Free Radicals

Antiinflammatory And Antioxidant Activity

Dandelion extract was shown to exhibit a mild analgesic and anti-inflammatory effect in mice (Tito et al 1993), and an aqueous dandelion extract was found to prevent diabetic complications due to lipid peroxidation and free radicals in diabetic rats (Cho et al 2002). Dandelion extract has also been found to have a protective effect against CCK octapeptide-induced acute pancreatitis in rats (Seo et al 2005) and dandelion flower extract demonstrated marked antioxidant activity that has been attributed to its phenolic content, with suppression of reactive oxygen species and nitric oxide (Hu & Kitts 2003, 2005, Kery et al 2004). Extracts of dandelion flowers, roots and stem have been found to have significant OH-radical scavenging activity (Kaurinovic et al

Spices as Antioxidants

Spices can prevent rancidity and extend shelf life by slowing the oxidation of fats and enzymes. Fats are broken down into peroxides (free radicals) with exposure to air or oxygen and finally into aldehydes and alcohols that give a rancid taste. Spices can halt the oxidative process by blocking or scavenging the free radicals. Today, with consumer demand for natural products, spices can be used commercially as natural antioxidants in foods. Sage, rosemary, oregano, thyme, cilantro, and marjoram are found to have stronger antioxidant properties than other spices. Rosemary and sage are currently used as natural antioxidants in foods, while other spices such as cilantro are being explored. Rosemary and sage antioxidants are available as oil-solubles, water-dispers-ibles, or dry-solubles, and can be used in seasoning blends, salad dressing mixes, lard, sausage, or instant potatoes. They are used as sprays, dips, or surface coatings in comminuted poultry, seafood, or meats before they are...

Vitamin E Is the Major Lipid Soluble Antioxidant in Cell Membranes Plasma Lipoproteins

The main function of vitamin E is as a chain-breaking, free radical trapping antioxidant in cell membranes and plasma lipoproteins. It reacts with the lipid peroxide radicals formed by peroxidation of polyun-saturated fatty acids before they can establish a chain reaction. The tocopheroxyl free radical product is relatively unreactive and ultimately forms nonradical compounds. Commonly, the tocopheroxyl radical is reduced back to tocopherol by reaction with vitamin C from plasma (Figure 45-6). The resultant monode-hydroascorbate free radical then undergoes enzymic or nonenzymic reaction to yield ascorbate and dehy-droascorbate, neither of which is a free radical. The stability of the tocopheroxyl free radical means that it can penetrate farther into cells and, potentially, propagate a chain reaction. Therefore, vitamin E may, like other antioxidants, also have pro-oxidant actions, especially at high concentrations. This may explain why, although studies have shown an association...

Regulation Of Gene Transcription By Antioxidants

The skin is the largest human organ and permanently exposed to a variety of stresses. Among those, oxidative insults such as ultraviolet radiation and ozone exposure account for the cause of many skin disorders. However, oxidative damage are not responsible for all biological effects engendered by these stressors in the skin. Indeed, ultraviolet radiation (UVR) causes changes in the expression of genes encoding, e.g., proinflammatory cyto-kines, growth factors, stress response proteins, oncoproteins, and matrix metalloprotei-nases 79 . Although the immediate target(s) of UVR is are still unknown, certain kinases and transcription factors can be activated by UVR thereby increasing gene transcription 80 . One transcription factor, NF-kB, appears of particular interest for the skin since the lack of its inhibitory protein, IKBa, is associated with the development of a widespread dermititis in knockout mice 81,82 . Furthermore, reactive oxygen species, such as the ones produced after UVR,...

The Antioxidant Network

When an antioxidant reacts with an oxidant, it is converted to a form that no longer functions as an antioxidant, and is said to be consumed. In order for the oxidized product to function again, it needs to be recycled to its native form. The antioxidant network describes the ability of the antioxidants to recycle and regenerate oxidized forms of each other thereby providing extra levels of protection (Fig. 5). Thus the process is synergistic the net antioxidant protection is always greater than the sum of the individual effects. The major systemic antioxidants vitamin E, vitamin C, and glutathione are present in different cellular compartments, and all have the ability to interact with one another. Typically the radicals formed on the antioxidants are more stable and longer lived than the damaging radicals produced in vivo, which is mostly attributable to delocalization of the unpaired electron. Thus they have more chance to interact with each other and be Figure 5 Schematics of the...

Lipid Peroxidation Is A Source Of Free Radicals

Peroxidation (auto-oxidation) of lipids exposed to oxygen is responsible not only for deterioration of foods (rancidity) but also for damage to tissues in vivo, where it may be a cause of cancer, inflammatory diseases, atherosclerosis, and aging. The deleterious effects are considered to be caused by free radicals (ROO , RO , OH ) produced during peroxide formation from fatty acids containing methylene-interrupted double bonds, ie, those found in the naturally occurring polyunsaturated fatty acids (Figure 14-21). Lipid peroxidation is a chain reaction providing a continuous supply of free radicals that initiate further peroxidation. The whole process can be depicted as follows Since the molecular precursor for the initiation process is generally the hydroperoxide product ROOH, lipid peroxidation is a chain reaction with potentially devastating effects. To control and reduce lipid peroxidation, both humans in their activities and nature invoke the use of antioxidants. Propyl gallate,...

Longer Life Expectancy In Organisms Belonging To The Same Cohort Group Is Associated With Relatively Higher Levels Of

All houseflies lose the ability to fly prior to death. Therefore, in an aging population, shorter-lived flies can be identified as flightless crawlers in contrast to their longer-lived cohorts, the fliers. The average lifespan of crawlers is about one-third shorter than the fliers. Levels of antioxidant defenses (superoxide dismutase (SOD), catalase (CAT), and glutathione) and products of

Antioxidants And Aging

Although Linus Pauling did not discuss the possibility that v itamin C might protect against mental deterioration associated with aging in Vitamin C and the Common Cold, this possibility has become one of the most popular reasons for taking large daily doses of v itamin C and other antioxidant s such as vitamin E and beta-carotene (p-carotene). The rationale is rooted in the chemical react ions of these compounds with reactive oxygen species. Cells of living organisms contain energy factories called mitochondria, which carry out the final steps in the conversion of energy to a form that can be used to do the work of the cells. These steps require oxygen, which we obtain by breathing. The process is quite efficient, but small amount s of oxygen are converted to byproduct s such as hydrogen peroxide, ozone, nitric oxide, superoxide radicals, and hydroxyl radicals. These substances are called reactive oxygen species because they are derived from oxygen and react readily with essential...

Antioxidants CellSupporting Agents

A number of theories as to what causes PD at the cellular level include oxidative stress and free radical formation, mitochondrial impairment, intracellular protein clumping, inflammation, apoptosis (programmed cell death), and excitotoxicity (5). Many of the prescribed supplements, minerals, and vitamins by alternative practitioners are based upon these theories and the belief or hope that cellular function will be restored and or future brain cell injury prevented with their use. Currently, there is little if any scientific study to support the use of most of these supplements in the treatment of PD and it is critical to acknowledge that their use specifically for the treatment of PD is based upon theory only and not upon evidence-based clinical research. Despite the lack of research supporting their use for PD, some of these, in particular, the antioxidants that control potentially damaging free radicals or support mitochondrial function may hold the greatest promise for finding a...

Antioxidant

Studies have found that several compounds present in aloe gel protect tissues against oxidative damage caused by free radicals ('t Hart et al 1990, Singh et al 2000, Wu et al 2006, Yagi et al 2002, Zhang et al 2006). This is achieved by direct antioxidant activity and indirect activity through stimulation of endogenous antioxidant systems. Three-year-old aloe plants appear to have the highest amounts of flavonoids and polysaccharides and hence the best free radical scavenging capacity, as compared to 2- and 4-year-old plants (Hu et al 2003). Interestingly, the 3-year-old plant demonstrated antioxidant activity of 72.19 , compared to alpha-tocopherol at 65.20 .

Antioxidants

Free radical production is enhanced in both the ischemic core and penumbral following stroke injury, and this is believed to cause much of the damage seen in the core as well as penumbra. There are many agents that either block free radical production or inhibit its activation that have been shown to be very effective in experimental models. Uric acid is a well-known natural antioxidant present in fluids and tissues. Administration of uric acid resulted in a highly significant reduction in ischemic damage and improved behavioral outcome (Yu et al., 1998). Edaravone, Tetramethylpyrazine, alpha-phenyl-N-tert-butyl-nitrone, FR210575, and NXY-59 are other free radical inhibitors that were effective against experimental stroke injury. EGb-761 is a free radical scavenger derived from a concentrated extract of Ginkgo that is currently in a phase 2 clinical trial (Legos et al., 2002). Clinical trials with free radical scavengers have had limited success after acute ischemic stroke, but have...

