed by many studies and it has been possible to attribute any par

Cf And Pancreatic Cancer

Although we may consider that CF has a link with cancer development, the question arises whether it is directly related to some not yet recognized functions of CFTR or is due to chronic disease conditions. To date, we do not have direct evidence that can relate the CFTR defect with cancer development. Moreover, almost all the cases have been recognized later in life, denying a direct involvement of CFTR with carcinogenesis.55,58,59 Therefore, it seems likely that cancer progression is secondary to the long-term disability of CFTR. The enhanced risks of organ-specific cancer (e.g., digestive tract cancer) in CF patients may be related to the differential expression patterns of CFTR gene in different body organs and to the susceptibility of that organ to damage by CFTR dysfunction. Pancreatic ducts and other digestive tissue (bile ducts, intestinal crypts, etc.) express high levels of the CFTR protein in comparison to several other body organ tissues. Furthermore, persistent pathologic...

Selective serotonin reuptake inhibitor SSRI A

Selenium A chemical element resembling sulfur. It is poisonous to certain animals that feed on plants grown in soil that contains an excess of it. Selenium is one of several antioxidants that people with HIV are often advised to take because of serious deficiencies and increased need for a number of nutrients.

The Effect Of Other Chemical Reactions

In meat curing, nitrite is traditionally used for developing the pink, heat-stable pigment. Its other important role is the inhibition of the outgrowth of Clostridium botulinum spores in pasteurized products and, in some countries, in several types of smoked fish. Nitrite also serves as an antioxidant and contributes positively to the development of the flavor of cured-meat. The undesirable side-effect, however, is the reaction of nitrite with amino groups of food constituents, leading to the formation of NNCs.

Endogenous Substances Toxic To Pancreatic Pcells

Studies have shown that pancreatic islet cells contain relatively small amounts of the antioxidant enzymes, such as CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase, and glutathione peroxidase.149,209 Due to the low level of antioxidant enzyme expression and activity, p-cells are at a greater risk of oxidative damage than other tissues with higher levels of antioxidant protection. Hence, the p-cell is an easy target for ROS. Thus, Robertson et al.207 hypothesized that chronic oxidative stress is an important mechanism for glucose toxicity. The observations that hyper-glycemia increases the intraislet peroxide levels provided further evidence It has been shown that both rat and human p-cells express high affinity receptors for low density lipoprotein (LDL) and very low density lipoprotein (VLDL), which can internalize both lipoproteins.222 The possible role of these lipoproteins was examined by the same group and was found that the uptake of LDL by islet p-cells and...

Drugs Of Natural Origin

The flavan-3-ols (+)-catechin and (-)-epicatechin are among these important dietary constituents owing to their potent antioxidant and anti-inflammatory properties 38 . These compounds usually occur together in plants. Nowadays, separation of catechins most often is achieved with such methods as HPLC or CE. For example, a micellar electrokinetic chromatography method was developed for the separation of (+)-catechin and (-)-epicatechin in Theobroma cacao beans. The method also proved suitable for the enantioseparation of ( )-catechin 39 .

Monomers Oligomers and Other Starting Substances 14321 Bisphenol Type Contaminants

Bisphenol A (BPA) (Figure 14.1a) is a starting substance utilized in the manufacture of most types of epoxy resins, which are then crosslinked and used to coat food cans. Another application of BPA is in the manufacture of plastic materials, in particular polycarbonates. BPA serves also as an antioxidant or stabilizing material for many types of plastics, e.g., polyvinyl chloride (PVC).

Toxicological And Carcinogenetic Effects Of CrIII

Chromium supplements have been shown to generate reactive oxygen species (ROS) in cells 27-29 . Reactive oxygen species are oxygen-containing and highly reactive molecules with unpaired electrons formed during oxidative metabolism. These species include the superoxide anion (O -), the hydroxyl radicals (*OH), and hydrogen peroxide (H2O2). Considerable evidence has shown that ROS play an important role in the initiation of cellular injury which can lead to the development of cancer. Chromium picolinate had greater effects than Cr nicotinate in cultured macrophage J774A.1 cells 29 . In addition, an increase of lipid peroxidation and generation of DNA fragmentation were also found by both supplements 29 . Mitochondrial damage and apoptosis were observed when Chinese hamster ovary (CHO) cells were exposed to Cr picolinate 30 . In another comparative study of Cr picolinate and niacin-bound Cr(III), it was revealed that Cr picolinate produced significantly more oxidative stress and DNA...