NO as an Antioxidant

Interestingly, it has been proposed that NO' also has a protective role and, under certain conditions, acts as an antioxidant. Indeed, it has been shown that NO' can terminate a common pathological manifestation of oxidant overload to biological membranes, the deleterious process of lipid peroxidation 27 , by reacting very rapidly with fatty alkoxyl (RO') and peroxyl (ROO') radical intermediates which would otherwise propagate the membrane damage. In addition, NO' can inhibit ferrylMb-induced oxidative damage by reducing ferrylMb to metMb 28 .

Enhance Intercellular Communication

In addition to its antioxidant activity, beta-carotene enhances gap junction intercellular communication by upregulation of the gap junction protein connexin 43. This action may be important in its control of tumour growth (Yeh & Hu 2003) and is likely to be independent of its ability to quench singlet molecular oxygen (Stahl et al 1997).

Natural Models Of Alzheimerlike Pathology

Af3 accumulation correlates with behavioral impairments in aged dogs (Colle et al., 2000), and with a regional loss of brain substance (particularly in the frontal lobes) beginning around 8 years of age (Tapp et al., 2004). As in all affected species, there is substantial variation in age-associated changes among animals of comparable age in addition, controlled comparative studies of the development and composition of lesions in different breeds of dogs are lacking. The age-related cognitive decline in aged dogs can be ameliorated by a diet rich in antioxidants and mitochondrial co-factors, as well as by behavioral enrichment (Milgram et al., 2005 Siwak et al., 2005), and there is evidence that drugs used to treat cognitive decline in humans can be usefully tested in aged canines (Studzinski et al., 2005).

What Do Chronologically Aged Cells Die From

The chronological life span of a yeast cell begins under conditions highly favorable for growth low cell density, optimal temperature, high nutrient availability, and the presence of a preferred carbon source (glucose). These conditions allow cells to enter an exponential growth phase, during which cells generate ATP primarily through glycolysis and fermentation of pyruvate to ethanol. As glucose becomes depleted, yeast cells progress through the diauxic shift, a growth phase characterized by large transcriptional changes resulting in enhanced expression of many enzymes involved in the TCA cycle, mito-chondrial function, and respiration. Associated with this transition to a less favorable environment is an up-regulation of many stress responsive and antioxidant genes. Eventually, as nutrients are depleted and cell density increases, a postdiauxic stationary phase is achieved in which cells exit from the cell cycle and enter into a G0-like quiescent state. A third mechanism by which...

Cristina Magi Galluzzi and Angelo M De Marzo Introduction

Etiologic factors associated with PCA are varied and comprise both genetic and environmental influences. Among the genetic factors aging, family clustering, race, and hormonal influences seem to play a major role. A diet high in animal fat and red meat and poor in fruits and vegetables, and the preventive use of antioxidants associated with a high intake oftomatoes are also critical factors (3,4).

Chemopreventative Effects

Chemopreventative actions demonstrated by n-3 EFAs include suppression of neoplastic transformation, cell growth inhibition and enhanced apoptosis, and anti-angiogenicity (Rose & Connolly 1999). The proposed mechanisms for these are extensive, including the suppression of n-6 eicosanoid synthesis influences on transcription factor activity, gene expression, and signal transduction pathways effects on oestrogen metabolism increased or decreased production of free radicals and reactive oxygen species, and influences on both insulin sensitivity and membrane fluidity (Larsson et al 2004). Ongoing research is attempting to elucidate the specific chemopreventative mechanisms of fish oils with the individual cancer cell lines.

Stress Resistance And Extended Longevity

As a result of our studies on the biochemistry and stress resistance properties of the long-lived La strains, we knew that the only predictive factor clearly and significantly associated with extended longevity in our strains was an enhanced resistance to oxidative stress (Arking et al., 1991 Force et al., 1995). Thus it seemed logical to conclude that the long-lived La animals probably live long because of higher-than-normal activity of the antioxidant defense system genes early in life. Quantitative trait loci (QTL) mapping is a genetic method of identifying small chromosome regions which have a significant statistical effect on longevity, and may be viewed as a genome-wide scan that allows one to identify interesting genes for further investigation. Curtsinger and Khazaeli (2002) did such a procedure on recombinant inbred strains derived from the La and Ra strains discussed above. They found four QTLs located on chromosomes 2 and 3 of the (La x Ra) recombinant inbred strains that...

How Do Different Pathways Yield a Common Type I Phenotype

The interesting thing about the Type 1 phenotype is that delaying the onset of senescence means that the inflection point characteristic of such survival and mortality curves is shifted to some later time (see Figures 25.1A, 25.2A). What happens at that inflection point, regardless of its chronological value, that shifts the population from a state of health into a state of senescence Senescence is the stochastic and nonpro-grammed loss of function which becomes obvious as the reproductive period ends. This is a time-independent process, occurring at about two years in a mouse but at about fifty-five years in a human. What triggers its onset In the fly, it has been shown that the repression of the ISP results in the activation of the dFOXO gene, and in the activation or repression of a whole suite of downstream genes under its singular or joint control (Murphy et al., 2003). These downstream genes include a variety of stress resistance genes, including a number of molecular chaperones...

Antiatherosclerotic Activity

Results from several recently published animal studies further confirm antiatherogenic effects and have investigated the mechanisms responsible (Durak et al 2002, Ferri et al 2003, Kwon et al 2003). One in-vivo study found that garlic activated antioxidant systems and decreased peroxidation in aortic tissue (Durak et al 2002) whereas ajoene inhibited smooth muscle cell proliferation in another (Ferri et al 2003).

Mutagenicity and Genotoxicity of Cd

IARC has determined that there is sufficient scientific evidence to classify cadmium and cadmium compounds carcinogenic in humans. In general, Cd compounds are weakly mutagenic in most assay systems (Filipic and Hei, 2004), but have been shown to be genotoxic to Leydig cells of the testes (Yang et al., 2003). The mechanism by which Cd may be genoto-xic is by indirectly inducing oxidative stress in cells as a result of its inhibition of antioxidant enzymes and depletion of antioxidant molecules such as GSH (Stohs et al., 2000). Cd has been reported to be very active in

Antiallergic Activity

Ginsenosides have been demonstrated to have anti-allergic activity in vitro. One of the metabolites, was found to inhibit beta-hexosaminidase release from rat basophil leukaemia cells and potently reduce passive cutaneous anaphylaxis reaction. The inhibitory activity of protopanaxadiol was more potent than that of disodium cromoglycate, an antiallergic drug. The compound stabilised membranes but had no effect on hyaluroni-dase and did not scavenge free radicals. These results suggest that the anti-allergic action of protopanaxadiol originates from its cell membrane-stabilising activity and that the ginsenosides are prodrugs with anti-allergic properties (Choo et al 2003)

Spontaneous Mutations

Another source of mutation that is often categorized as spontaneous mutation is oxidative damage. You may have heard that vitamins C and E and other foods are antioxidants and that people take them to reduce oxidative damage to their cells. As its name implies, oxidation involves oxygen. Our cells require oxygen to live, yet oxygen is a very reactive molecule and can be damaging to chemicals in our body. For example, oxidative damage changes guanine in our DNA to a chemical called oxoguanine. Because oxoguanine can pair with A, adenine, oxidative damage changes a G-C base pair in DNA to an oxoG-A pair, which after replication ends up as a T-A base pair. Proofreading enzymes can, however, spot and repair oxoG.

Pathogenic Mechanisms in Friedreich Ataxia

Altered iron metabolism, free-radical damage, and mitochondrial dysfunction all occur in FA patients, suggesting that information derived from investigations on frataxin function and from the yeast and animal models is relevant for the pathogenesis of the human disease. Oxidative stress is revealed by increased plasma levels of malondialdheyde, a lipid peroxidation product (Emond et al. 2000), increased urinary 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage (Schulz et al. 2000), decreased plasmafree glutathione (Piemonte et al. 2001) and elevated plasma glutathione S-transferase activity (Tozzi et al. 2002). Increased free-radical production could be directly demonstrated in cultured cells engineered to produce reduced levels of frataxin (Santos et al. 2001). In addition, H2O2 induces apop-tosis in patients' fibroblasts at lower doses than in control fibroblasts (Wong et al. 1999), suggesting that even nonaffected cells are at risk for oxidative stress as a consequence...

Cardioprotective Effects

Considering that GSE demonstrates antioxidant, antiplatelet and anti-inflammatory actions, it may have a role in the prevention of cardiovascular disease. A number of researchers have investigated this issue further, mainly using animal models. One series of studies was conducted by Bagchi et al (2003) using a natural, standardised, water-ethanol extract made from California red grapeseeds, which contained Grapeseed extract 646

Leslie Helou and Ha M Harris

Garlic possesses a variety of beneficial pharmacological properties affecting most notably the cardiovascular system (lipid management, decreased blood pressure, platelet inhibition, and decreased fibrinolytic activity), and the immune system as an antineoplastic and immunostimulant agent. It is also a potent antioxidant. Although its effects are modest in some clinical applications, its inherent safety and culinary benefits usually support its use when a mild clinical effect is acceptable. There is the potential for interactions with drugs possessing antiplatelet and anticoagulant effects. Additionally, potential induction of various cytochrome P450 enzymes warrants closer monitoring of drugs metabolized through this pathway when garlic is concomitantly administered. Key Words Allium sativum antilipemic platelet inhibition antioxidants cancer prevention P450 enzyme induction.

Pharmacological Toxicological Effects 51 Cardiovascular Effects

Antioxidant and Antiatherosclerotic Effects Garlic has been shown to have significant effects on the cardiovascular system. Such areas include improvement in lipids, modest effects on blood pressure, platelet inhibition, antioxidant effects, and a decrease in fibrinolytic activity. In vitro studies have shown garlic possesses specific antiatherosclerotic effects such as reducing inducible nitric oxide synthase (iNOS) mRNA expression (10), inhibition of oxidized low-density lipopro-tein (LDL)-induced lactate dehydrogenase (LDH) release and inhibition of oxidized LDL-induced depletion of glutathione (11). The effects of garlic as an antioxidant and its ability to alter the atherosclerotic process require additional study. To date, no trials evaluating patient outcomes have been completed.

An Experimentally Induced Decrease In Oxidative Stress Retards Ageassociated Deterioration At The Organelle And

Reducing dietary intake has been shown to be the most effective means for modulating the aging processes in laboratory rodents (Weindruch et al., 1986). Dietary restriction also has been shown to be a modulator of membrane lipid peroxidation and cytosolic antioxidant status. Lee et al. studied the anti-ROS action of dietary restriction by quantifying the formation of the O2* OH , and H2O2 by liver microsomes from rats of various ages. The results show that the ad libitum-fed group maintained a higher production of O2*_ and OH radicals when compared to the food-restricted group of the same age. H2O2 formation followed the same trend but was statistically greater only at three and six months of age. The food-restricted group displayed higher SOD activity in both cytosolic and mitochondrial fractions compared to ad libitum-fed controls (Lee and Yu, 1990). These data indicate that the ROS activity observed in liver micro-somes of ad libitum-fed rats can be attenuated by dietary...

Experimental Evidence that Is not Readily Explained by the Mitochondrial Theory of Aging

H2O2 formation are much lower (less than 0.1 of respiratory chain electron flux). This H2O2 production may be stimulated by the complex III inhibitor antimycin A, but not by myxothiazol (Hansford et al., 1997). Staniek and Nohl further reported that mitochondria respiring on complex I and complex II substrates generate detectable H2O2 only in the presence of the antimycin A. They also suggested that the rates of mitochondrial H2O2 production reported by others are artificially high due to flaws in experimental design (Staniek and Nohl, 2000). Martin Brand's group capitalized on these findings and used an improved experimental design to show that mitochondria do not release measurable amounts of superoxide or hydrogen peroxide when respiring on complex I or complex II substrates, but release significant amounts of superoxide from complex I when respiring on palmitoyl carnitine (St-Pierre et al., 2002). However, even at saturating concentrations of palmitoyl carnitine, in their...

Significant Interactions

Lutein showed increased antioxidant efficacy with vitamin C in an animal study (Blakeley et al 2003). Further to this, a small in vivo study showed 2000 mg of vitamin C enhanced the absorption of lutein (Tanumihardjo et al 2005). Vitamin E showed increased antioxidant efficacy with lutein according to an animal study (Blakeley etal 2003).

Systemic and Local Suppression of T Cells

The indirect influence of tumors on the development of a systemic immunosuppresion can be attributed to hyperproduction of IL-10, oxygen metabolism intermediates, and some enzymes. IL-10 is a type 2 cytokine that is produced by APCs and Th2 cells. It is involved in the development of T-cell anergy, promotion of Th2 responses, and inhibition of Th1 responses, which are important for the generation of efficient antitumor responses. Increased production of oxygen metabolites by macrophages isolated from the metastatic lymph nodes of patients with malignant melanoma was found to be responsible for decreased CD3-mediated stimulation of T cells and the reduction of CTL and NK cell activity (22). The inhibitory effect of macrophages on melanoma-specific CTL lines and NK cells was abrogated in the presence of catalase, a scavenger for H2O2. The mechanism of H2O2-induced immunosuppression by monocytes macrophages derived from the blood of cancer patients was attributed to the inhibition of Th1...

Discussion and Conclusions

Our data indicate that chronic E2 treatment did not alter the specific activity of antioxidant enzymes in the MG as it did in the liver. This finding indicates that the regulation of expression of these enzymes by E2 differs in liver and MG. The expression ofNQO1 and GST is mediated, at least in part, through the antioxidant electrophile response element (ARE EphRE) (31) found in the regulatory regions of their genes. GPx is also induced in response to oxidative stress but through mechanisms that involve sp-1 and AP-2 regulatory sequences in the promoter region of the rat liver GPx gene which lacks the ARE EphRE regulatory sequences (32). Also, the induction of cytosolic CAT activity suggests that oxidative stress after 28 weeks of treatment may be a consequence of the presence of MG tumors, and may not be a predominant factor during the initiation development of these tumors in the rat.

Damage to the Nucleobases

Free radicals and radiation can both damage nucleobases. On the basis of its reactivity the most important radical in cells is HO', which reacts with pyrimidine and purine nucleobases mainly by addition to the unsaturated bonds. In purines, HO' attack occurs preferentially at C4 and C8 this is shown as an example in Scheme B.21.2 for the reaction with guanosine (G) 9 3a,b . Elimination of water from the C4 adduct 10 leads to the comparatively stable radical 11 which can undergo oxidative degradation to the ox-azolone 14 3c . The C8 adduct 12 can either undergo further oxidation to yield 8-oxoguanosine 15, or ring opening followed by reduction to the for-mamide 16.

Perspectives for Treatment

Additional ways to treat the disease may become apparent from studies on the function of frataxin. On the basis of these findings, therapeutic approaches aimed at controlling the levels of free radicals and regulating respiratory chain activation may be proposed. Concerning antioxidant molecules and respiratory chain stimulants, some coenzyme Q derivatives (idebenone, CoQ-10) have already yielded promising results, not only in experimental models (Seznec et al. 2004), but also in clinical trials, at least with respect to FA cardiomyopathy (Buyse et al. 2003 Mariotti et al. 2003). Automated high-throughput tests to evaluate a large number of molecules for their ability to correct the functional consequences of frataxin deficiency are under way. An intriguing possibility would be the identification of small molecules capable of effectively replacing frataxin by binding mitochondrial iron and increasing its bioavailability.

Mechanisms of Premature Aging in Diabetes

These include the polyol pathway, protein kinase C pathway, glycosylation pathway, and the oxidative pathway. These pathways, although conceptually separate, are interlinked biochemically (Brownlee, 2001). It has been suggested that a unifying hypothesis that incorporates these different pathways of glucotoxicity is hinged upon the mitochondrial generation of free radicals (Brownlee, 2001). According to this hypothesis, excess superoxide (oxidation pathway) partially inhibits the glycolytic enzyme GAPDH, thereby diverting upstream metabolites from glycolysis into pathways of glucose over utilization. This increases the flux of dihydroxyacetone phosphate (DHAP) to DAG, an activator of PKC (PKC activation pathway), and of triose phosphates to methyl-glyoxal, the main intracellular AGE precursor (glycation pathway). Increased flux of fructose-6-phosphate to UDP-N-acetylglucosamine increases modification of proteins by O-linked N-acetylglucosamine (GlcNAc) (hexosamine pathway), and...

Copper In Human And Animal Nutrition

Copper was identified as an essential human dietary element approximately 65 years ago (120). Copper is a required catalytic cofactor of selective oxidoreductases and is important for ATP synthesis, normal brain development and neurological function, immune system integrity, cardiovascular health, and bone density in elderly adults (120). Animals and humans exploit copper by cycling the element between the oxidized cupric ion and the reduced cuprous ion for single-electron transfer reactions (120). Because free or loosely bound copper has the potential to generate free radicals capable of causing tissue pathology, organisms have developed sophisticated mechanisms for its orderly acquisition, distribution, use, and excretion (120).