Studies examining nonglycemic therapies

Finally, a related topic is whether antioxidant vitamins, B-vitamin supplementation to lower homocysteine, or various fatty acids can promote CV health in diabetes mellitus. All have been associated with lower risk in epidemiologic analysis, although no consistent findings have emerged from large-scale randomized trials in people who have diabetes mellitus 42-44 . The ORIGIN trial will evaluate the effect of omega fatty acids in patients who have diabetes mellitus and predia-betes and CVD risk factors ASCEND (A Study of Cardiovascular Events in Diabetes) also will do so in patients who have diabetes mellitus in the setting of primary prevention in a 2 x 2 factorial design in which the second randomization will be to aspirin, 100 mg d, versus placebo 45 . SEARCH and HPS II will randomize subjects to various vitamin supplements or placebo to examine whether these relatively inexpensive interventions provide clinical benefit to reduce CVD as well.

Lipidrelated biomarkers Myeloperoxidase

Been assumed that the physiological role of this enzyme could be considered as part of the innate immune system and therefore consist in the host defense against infection, taking into account very potent bactericidal and viricidal properties of MPO. Indeed, generation of free radicals and diffusible oxidants by catalyzation of chloride and hydrogen peroxide (H2O2) to hypochlorous acid (HOCl) represents a major source of its antimicrobial activity, presumably by oxidizing key functional components of ingested microorganisms (182). MPO is only one enzyme known to generate HOCl in vivo. However, the fact that under certain circumstances MPO-derived reactive oxidizing and chlorinating species can overwhelm local antioxidant defenses and therefore might lead to oxidative damage of the arterial wall have highlighted their possible proathero-genic role.

Hydroxytryptamine2 Receptors

One group has used proteomic methods to demonstrate that the 5-HT2A receptor (or fusion protein derived from it) can bind to multiple cellular proteins (Table 2) (238,239). Many of those proteins are important for subcellular targeting or trafficking. Putative 5-HT2A receptor-interacting proteins include multi-PDZ-domain protein (MUPP1), activin receptor-interacting protein 1, SAP97, PSD-95, membrane protein palmitoylated 3 (MPP-3), and channel-interacting PDZ protein (CIPP), all of which interact through the PDZ domain on the carboxyl terminus of the receptor, and antioxidant protein 2, which interacts with the carboxyl terminus of the 5-HT2A receptor through a PDZ-independent mechanism (238,239). The functional significance of these interactions remains to be defined, although it is known that MUPP1 binding to the 5-HT2C receptor regulates receptor phosphorylation and resensitization (240,241).

Biochemical Basis Of The Responses

Exposure to different types of oxidative agents. The induction of some key proteins in response to oxidative stress has been known for some time. For example, SOD activity increases in E. coli that is grown in high levels of oxygen or exposed to the redox-cycling agent paraquat. Paraquat also induces glucose-6-phosphate dehydrogenase, evidently to replenish NADPH used up in antioxidant reactions (e.g. by GSH reductase). Exposure to H2O2 induces catalase activity in many organisms and increases GSH reductase levels in E. coli and S. typhimurium. We now know that these inductions reflect the activation of coregu-lated groups of genes affecting the expression of many additional proteins.

Pharmacological interventions

Thiazolidinediones (TZDs) reduce insulin resistance in the peripheral tissues. This allows the effects of decreasing insulin resistance on vascular function to be studied. Activation of PPARy within endothelial cells may explain why TZDs appear to bolster antioxidant activity. This reduction in oxidative stress is thought to be responsible for a decrease in inflammation, improvement of endothelial function and VSMC proliferation (Gonzalez and Selwyn, 2003). In vitro and in vivo studies have shown the potential of TZDs to prevent or delay atherosclerosis, and improvements have been noted in markers of endothelial function in parallel with improved insulin action (Caballero, 2003). Long-term trials with TZDs to measure cardiovascular end-points are in progress. Antioxidants and folate In theory, antioxidants should increase NO bioavailability, improve endothelial protection and function, reduce lipid peroxidation and reduce telomere shortening. Although observational studies of...

Basis For Agerelated Changes In The Proteasome

Increasing evidence suggests that oxidative damage to the proteasome complex may be a mediator of at least some forms of proteasome inhibition in the CNS. Studies from our laboratory demonstrate that dopamine may support ROS-induced impairment of proteasome function in the CNS(23). Several features of the CNS presumably make it very vulnerable to oxidative stress including the fact that the CNS has a high metabolic rate that may produce a higher level of mitochondrial derived ROS, may undergo age-related decreases in antioxidant levels, and has a high content of readily oxidized lipids that are capable of promoting oxidative stress. Post mitotic cells in the CNS, which survive for decades, are particularly susceptible to an age-related accrual and elevation in oxidative damage. Proteasomes can undergo direct oxidative modification by a variety of mechanisms. For example, peroxynitrite and HNE can be generated in the intraceullular environment and directly interact with the pro-teasome...