Mechanistic cellculture studies

The mechanisms by which transport-related air pollution induces respiratory morbidity have also been investigated. Inhaled particles encounter the epithelial lining fluid, which contains antioxidants that may alter the effects of these particles. The antioxidants are depleted in the presence of at least some particles, though this has not yet been shown for urban-air particles (Zielinski et al., 1999). As with many other particles, CAPs induce oxygen radical-mediated lesions in cell-free DNA and intact cells, as measured by different methods (Donaldson et al., 1997 Smith & Aust, 1997 Prahalad et al., 2001 Knaapen et al., 2002 Shi et al., 2003). For PM10 or finer particles collected in different locations, non-enzymatic and enzymatic antioxidants reduced the formation of oxidants in most samples. Some studies showed that trivalent cations are associated with the oxidative effect (Upadhyay et al., 2003). In addition to metal ions, organic compounds (such as semiquinone radicals derived...

Synthesis of phenethyl PDglycopyranoside

Phenylethanoid glycosides are a group of water-soluble natural products widely distributed in the plant kingdom. The biological activity of some compounds has been investigated and they are reported to indicate antibacterial activity, cytotoxic and antioxidant properties, enzyme inhibition and immunomod-ulatory properties. Among them, three kinds of naturally occurring phenethyl 6-O-P-D-glucopyranoside congeners, phenethyl (65), phenethyl (66) and phenethyl (67) were isolated from a methanol extract of Rehmannia glutinosa var. purpurea, Rhodiola sacra and Citrus unshi, respectively (Fig. 11). These P-D-glucopyranosides were synthesized from phenethyl P-D-glucopyranoside (14) as shown in Fig. 12.

Functions In Plants

Catalase has a major role in the photorespiration reactions, as well as in the glycolate pathway, and is involved in the protection of chloroplasts from free radicals produced during the water-splitting reaction of photosynthesis. The reaction sequence of peroxidase shown above includes cell wall peroxidases, which catalyze the polymerization of phenols to form lignin. Peroxidase activity is noticeably depressed in roots of iron-deficient plants, and inhibited cell wall formation and lignification, and accumulation of phenolic compounds have been reported in iron-deficient roots.

Hepatoprotective Activity

Decreases hepatotoxic damage Several In vitro and in vivo studies have identified hepatoprotective effects with schisandra against carbon tetrachloride toxicity (Ip et al 1995, Mak & Ko 1997, Zhu et al 1999, 2000). Research with schisandrin B suggests it is the main constituent responsible for these beneficial effects (Ip et al 1995, Mak et al 1996, Pan et al 2002). Further investigation reveals that schisandrin B increases the efficiency of the hepatic glutathione antioxidant system, thereby inhibiting carbon tetrachloride induced lipid peroxidation however, additional mechanisms appear likely (Ip et al 1995).

Rheuma Toid Arthritis

Selenium supplements have been used in RA because of its antioxidant activity and the observation that some patients with RA have been reported with low selenium status (O'Dell et al 1991, Rosenstein & Caldwell 1999). One double-blind, placebo-controlled intervention study of 55 patients with moderate RA found that both placebo and selenium appeared to have significant effects on a number of symptoms however, only selenium significantly improved arm movements and sense of wellbeing (Peretz et al 2001).

Ototoxicity Prophylaxis

Most forms of ototoxicity ultimately result from the generation of free radicals in the affected portions of the inner ear. A considerable amount of basic science literature has accumulated investigating the systemic and transtympanic (through the middle ear) administration of agents that counteract free radical formation. A variety of promising candidates have been identified. Thus, within the coming years, it is reasonable to anticipate the development of an agent or agents that will be administered prophylactically to patients at risk for ototoxic reactions (e.g., patients undergoing chemotherapy with cisplatin).

Synthesis of Sacranosides A 89 and B 9021

Monoterpene glycosides are a group of water-soluble natural products widely distributed in the plant kingdom. The biological activity of some compounds has been determined and has been reported to indicate antibacterial activity, cytotoxic and antioxidant properties, enzyme inhibition and immunomodulatory properties. Among them, two kinds of naturally occurring monoterpene alcohol 6-O-glycosy-P-D-glucopyranoside congeners (Fig. 17), myrtenyl (Sacranoside A, 89) and neryl (Sacranoside B, 90) were isolated from a methanol extract of R. sacra (Prain ex Hamet) S. H. Fu (Crassulaceae). These P-D-glucopyranosides were synthesized from myrtenyl P-D-glucopyranoside (53) or neryl P-D-glucopyranoside (52) as shown in Figs 18 and 19.

Potential Therapeutic Strategies

Paradoxically, a recent report indicates that the antioxidant resveratrol, a component of red wine and an activator of sirtuin deacetylases, can attenuate polyQ-mediated neuronal death. Resveratrol treatment was effective in both a C. elegans HD model, which expressed an N-terminal htt fragment

Cancer Prevention

Most forms of cancer arise from cells that are influenced by vitamin A (Wardlaw et al 1997). Combined with its antioxidant and immunomodulatory activities, vitamin A has been considered as a potential chemopreventive agent. Research thus far using cell cultures and animal models has identified the ability for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites (Krinsky 2002). A look at the literature shows that impressive treatment results have mainly been obtained for synthetic retinoids and the relationship between natural vitamin A ingestion and cancer is less clear in humans. Lung cancer A number of epidemiological studies have identified an inverse association between risk of lung cancer and serum carotenoid levels, but intervention studies have produced conflicting results. In general, vitamin A is supplied together with carotenoids making it difficult to determine the role of vitamin A as a stand alone...

Biomedical Importance

The lipid-soluble vitamins are apolar hydrophobic compounds that can only be absorbed efficiently when there is normal fat absorption. They are transported in the blood, like any other apolar lipid, in lipoproteins or attached to specific binding proteins. They have diverse functions, eg, vitamin A, vision vitamin D, calcium and phosphate metabolism vitamin E, antioxidant vitamin K, blood clotting. As well as dietary inadequacy, conditions affecting the digestion and absorption of the lipid-soluble vitamins such as steatorrhea and disorders of the biliary system can all lead to deficiency syndromes, including night blindness and xerophthalmia (vitamin A) rickets in young children and osteomalacia in adults (vitamin D) neurologic disorders and anemia of the newborn (vitamin E) and hemorrhage of the newborn (vitamin K). Toxicity can result from excessive intake of vitamins A and D. Vitamin A and P-carotene (provitamin A), as well as vitamin E, are antioxidants and have possible roles in...

Vitamin E Does Not Have A Precisely Defined Metabolic Function

No unequivocal unique function for vitamin E has been defined. However, it does act as a lipid-soluble antioxidant in cell membranes, where many of its functions can be provided by synthetic antioxidants. Vitamin E is the generic descriptor for two families of compounds, the tocopherols and the tocotrienols (Figure 45-5). The different vitamers (compounds having similar vitamin activity) have different biologic potencies the most active is d-a-tocopherol, and it is usual to express vitamin E intake in milligrams of d-a-tocoph-erol equivalents. Synthetic dl-a-tocopherol does not have the same biologic potency as the naturally occurring compound.

Iatrogenic Causes of Dysphagia

Mucosal adhesions in the hypopharynx and proximal esophagus. Amifostine is an organic thiophosphate protecting normal tissues from free radicals produced by RT and or chemotherapy. Prospective studies have demonstrated its cytoprotective effect in the oropharyngeal mucosa (13).

Enhances Immunity In The Elderly

Immune cell function Is Influenced by the oxidant and antioxidant balance, so antioxidant supplements have been investigated clinically for their ability to enhance immune responses (Meydani et al 1998). Increased markers of T-cell-mediated immunity were enhanced with all doses of synthetic vitamin E tested, according to a randomised, double-blind study of 78 healthy elderly subjects. Doses used were 60, 200 and 800 mg day for 4 months, with best overall responses obtained with the 200 mg dosage (Meydani et al 1997). Another double-blind study found no significant changes to either cellular or humoral immune responses with a low dose of 100 mg day of synthetic vitamin E taken over 3 months (de Waart et al 1997).

B KCa Channel Openers

NDGA, a lipoxygenase inhibitor and antioxidant, is also a potent opener of KCa channels in porcine coronary artery and is possibly a potential tool for designing more potent vasodilators and or bronchodilators (117). Interestingly, NDGA was ineffective at low calcium concentrations, indicating that calcium is necessary, possibly as a way to couple a and 0 subunits.

Important Cofactor In Many Biochemical Reactions

As a constituent of over 300 metalloenzymes, zinc is involved in myriad chemical reactions that are important for normal body functioning, such as carbohydrate metabolism, protein and DNA synthesis, protein digestion, bone metabolism and endogenous antioxidant systems (Beers et al 1999, Wahlqvist et al 1997, Wardlaw et al 1997). At the cellular level, the function of zinc can be divided into three categories catalytic, structural and regulatory (King 2003). Antioxidant Zinc limits oxidant-induced damage in a number of indirect ways, such as protecting against vitamin E depletion, controlling vitamin A release, contributing to the structure of the antioxidant enzyme extracellular superoxide dismutase, restricting endogenous free radical production, maintaining tissue concentrations of metallothionein, a possible scavenger of free radicals, and stabilising membrane structure (DiSilvestro 2000). More recently it was observed to decrease Zinc 1385

Agerelated Macular Degeneration

A 2002 Cochrane review assessed the effects of antioxidant vitamin and or mineral supplementation on the progression of ARMD and found that evidence of effectiveness is currently dominated by one large trial that showed modest benefit in people with moderate to severe signs of the disease who were administered antioxidant vitamins and zinc together (Evans 2002). More recently, results of the Age-Related Eye Disease Study were published (AREDS 2001 ), which showed that high-dose vitamins C and E, beta-carotene, and zinc supplementation delayed the progression from intermediate to advanced disease by 25 over 5 years. The 11 centre, doubleblind, prospective study involved 3640 volunteers aged between 55 and 80 years who were randomly divided into four treatment groups, receiving either antioxidant supplements (500 mg vitamin C, 400 international units (IU) vitamin E, and 1 5 mg beta carotene daily), zinc oxide and cupric oxide (80 mg elemental zinc, 2 mg elemental copper daily),...

Disruption of the Cytoskeleton

Another possibility proposed by Ikegawa et al. (156) is aluminum-enhanced, Fe(II)-medicated peroxidation of lipids as a cause of cell death. Exposure of tobacco suspension cultures to aluminum alone for 24h resulted in aluminum accumulation but no significant cell death (156). Addition of Fe(II) (a redox active metal) to cells with accumulated aluminum after 12 h resulted in enhanced lipid peroxidation and cell death. Lipid peroxidation does not appear to be the mechanism involved in reduction of root elongation (154). In pea roots, treatment with an antioxidant prevented aluminum-enhanced lipid peroxidation, reduced callose formation, but did not prevent aluminum-induced inhibition of root elongation (154).

Reducing Oxidative Stress

Increased oxidative stress in response to expansion was reported in a variety of disorders, including FRDA and the polyQ disorders. Clinical trials with antioxidants such as idebenone, an analog of coenzyme Q (ubiquinone) have led to decreased cardiac hypertrophy in a mouse model of FRDA (Seznec et al. 2004) and humans (Rustin 2003). However, additional double-blind placebo controlled studies are needed to assess neurological outcomes. Antioxidants also attenuate the HD phenotype in mouse models of this disorder (Beal 2002). Since in both disorders mitochondrial dysregulation is observed, the development of agents targeted to the mitochondria might be desirable. One such compound, mitoquinone, a ubiquinone derivative, has been shown to be more effective in protecting cells from FRDA patients from oxidative stress than idebenone (Jauslin et al. 2003), and is currently being tested in phase I clinical trials.

Rate Of Living Metabolism And Oxidative Damage

In addition, many Drosophila-based studies have tested the oxidative damage hypothesis a popular approach has been to reduce the level of oxidative stress and see if lifespan can be extended. For example, using the candidate gene approach, attempts have been made to lower levels of oxidative stress either by overexpress-ing antioxidant enzymes or by lowering mitochondrial reactive oxygen species production through elevating proton conductance (Miwa et al., 2004 Fridell et al., 2005). Dietary antioxidant supplementation has also been performed (reviewed in Le Bourg, 2001). However, not all studies support the hypothesis. Initial studies genetically inducing increased antioxidant defenses had technical problems use of short-lived flies, different sized inserts between control and experimental groups, and uncontrolled position effects in transgene constructs (Tower, 2000 Partridge and Pletcher, 2003). Later work found that overexpression of Cu,Zn-SOD, Mn-SOD, or both with the FLP FRT...

Effects of Oxidative Stress and Genotoxic Stress on Zebrafish Aging and Senescence

There are several lines of evidence that suggest that oxygen free radicals can contribute in an undetermined way to the aging process (Balaban et al., 2005). Physiologically, superoxide is generated by the mitochon-drial respiratory chain. The transformation of superoxide into HP and then, under certain conditions, into hydroxyl radicals appears to play an important role in various respiratory chain diseases (Taylor et al., 2003). These may influence the aging process through mutagenesis of mitochondrial DNA (mtDNA) and an increased rate of shortening of telomeric DNA. Therefore, we are interested in the relationship between ROS production and telomere metabolism resulting from genotoxic and oxidative stress in zebrafish by measuring protein

Astroglia protect the brain against ischaemia

Ascorbate Glutathione Cycle

Second, astrocytes are powerful scavengers of ROS the latter being one of the main mediators of ischaemic brain injury. Astrocytes contain high concentrations of glutathione and ascorbate, which are the principal antioxidants in the brain. Ascorbate is a component of neuronal-astroglial exchange, as neurones release oxidized ascorbate, which is accumulated by astrocytes, and subsequently converted into ascorbate ready for a new cycle of ROS scavenging. The ability of astrocytes to protect neurones against ROS has been clearly demonstrated

Examples Of Current Pharmacological Cardioprotective Therapies

Antioxidants Antioxidants are speculated to attenuate or prevent reperfusion injury by acting as (1) free-radical scavengers (2) inhibitors of free-radical generation (3) metal chelators, thereby removing the free-radical-generating catalyst (4) promoters of endogenous antioxidant production or (5) inhibitors of apoptosis via the upregulation of Bcl-2 (a gene involved in the apoptosis signaling pathway) (45). However, experimental animal models and human clinical trials have together provided conflicting results concerning the therapeutic benefits of antioxidants to attenuate reperfusion injury. Interestingly, many typical thiol-containing drugs commonly used for treating both coronary artery disease and heart failure have also been shown to exhibit antioxidantlike effects within the myocardium these include p-adrenergic antagonists propanolol (46), metoprolol (47), and carvedilol (48), as well as angio-tensin-converting enzyme inhibitors, iron-chelating agents, and Ca2+ channel...

Enzymatic synthesis and biological properties of flavonoid polymers

Bioactive polyphenols are present in a variety of plants and used as important components of human and animal diets.215 Flavonoids are a broad class of low molecular weight secondary plant polyphenolics, which are benzo-7-pyrone derivatives consisting of phenolic and pyrane rings. Their biological and pharmacological effects including antioxidant, antimutagenic, anticarcinogenic, antiviral, and anti-inflammatory properties have been demonstrated in numerous human, animal, and in vitro studies. These properties are potentially beneficial in preventing diseases and protecting the stability of the genome. Many of these activities have been related to their antioxidant actions. Green tea is derived from Camellia sinensis, an evergreen shrub of the Theaceae family. Most of the polyphenols in green tea are flavanols, commonly known as catechins the major catechins in green tea are (+)-catechin, ( )-epicatechin, ( )-epigallocatechin, ( )-epicatechin gallate, and ( )-epigallocatechin gallate...

Mechanisms Of Methamphetamine Toxicity

Overall, there is substantial support for the hypothesis that increased DA and glutamate efflux leads to excitotoxic, oxidative, and metabolic stress and that substrates that attenuate the consequences of such stressors (glutamate receptor antagonists, antioxidants, free-radical scavengers, or substrates for the electron-transport chain) are neuroprotective. Evidence for the ability of DA and glutamate to induce excitotoxic, oxidative, and metabolic stress, as well as evidence for their involvement in MA toxicity, are discussed below (Fig. 5). xanthine oxidase. Xanthine oxidase, in turn, promotes the catabolism of xanthine and hypoxanthine to uric acid, yielding oxygen free radicals in the process (84). We have recently shown that MA treatment increases the concentration of uric acid in the striatum, providing evidence that glutamate-mediated excitotoxic stress accompanies MA administration (85). In summary, excitotoxic mechanisms may underlie, in part, the damage to dopaminergic...

Dean Filandrinos Thomas R Yentsch and Katie L Meyers

John's wort has demonstrated clinical efficacy for mild to moderate depression and compares favorably to other more potent or toxic antidepressants. Low side effects and potential benefits warrant its use as a first-line agent for select patients with mild to moderate depression or anxiety-related conditions. Benefits related to other reported uses such as an antimicrobial, agent to treat neuropathic pain, antiinflammatory, treatment alternative for atopic dermatitis, and antioxidant are either not well documented or evidence is encouraging but not conclusive and further study is needed. St. John's wort has an inherently wide margin of safety when taken by itself, with most reported adverse drug reactions (ADRs) being related to skin reactions. Isolated, but more significant ADRs have been reported in relation to neurological effects, impact on thyroid function, and increased prothrombin time. Of greatest concern is the potential for interactions between St. John's wort and...