Vocational Rehabilitation Act of 1973 525

Is an antioxidant, which means it opposes oxidation of substances in the body. oxidation involves a compound called an oxidizer that attacks another compound, removing an electron from it. Vitamin E protects other substances by being oxidized itself, taking the brunt of any attack on lipids or other components of the membranes. Vitamin E prevents saturated fatty acids and vitamin a from breaking down and combining with other substances that may become harmful to the body. Fat oxidation results in the formation of free radicals. Free radicals are highly destructive molecules that can alter DNA and cause extensive damage to the body, from blood clots to cancer. The vitamin b complex and ascorbic acid are also protected against oxidation when vitamin E is present in the digestive tract. Fats and oils containing vitamin E are less susceptible to rancidity than those devoid of vitamin E. Vitamin E is also of great importance in energy production. It plays an essential role in the cellular...

Effects Of Proteasome Inhibition Within The

The clearance of oxidized proteins is an important means by which cells are able to prevent the increase in oxidative damage (most notably increased protein oxidation), and thus proteasome-mediated protein degradation is an important antioxidant (62-64). In this capacity the proteasome aids in preventing the elevation in oxidative damage and induction of oxidative stress. This antioxi-dant feature of the 20S proteasome is not only important in the aging of the CNS, but also is likely important in numerous age-related disorders of the CNS. Together, these data that there are multiple mechanisms by which protea-some inhibition can contribute to increased oxidative damage, and potentially the induction of oxidative stress. The ability of proteasome inhibition to induce so many disparaging effects should not be considered surprising when one considers the large number of proteasome substrates, and the likelihood that alterations in bulk protein turnover may impact multiple systems. The...

Toxicological Effects Of CrIII

A single acute oral dose of 895,000 gCr(III) kg to rats, as aqueous CrCl3, causes increases in several markers of oxidative stress 21 , but 5000 gCr(III) mL water as chromium acetate fed to mice for 17 months did not have any apparent toxic effects 16 . These findings indicate that the amount of orally ingested Cr(III) has to be relatively high to cause an oxidative stress that the body cannot handle and thus result in toxicological consequences. However, if Cr(III) is made more readily available for oxidation by direct administration to cells or intravenous injection in animals, amounts closer to physiological may induce free radicals that have pathological consequences. For example, daily injection of chromium picolinate for 60 days into rats in amounts about 20 times that entering the circulation in humans consuming commercial supplements (on a per kg body weight basis) significantly increased the urinary excretion of 8-hydroxydeoxyguanosine, a product of oxidative DNA damage 18 ....

Role Of Proteasome Inhibition As Mediator Of Aging

Successfully adapt to stressors and that the accumulation of adaptations alters cellular function in a manner that ultimately causes aging. In this model the pro-teasome serves as the trigger for the majority of age-related alterations. In young healthy cells there is considerable proteasome plasticity, allowing the cells to rapidly respond to stressors, and the proteasome providing a barrier of safety from the deleterious effects of cellular stressors. Following exposure to stress, in young healthy cells the proteasome becomes inhibited for a brief period, with proteasome capacity rapidly brought back to basal levels through a host of events including antioxidants, heat shock proteins, and proteasome plasticity. With continual adaptation to stress revolving around the capacity of cells to maintain proteasome function. In aging cells, the ability of the proteasome to regain its full capacity is impaired, thus allowing for the persistence of pro-teasome inhibition. Sustained proteasome...

Phase 2 Reversal Lipid Efflux

HDL also prevents LDL accumulation in the vessel wall by two principal mechanisms prevention of LDL oxidation and CAM downregulation. HDL hydrolyzes oxidized LDL, preventing LDL absorption via SRA and CD36 (70), and HDL also downregulates endothelial CAMs that could prevent monocyte entry into the vessel wall (71). Not only does HDL have a high antioxidant content, but it also contains several enzymes that prevent LDL oxidation or degrade bioactive products of oxidized LDLs. HDL carries paraoxonase (PON) that breaks down oxidized LDL phospholipids (72) by lowering oxidized phospholipids, HDL prevents their inflammatory response via cytokine release and subsequent monocyte infiltration (73). ApoA-I may directly exert an antioxidant effect by reducing phospholipids and CE peroxides and removing the seeding molecules hydroperoxyeicosatetraenoic acid (HPETE) and hydroperoxyoctadecadienoic acid (HPODE) which induce the oxidation of lipoprotein phospholipids (74).