Cardiovascular Effects

Hawthorn flavonoids have also been shown to decrease the cytotoxicity of hypoxia to human umbilical vein endothelial cells in vitro (Lan et al 2005), as well as protect against delayed cell death caused by ischaemia reperfusion brain injury in gerbils (Zhang et al 2004). These effects have been attributed to improving energy metabolism, scavenging oxygen free radicals and inhibiting production of free radicals in ischaemic myocardium (Min et al 2005, Zhang et al 2004).

Pharmacological Toxicological Effects

Antioxidant Free radicals are highly reactive molecules that have been implicated in cardiovascular and neurodegenerative disease. Hunt et al. generated superoxide radicals in both cell-free and human placental tissue to determine if St. John's wort has antioxidant qualities. They then tested St. John's wort samples that were standardized to either hypericin or hyperforin. In cell-free studies, both samples had a prooxidant effect at a 1 1 concentration. Both showed an inverse dose-related relationship in their antioxidant effect at concentrations from 1 2.5 to 1 20, with 1 20 having the greatest antioxidant effect in both groups. St. John's wort standardized to hypericin was superior in its antioxi-dant properties compared with hyperforin. Both were shown to be significant antioxidants in human placental vein tissue at a 1 20 dilution, the only concentration tested owing to results in the cell-free experiments.

Genetic Models Of Hypertension

In addition to the RAS and sympathetic nervous system in mediating the hypertension in SHR, treatment with antioxidants also reduces blood pressure, suggesting a role for oxidative stress in the hypertension of SHR. For example, treatment with tempol, a superoxide scavenger, reduces blood pressure as does apocynin, an inhibitor of the assembly of the subunits of NADPH oxidase. However, treatment with allopurinol protects against some of the end organ injury in SHR but fails to reduce blood pressure, suggesting that the oxidative stress in SHR that plays a role in their hypertension is mediated via NADPH oxidase, but not xanthine oxidase.

Ophthalmic Conditions

Gold And Black Cheer Clip Art

Bilberry preparations have been used to improve poor night vision, light adaptation and photophobia, myopia and to prevent or retard diabetic retinopathy, macular degeneration and cataracts. Primarily the collagen-enhancing and antioxidant activities of bilberry provide a theoretical basis for these indications. Visual acuity and light adaptation A systemic review of 12 placebo-controlled trials (5 RCTs and 7 placebo-controlled non-randomised trials) concluded that the 2007 Elsevier Australia

Reaction of allyl tetraacetyl fDglucopyranoside and phenyl boronic acid2425

Golden root (Roseroot, Rhodiola rosea L., Crassulaceae) has been used for a long time as a resource in Chinese traditional medicine. Phenylpropenoid glu-coside, such as Rosin (cinnamyl O-P-D-glucopyranoside 118a), was isolated from R. rosea as one of the major active ingredients and reported to be pharmacologically active as antioxidants and neurostimulants. Moreover, some other phenylpropenoid glucoside analogs have been isolated as bioactive substances. For instance, Sachaliside 1 (Triandrin 4-hydroxycinnamyl O-P-D-glucopyranoside 118b) and Vimalin (4-methoxycinnamyl O-P-D-glucopyranoside 118c) have been isolated from the callus cultures of the plant. In addition, Citrusin D (Coniferin 4-hydroxy-3-methoxycinnamyl O-P-D-glucopyranoside 118d) has been isolated from Citrus unshiu as an antihypertensive ingredient, and Icariside H1 (3,4,5-trimethoxycinnamyl O-P-D-glucopyranoside 118e), from Epimedium Sagittatuma (Fig. 24).

Aging Research on Bats

A more recent study tested the free radical theory of aging (Harman, 1956) as an explanation for the extreme longevity of bats. In a comparative study, Brunet-Rossinni (2004) measured mitochondrial hydrogen peroxide production in heart, kidney and brain tissue of the little brown bat, Myotis lucifugus, the short-tailed shrew, Blarina brevicauda, and the white-footed mouse, Pero-myscus leucopus. Hydrogen peroxide production per unit of oxygen consumed was significantly lower in the bat tissues than in the two nonflying mammals. Brunet-Rossinni also measured activity of superoxide dismutase, a key enzyme in the antioxidant defense system of mammalian tissues. Activity of this enzyme did not differ between the three species. Though not an all-inclusive assessment of antioxidant defenses, this study suggests that free radical production is a better predictor of bat longevity than metabolic rate and antioxidant activity. Similar results have been found in birds and other mammals (Herrero...

Cosmetic Skin Irritants

Preservatives antimicrobials, antioxidants, fragrances, colors, and UV filters are potentially irritant components. However, these components are often present in cosmetic preparations at low concentrations and are consequently not affecting the overall irritation potential of the final product. These substances are more often incriminated for their allergic reactions. Antioxidants

Spice Forms And Composition

Most spices owe their distinctive fresh character to their essential oil content that generally ranges from 1 to 5 but even goes up to 15 in certain spices. The nonvolatiles include fixed oils, gums, resins, antioxidants, and hydrophilic compounds, and they contribute to the taste or bite of a spice. Spice extractives come as natural liquids (which include essential oils, ole-oresins, and aquaresins) and dry encapsulated oils (spray-dried powders and dry solubles). Developed from fresh or coarsely ground spices, spice extractives are standardized for color, aroma, and, with some spices, for their antioxidant activity. They are more concentrated than dried or fresh spices and so are used at much lower levels. These extractives provide more consistency than dried spices in prepared foods.

Glucose6phosphate Dehydrogenase Deficiency

There are a limited number of inherited disorders of red cells related to biochemical deficiencies. Glucoses-phosphate dehydrogenase (G6PD) deficiency represents a fascinating and far-reaching disorder that has at its core a metabolic misstep. G6PD is the catalyst in the first stages of the oxidative portion of the red cell's metabolism and a key player is the phosphogluconate pathway, whose role it is to keep glutathione in the reduced state. Glutathione is the chief red cell antioxidant and serves to protect the red cell from oxidant stress due to peroxide buildup and other compounds or drugs. The pathway to reduced glutathione is initiated when NADP (nicotinamide adenine dinucleotide phosphate) is converted to NADPH by the action of G6PD, an essential enzyme in the hexose monophosphate shunt. Once this occurs, NADPH converts oxidized glutathione to reduced glu-tathione and the red cell is protected.

Ginseng And The Cardiovascular System

P. notoginseng saponins (50 mg L and 100 mg L) slowed the breakdown of adenosine triphosphate (ATP) in cultured chick embryo neurons after 2 hours of hypoxia and stimulated the restoration of ATP during 30 min reoxygenation. The saponins (100 mg L), whether administered at the commencement of hypoxia or after induction of hypoxia, also reduced the release of creatine kinase (Jiang et al., 1995). Ginsenosides improved the survival rate of cultured rat hippocampal neurons under anoxic conditions, reducing the efflux of K+ and lactate dehydrogenase (Wang et al., 1995). Similar conditions probably apply to myocardial neurons. Chan et al. (1997) confirmed the myocardial protective effect in the rat heart of the naturally occurring triacylglycerol trilinolein isolated from ginseng. Pretreatment of isolated cardiomyocytes with trilinolein at the low concentration of 10-9 M reduced the 45Ca2+ influx caused by hypoxia normoxia by 34 per cent. When the isolated perfused rat heart was subjected...

Ginseng And The Ageing Process

Diseases of old age may be related to the membrane damage caused by free radical chain reactions and the protein binding of malondialdehyde. Therefore naturally occurring antioxidants able to reduce the lipid peroxide content of the cells are regarded as anti-ageing compounds It is also suggested that internally in the nervous system ginseng acts in the presence of tocopherol against the free radicals by interruption of their formation. Study of the ultrastructure of the myocardium for degenerative signs such as accumulation of lipofuscin and indistinct appearance of the crustae and outer membrane of the mitochondria and collagenous fibres and fibroblasts revealed that ginseng treatment produced decreased degeneration (Wang et al., 1986). Aerobic cells are usually protected from free radical damage by enzymic antioxidants such as catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase and superoxide dismutases, enzymes...

Aging of the Macroglia Mller Cells and Astrocytes

The functional weakening of the CNS that occurs with aging and age-related neurodegenerative disorders has been partially attributed to a decline in mitochondrial function. In particular, it has been demonstrated that oxidative damage occurs to mitochondrial DNA in elderly human brains. Recently, it has been shown that mito-chondrial DNA is particularly sensitive to damage that accumulates due to the loss of protective histones, the reduction in repair systems, and the vicinity of the internal mitochondrial membrane to active oxygen species. The hypothesis that free radicals are involved in the weakening of the mitochondrial function has been confirmed by recent discoveries, that is, the fact that the administration of free radical scavengers such as extract of Ginkgo Biloba (Egb761) improves the function of the brain and liver in elderly animals. Astrocytes are interconnecting cells between the neurons and the surrounding connective tissue (fibroblasts, mesenchymal cells, and...

Patient History And Risk Factors

However, even though recent clinical trials have shown the benefits of lowering IOP in managing glaucoma, some patients continue to lose visual function from glaucoma despite what may appear to be adequately controlled IOP. Of course, IOP-related factors such as nonadherence with medical therapy and IOP fluctuation may contribute to this phenomenon. Other factors, however, may play a role. Research continues to look for IOP independent treatment modalities.18,19 Current areas of research include ocular blood flow, calcium metabolism, blockage of glutamate excitotoxicity, inhibition of nitric oxide production, prevention of tumor necrosis factor activation, modulation of heat-shock protein expression, free radicals, neurotrophins, alpha-2-adrenergic receptor agonists, and other approaches to inhibit apoptosis. The results from a large randomized clinical trial investigating the use of memantine, an N-methyl-D-aspartate receptor antagonist, as a potential neuroprotectant are expected in...

Supportive Therapeutics

The use of corticosteroids is often necessary in PBT and MBT patients to control the symptoms caused by increased intracranial pressure (e.g., headache, nausea and emesis, confusion, and weakness) 1,2,21 . Peritumoral edema is the principal cause of elevated intracranial pressure and is mediated through numerous mechanisms, including the leaky neovasculature associated with tumor angiogenesis, as well as increased permeability induced by factors secreted by the tumor and surrounding tissues, such as oxygen-free radicals, arachidonic acid, glutumate, histamine, bradykinin, atrial natriuretic peptide, and vascular endothelial growth factor (VEGF) 22-24 . Dexamethasone is the high-potency steroid used most often to treat the edema associated with brain tumors 1,21 . It has several advantages over other synthetic glucocorti-coids, including a longer half-life, reduced miner-alocorticoid effect, lower incidence of cognitive and behavioral complications, and diminished...

Nutrition And Esophageal Adenocarcinoma

One particular study observed that the dietary nutrients most beneficial in the prevention of esophageal adenocarcinoma are the antioxidants, principally vitamin C, beta-carotene, and vitamin E (86). In support of this finding is a scientific study that isolated lower levels of vitamin C in the plasma and mucosa of patients with BE compared with those with squamous mucosa (87). This would be consistent with the suggested role of oxidative stress in the patho-genesis and neoplastic progression of BE.

Functional Role Of

The RPE plays a fundamental role in the transport and storage of the retinoids, essential for maintaining the visual cycle. Another function of the RPE is to eliminate components of the acromeres of the photoreceptors through phagocytosis activity mediated by cathepsin D and by the integrins that act as membrane receptors that mediate the phagocytosis. The phagosomes are linked to lysosomes to form phagolysosomes, where they are digested by the intracellular digestive enzymes located at the basal surface of the cell. The final metabolism products are expelled into the choroidal circulation by exocytosis through the Bruch's membrane. If they are not completely digested, they accumulate inside the cells as granules of lipofuscin. These granules increase with age (Iwasaki and Inomata, 1988), especially in the macular area. The constant exposure of the RPE to light, at elevated concentrations of oxygen, together with the high metabolic activity of these cells, creates an environment...

Age Dependent Ultrastructural Changes in Insect Tissues

As mentioned above, adult insects are composed of nondividing (postmitotic) cells. Tissue degeneration with advancing age resembles that of brain and other postmitotic tissues in mammals. The observed changes in dipterans like Drosophila or Musca, however, are not uniform, ranging from ''total degeneration'' to ''poorly developed changes.'' We use Panorpa as a model organism not only for comparative reasons but also because, as said above, this insect shows senescent tissue degeneration even under free-living conditions (Collatz and Collatz, 1981). Figure 21.3 shows an example of tissue degeneration in senescent Panorpa. It should be possible in such an organism to demonstrate protective effects of various drugs (e.g., antioxidants) on tissue degeneration.

Measuring The Changes In The Levels Of Dna Repair Enzymes

Earlier we mentioned the lack of consensus regarding the age-related trend in mitochondrial content of DNA-repair enzymes, with some groups reporting an increase and others reporting a decrease. Both increase and decrease in the activity of DNA-repair enzymes in mitochondria appear to be consistent with increased oxidative stress and an increased number of oxidative mtDNA lesions with aging, phenomena on which a consensus does exist. Therefore, decreased expression of DNA repair enzymes is believed to result in a decreased ability of mitochondria to repair oxidative lesions, which leads to their accumulation. On the other hand, increased expression of DNA repair enzymes was interpreted to represent an adaptive response to increased oxidative stress. The magnitude of this response is believed to be insufficient to completely protect mtDNA when oxidative stress overwhelms antioxidant and DNA-repair systems, resulting in the net accumulation of oxidative DNA lesions. This ambiguity in...

Retinal Nervous Cells

All retinal nervous cells have numerous lysosomes in their cytoplasm. In the NFL the axons of the glial cells contain dense bodies, formed from incompletely digested myelin, which causes the axon's swelling. In some cases, in elderly retinas, astrocytes of large dimensions are found that have very elevated cellular activity and a higher density of intermediate filaments these are called reactive astrocytes. The function of the reactive astrocytes is to protect the neurons (in this case, the ganglion cells) from ischemia producing neurotrophic factors, increasing the expression of antioxidant substances (glutathione, vitamin C) and increasing the production and transport of glucose. However, it has been observed that astrocytes are more vulnerable to oxidative damage during aging. In fact, as the years rollby, the reactive astrocytes cause changes in the geometry and volume of the extracellular space, which slows the diffusion of neuroactive substances.

Annual Fish as a Tool for Screening for Antiaging Drugs

In 1999, we suggested that zebrafish could be used as a model for drug discovery (Jagadeeswaran et al., 1999). Due to the availability of a large number of chemical compounds and the ease of screening the larvae, a number of mutants are being investigated to reverse the phenotype with these chemicals. Such reversal of phenotypes has been applied to aortic coarctation (Peterson et al., 2004). This phenotypic reversal is feasible because the larvae are small and it is possible to accommodate screening in a 96-well format in tiny volumes such that only small amounts of chemical are used. However, in longevity studies such screening depends on the availability of compounds on a large scale and continuous replacement of the chemicals to accommodate for their half-lives. Interestingly, there are several naturally occurring compounds that are either antioxidants or participate in metabolic pathways that affect aging. Thus, in the future, it is anticipated that large-scale screens could be...

Immunofluorescence Flow Cytometry

DNA content, cell cycle, and cell kinetics measurement are used in the assessment of DNA content (ploidy), proliferative activities of cells and tissues, for observing evidence of cell-cycle checkpoint arrest following exposure to DNA damaging agents, and assessing cell survival and death. A broad spectrum of assays for these purposes is available, ranging from simple univariate DNA content measurements, through dual DNA RNA staining. The BrdU-Hoechst method is based on continuous exposure to BrdU.17 In addition, BrdU can be used for pulse labeling, and the incorporated BrdU can be detected by using an anti-BrdU antibody, or by UV exposure (BrdU containing DNA undergoes photolysis) followed by labeling of resultant DNA strand breaks by terminal transferase incorporation of FITC-dUTP. The cyclical expression of cyclins (e.g., cyclin A, B1, D, E) is believed to be central to the regulation of the cell cycle. Abnormal expression may be associated with conditions of altered cell...

Metabolic Aging Studies

All metabolic aging studies on substrate and enzymatic level can profit by the basic similarity of the insect metabolism with that of other organisms, including man. It is therefore not surprising that many studies deal with enzyme activity or substrate changes in aging insects. Their antioxidative system garnered more attention with increasing knowledge of the role of free radicals and oxidative stress in aging and disease. Before showing some examples of such measurements, it seems advantageous to give some technical comments for the work with insects like Phormia.

Chemical Components

Beta-carotene comes in natural and synthetic forms, with the natural form being derived mainly from algal sources and consisting of roughly equal amount of 9-c s and all-trans isomers, with small amounts of the 13-c s isomer. Synthetic beta-carotene is primarily composed of the all-trans isomer with small residues of the 13-c s isomer (PDRHealth 2005). Although all-trans beta-carotene is converted into vitamin A, which plays an essential role in vision, growth, reproduction, immune function and maintenance of the skin and mucous membranes (see Vitamin A monograph), the 9-c s isomer is not converted into vitamin A but does act as an antioxidant (Ben-Amotz & Levy 1996).