Gilles de la Tourettes syndrome See tourettes

Ginkgo biloba This extract from the oldest known species of tree (also known as a maidenhair tree) seems to increase the flow of nutrients and oxygen to the brain. As it increases circulation, it also boosts the production of adenosine triphosphate (atp) and streamlines the brain's ability to metabolize glucose. It also appears to prevent platelet clumping in arteries and serves as a powerful ANTIOXIDANT. Extracts are made up of flavone glycosides, several terpene molecules unique to the tree, and organic acids. Scientists believe the special terpenes improve circulation in the brain, and extracts are thought to have both anti- inflammatory and antioxidant properties. Some experts believe ginkgo biloba may have both antioxidant and anti-inflammatory properties, protect cell membranes, and regulate neurotransmitter function.

Meat and micronutrients 9111 Iron in meat

Selenium acts as an antioxidant and is considered to protect against coronary heart disease and certain cancers, such as prostate. Meat contains about 10 mg selenium per 100 g, which is approximately 25 of our daily requirement. Beef and pork contain more selenium than does lamb, which may be due to the age of the animal as selenium may collect in the meat over time. Bioavailability of selenium from plant foods was thought to be greater than that from animal foods, but

Viral load test See viral load

Maintenance of the integrity of intercellular cement in many tissues, especially capillary walls. Deficiency leads to scurvy, a disorder of skin and bone that causes capillary bleeding. Except guinea pigs, primates are the only mammals who cannot make it in their bodies. Few nutrients are as active in human metabolism as ascorbic acid. It is known to be the most important water-soluble antioxidant and cofactor in cellular metabolism. Researchers have clearly demonstrated that the immune system is sensitive to intake levels of vitamin C and that numerous immunological functions are dependent on it for their mediation. Vitamin C is possibly the most often used dietary supplement, particularly by immune-suppressed individuals and those suffering from other degenerative illnesses. Vitamin C can be purchased in tablet, capsule, or powdered form. If vitamin C powder is taken dissolved in water or juice, it should be drunk with a straw, as ascorbic acid can, over time, erode tooth enamel....

Huntingtons Disease Society of America A

Its effectiveness in reducing symptoms of senility have been well established. Scientists think it works by interfering with dangerous forms of oxygen (called free radicals), enhancing brain cell metabolism and increasing blood supply and oxygen to the brain. Some scientists believe it may boost memory by mimicking the effect of nerve growth factor, a substance that stimulates dendrite growth in the brain.

Impact of oxidative stress on spermatozoa

These authors observed a correlation between the lipid peroxide content of human spermatozoa and severe motility loss. This relationship between motility loss and oxidative stress is striking and has been repeatedly demonstrated in independent studies (Aitken and Clarkson, 1988 Aitken and Fisher, 1994 Alvarez et al., 1987 Sharma and Agarwal, 1996). Thus exposure of human spermatozoa to extracellularly generated ROS induces a loss of motility that is directly correlated with the level of lipid peroxidation experienced by the spermatozoa (Gomez et al., 1998). Similarly, the loss of motility observed when spermatozoa are subjected to an overnight incubation is highly correlated with the lipid peroxidation status of the spermatozoa at the end of the incubation period (Gomez et al., 1998). The prognostic value of stress tests based on the loss of motility observed when spermatozoa are incubated for defined periods of time in the presence of transition...

The Skin as an Immunologic Organ

UV radiation induces the formation of free radicals, but many defence mechanisms (free radical-trapping molecules, thiols, melanin and enzyme systems) can neutralize these DNA-damaging, potentially carcinogenous substances (Parrish, 1983 Agar and Young, 2005). Other relevant physiological functions of the skin are the maintenance of body temperature, production of hormones and bearing of peripheral nerve receptors and endings. Free radicals Free radicals

The White Cell Trapping Hypothesis

White cell margination is a normal event in the arterioles, capillaries, and venules. This phenomenon is thought to be important in the mechanism that results in tissue injury following ischemia. White blood cells are substantially larger than red cells and are responsible for many of the rheological properties of blood. White cells take 1000 times longer than red cells to deform on entering a capillary bed, and are responsible for about half the peripheral vascular resistance despite their small numbers in the circulation compared to red cells.13 In myocardial infarction they cause capillary occlusion, which can be prevented in experimental animals by first rendering the animal leukopenic.14,15 White blood cells have been implicated as the mediators of ischemia in many tissues including myocardium, brain, lung, and kidneys.1619 Polymorphonuclear leukocytes, particularly those attached to capillary endothelium, may become activated, in which cytoplasmic granules containing proteolytic...

Neurological Conditions Associated With Amnesia

Anoxic brain injury occurs as a result of reduced oxygen to the brain, due to decreased vascular perfusion or reduced oxygen content in the blood. This may be caused by a variety of conditions, such as cardiac arrest or respiratory distress, which in turn may be a result of severe allergic reactions, strangulation or near-drowning episodes. When the brain is deprived of oxygen, excitatory neurotransmitters are released which are accompanied by increased sodium, cell swelling and neuronal damage. Persistent oxygen deprivation leads to neuronal excitation, which results in increased calcium, and to increased free radicals events that cause significant cell damage (Caine & Watson, 2000). Specific brain areas are vulnerable to anoxic injury, in part due to their physical location and in part due to their biochemical make-up. Peripheral blood vessels are particularly sensitive to reductions in oxygenation (Brierley & Graham, 1984). Also sensitive to damage are areas with high metabolic...

Pathogenesis of Phase 1 Endothelial Dysfunction

Glycation Inhibitor

HDL, however, may enhance endothelial function through its anti-inflammatory and antioxidant properties (49), and HDL mediates other mechanisms that may enhance endothelial function (Fig. 9). HDL decreases CAM expression by inhibiting the expression of IL-1a-induced E-selectin (50,51). Also, HDL binds to endothelial SRB1 receptors, thereby activating endothelial NO synthase (52) this mechanism may improve endothelial function by restoring NO bioavailability (53,54). Therefore, by inhibiting endothelial dysfunction, HDL may play a critical role in limiting atheroge-nesis in addition to its role in reverse cholesterol transport.

Genetic Susceptibilities And Resistance To Toxicants

Genetic susceptibilities exist to the chemically induced adverse effects of ultraviolet radiation and visible light, a condition known as photosensitivity. Porphyria, an abnormal extreme sensitivity to sunlight, can result from chemical exposure in genetically susceptible individuals. Lupus erythematosus, a heritable disease manifested by red, scaly skin patches, is characterized by abnormal sensitivity to ultraviolet radiation. Porphyrias in genetically susceptible individuals, which can be induced by chemicals such as hexachlorobenzene and dioxin, occur through the malfunction of enzymes involved in producing the porphyrin heme used in hemoglobin. This results in the accumulation of porphyrin precursors in the skin. Exposed to ultraviolet light at 400 to 410 nm, these precursors reach excited states (see Chapter 2), which may generate damaging free radicals through interaction with cellular macromolecules and O2. Phototoxicity can also be caused by xenobiotic substances either...

Trigger Mechanisms For Cell Activation

Mechanical Phlebitis Stages

A) Positive feedback mechanisms There exists a class of inflammatory reactions that are mediated by direct action of plasma inflammatory stimulators (oxygen free radicals,82 platelet activating factor (PAF),83 cytokines (e.g., TNF-a, IL-1, IL-8),84 complement fragments,85 endotoxins, coagulation and fibrinolytic factors, leukotrienes, thrombin, and oxidized LDL). The list of inflammatory mediators is long, and may in part be triggered by trauma or by bacterial, viral, or fungal sources.

Effects Of Toxic Agents To The Exocrine Pancreas

The mechanism of pancreatic tissue injury may vary with the toxic agents. The effect of ethanol, however, is studied most extensively (see Chapter 15). The cause of pancreatic damage by alcohol may be due to premature activation of digestive enzyme in the acinar cells. It has been shown that alcohol increases the synthesis of digestive enzyme in the pancreas45 and increases the fragility of the zymogen granules46 and lysosomes.47 Premature activation of pancreatic protease by lysosomal cathepsin B may lead to the subsequent tissue damage. Long-term consumption of alcohol increases gene expression of pancreatic cholesterol esterase, ES-10 and fatty acid ethyl ester synthase III in rats48 that may be the cause of accumulation of cholesteryl esters and fatty acid ethyl esters (FAEEs), ethanol metabolites that increase the fragility of the lysosomes, in the pancreas.47,49 On the other hand, the fragility of zymogen granules is increased by alcohol through reduced synthesis of the granule...

Watersoluble vitamins

Most of the stability studies have been carried out with the commercially available folic acid, which has been found to be moderately stable to heat and atmospheric oxygen. In solution it is stable at around pH 7 but becomes increasingly unstable in acid or alkali media, particularly at pH less than 5. Folic acid is decomposed by oxidising and reducing agents. Sunlight, and particularly ultraviolet radiation, has a serious effect on the stability of folic acid. Cleavage by light is more rapid in the presence of riboflavin, but this reaction can be retarded by the addition of the antioxidant BHA to solutions containing folic acid and riboflavin.11 The l-ascorbic acid in foods is easily oxidised to the dehydro-l-ascorbic acid. In fresh foods the reduced form normally predominates but processing, storage and cooking increase the proportions of the dehydro form. Commercially, vitamin C is available as l-ascorbic acid and its calcium, sodium and magnesium salts, the ascorbates. It is also...

Automated Analysis of Conserved Syntenies for the Zebrafish Genome

A number of genes from other organisms demonstrate homology with zebrafish and provide insight into the likely function of the zebrafish gene, including nuclear factor erythroid 2 (nrf2) a member of the Cap 'n' Collar family of transcription factors with a basic region leucine zipper structure, and kelch-like ECH-associated protein 1 (keapT), a cytoskeleton-associated protein (Itoh et al., 1999). It has been shown in knockout mice that regulation of oxidative stress response genes through electrophile response elements (EPREs, also known as antioxidant response elements) is dependent on both Nrf2 (Itoh et al., 1997) and Keapl, which sequesters Nrf2 to the cytoplasm under normal redox conditions (Itoh et al., 1999 Kwak et al., 2002). Dissociation of Nrf2 from Keap1 is apparently regulated by protein kinase C phosphorylation of specific residues on Nrf2 and by direct interactions between electrophiles and the sulfhydryl groups on Keap1 (Dinkova-Kostova et al., 2002 Huang et al., 2002)....

Beneficial effects of aspirin

As an anti-inflammatory drug aspirin may also have a beneficial effect here. Similarly the anti-inflammatory and antioxidant effects of aspirin have been suggested as being responsible for the apparent beneficial effect of aspirin in Alzheimer's disease. Two factors in this neurodegenerative disease are oxidative damage to the fats in the brain (see box, p. 23) and inflammation that can damage nerve cells. Aspirin could contribute to the prevention of both.

Prevalenceepidemiology

Joint Contractures And Scleroderma

The vasodilator nitric oxide is diminished in some patients with SSc, suggesting an impairment of its synthesis on endothelial damage. The initial damages caused by tissue hypoxia can be aggravated by reperfusion, which can declench the release of oxygen free radicals. Laminin and type IV collagen have been proposed as possible targets for cell-mediated immunity in the early stages of SSc. The tissue surrounding small blood vessels in the dermis shows high contents of mononuclear and activated helper-inducer T cells.

Definition of Alcoholic Liver Disease

Oxidation of ethanol in the liver by the enzyme alcohol dehydrogenase produces acetaldehyde, which is rapidly dehydrogenated with the reduction of NAD to NADH. Excess aldehyde may accumulate and act as a hepatotoxin. The highly reduced environment of cytoplasm and mitochondria inhibits fatty acid oxidation and the citric acid cycle so that lipogenesis is stimulated (leading to steatosis). Hyperuricemia and hyper-lactic acidemia may also develop, which stimulates collagen synthesis in myofibroblasts. Ethanol induces the hepatic cytochrome P-450 2E1 (CYP2E1) which generates release of free radicals, causing oxidative stress, with peroxidation of lipids, membrane damage, and altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of tumor necrosis factor-alpha (TNF-a) in the Kupfer cells, thereby...

Relationship of structure to nutritional quality bioavailability

The chemical form of the phytochemical present in food is very important in determining uptake through the gastro-intestinal tract. Quercitin-b-glucoside is more easily absorbed than the aglycone quercitin. Isorhamnetin-b-glucoside, which is chemically similar to quercitin, differing only by a single methoxyl group, is more readily absorbed. Flavonoid rutinosides (rhamnosyl 1-6 gluco-sides) are less easily absorbed.24 Thus whilst some phenols might be better antioxidants than others when tested in in vitro systems, this is of little significance in terms of health relevance. What matters is whether the compounds are easily absorbed, are not quickly degraded in tissues, and are able to reach the target sites. Flavonoids that are not absorbed undergo extensive degradation by gut microorganisms, and may play only a limited role in preventing oxidative damage in the colon.