International Variation In Rates

In their systematic review of cancer causation, Doll and Peto7 placed the majority of the unexplained excess of cancer observed in migrating populations on dietary factors acting directly or indirectly through their potential impact on lifestyle factors (e.g., reproduction, exercise). During the past 20 years, there has been a concerted effort by epidemiologists and experimentalists to verify the role of dietary factors in the etiology of cancer. Much of this effort has been directed toward proving the detrimental effects of dietary fat and the potential protective effect of a wide range of dietary antioxidants.8 Unfortunately, it now seems likely that dietary factors are directly related to only a relatively small number of cancers, primarily, and not surprisingly, those of the digestive tract (esophagus, stomach, and large bowel). At the same time, it appears increasingly likely that the majority, if not all, of the hormone-related cancers have little direct relationship to any...

Pharmacological Toxicological Effects 51 Immunological Effects

One constituent of Echinacea, the polysaccharide arabinogalactan, has been identified as a macrophage activator in vitro, causing macrophages to attack tumor cells and microorganisms. When injected into mice intraperito-neally, arabinogalactan was able to activate macrophages. Macrophage production of tumor necrosis factor (TNF)-a, interleukin (IL)-1, and interferon-B2 was increased in vitro, and production of oxygen free radicals was increased both in vitro and in vivo (6).

Antimicrobial Activity

Repair, immune stimulation, and antiproliferative effects (regulation of cell cycle progression, modification of pathways of signal transduction, and induction of apoptosis) (47,48). Other factors that may play a role in cancer prevention are cytochrome P450 enzyme stimulation, sulfur compound binding, or antioxidant activity (49). The chemical components of garlic that have shown these effects are ajoene, allicin, diallyl sulfide, diallyl disulfide, diallyl trisul-fide, SAC, and S-allylmercaptocysteine (48). Heating garlic (microwave or oven) destroys the active allyl sulfur compound formation however, if crushed garlic is allowed to stand for 10 minutes before heating, the total loss of anticancer activity is prevented (50). Although much of the anticancer data is from in vitro and animal studies, epidemiological studies are available (51).

Nervous System Effects

The pharmacological basis of the effects of GBE on brain function has been addressed in a number of studies. One study (6) showed that dietary GBE 761 (prepared by the Henri Baeufour Institute) protected striatal dopaminergic neurons of male Sprague-Dawley rats from damage caused by (MPTP). MPTP, which has caused Parkinsonism in young drug abusers, is thought to damage these neurons through formation of free radicals. The mechanism of GBE's protective effect was attributed to an antioxidant action, rather than to prevention of neuronal uptake of MPTP. Whether chronic GBE ingestion could prevent development of idiopathic Parkinson's disease in humans remains to be seen.

Hiv1 Infection And Nmda Receptorrelated Neuronal Apoptosis

Additionally, activated macrophages microglia and possibly astrocytes produce inflammatory cytokines, including tumor necrosis factor (TNF)-a and interleukin (IL)-1p, arachidonic acid metabolites, and free radicals (ROS and NO) that may contribute to excitotoxic neuronal damage (7,45). TNF-a and IL-1P may amplify neurotoxin production by stimulating adjacent glial cells and by increasing iNOS activity (45) Fig. 2 . Fig. 2. Current model of HIV-associated neuronal injury. Immune activated and HIV-infected brain macrophages microglia release potentially neurotoxic substances. These substances, emanating from macrophages and also possibly from reactive astrocytes, contribute to neuronal injury and apoptosis as well as to proliferation and activation of astrocytes (astrocytosis). A major mode of entry of HIV-1 into monocytoid cells occurs via the binding of gp120 and, therefore, it is not surprising that gp120 (or a fragment thereof) is capable of activating uninfected macrophages to...

Biochemical Studies Of Agerelated Cataracts

Crystallin modifications associated with cataracts The lens crystallins are a major potential target for accumulating damage associated with age-related cataracts, although there are certainly others. Thus, as the crystal-lins accumulate modifications and damage over the lifetime of an individual, their ability to participate in appropriate intermolecular interactions, and even to remain in solution, decreases. Whether proteins in age-related cataracts become insoluble as a result of complete or partial denaturation, or whether they simply become less soluble due to modifications that leave their protein folds largely intact or both, is not currently known. However, it seems clear that modifications to crystallin proteins accumulate with aging and accelerate during cataractogenesis, and the combination of crystallin modification, disulfide-crosslinking, denaturation, and aggregation results in loss of lens transparency and cataract formation (Hanson et al., 2000). The protein...

Cardiovascular Complications

Cardiac late effects are most closely associated with the anthracycline class of chemotherapeutic agents (doxorubicin, mitoxantrone, epirubicin). One of the mechanisms by which these drugs work is the creation of free radicals which damage the DNA of replicating cancer cells. However, free radicals also damage normal tissue. Cardiac muscle is particularly vulnerable because it lacks sufficient glutathione, which neutralizes free radicals. As a result, cardiac muscle accumulates progressive damage with increasing exposure to anthracycline drugs resulting in cardiomyopa-thy and congestive heart failure. This may also lead to arrhythmias. Consequently, the anthracycline class of chemotherapeutic agents each has limits above which exposure is not considered safe for example, 450 mg m2 for doxorubicin and 900 mg m2 for epirubicin. Several drugs commonly combined with anthracyclines in breast cancer, such as cyclophosphamide, paclitaxel, and herceptin also have cardiac toxicity, thereby...

Prevention Of Cataracts

Numerous observational and prospective clinical studies have been performed to examine the effect of vitamin C alone or in combination with other antioxidants on cataract. It is suspected that vitamin C protects the lens of the eye from oxygen-related damage over time by both direct free radical scavenging activity and indirect activity. This is achieved primarily by protecting endogenous alpha-tocopherol (the major Iipid-soluble antioxidant of retinal membranes) against oxidation induced by UV radiation and by regenerating it (Stoyanovsky et al 1995).

Ginseng Memory And Intellectual Skills

Although brain function is still poorly understood it seems clear that the chemistry of the cholinergic system in the brain reticular formation and hippocampus is critical. In living systems free radicals, strongly active, highly reactive substances, such as singlet oxygen, superoxide anion and hydroxy radical are formed at tissue level in parallel with oxygen consumption for cell respiration and such radicals can affect targetted cells. Naturally occurring endogenous protective systems normally neutralise free radicals but if such systems are inadequate or the production of free radicals is excessive, the brain becomes disturbed. Free radicals are normally produced in small amounts only and are mopped up endogenously by scavenger enzymes e.g. superoxidodismutase, catalase, peroxidase, tocopherols, ascorbic acid, etc. In the event of scavenger enzymes and antioxidants failing to neutralise the free radicals, reaction with unsaturated fatty acids in the various biomembranes yields...

Biochemistry And Pathology Of Macular Degeneration

Oxidative aspects Oxidative damage is implicated in the pathogenesis of AMD by both theoretical considerations and experimental data (Roth, Bindewald, and Holz, 2004). The retina has a highly active metabolism with a resultant high oxygen demand, and is exposed to light and polyunsatu-rated fatty acids, all of which tend to increase its susceptibility to photo-oxidative damage. In a fashion somewhat analogous to that seen in the lens, as the retina ages its antioxidant defenses begin to decline, here including both antioxidant enzymes and antioxidants such as lutein, and macular pigment density. As the RPE age oxidation of lipids and other cellular components result in accumulation of nonmetabolizable material as lipofuscin in the lysosomes, leading to their enlargement and formation of lipofuscin granules. These closely parallel drusen formation in time and distribution in the retina. In addition, epidemiological correlation of AMD with light exposure, age, and light pigmentation as...

Examples Of Metabolic Determinations

The thiole glutathione (GSH) is the most important nonenzymatic antioxidant in organisms and exists in considerably high concentrations in all cell types. GSH can react with electrophilic compounds or free radicals. The content of GSH in aging tissues generally declines, and it is assumed that this decline reduces the capacity to defend toxic effects of free radicals. Buthionin sulfoximine (BSO) is an irreversible inhibitor of the y-glutamylcystein synthetase, which is a key enzyme for the synthesis of GSH. BSO can be used to empty the intracellular stores of GSH. This allows conclusions about the protective role of GSH.

Cardiovascular Protection

There are a number of ways in which beta-carotene may act to protect against cardiovascular disease. Free radical scavenging may prevent cellular transformations leading to atherosclerosis and protection of LDL oxidation may further act to protect against atheroma formation (Halliwell 1993). Other mechanisms proposed for the possible favourable effect of antioxidants include an increase of HDL cholesterol and the preservation of endothelial functions (Tavani & La Vecchia 1999). Patients with acute myocardial infarction (AMI) have also been shown to have reduced plasma antioxidant vitamins and enhanced lipid peroxidation upon thrombolysis, suggesting that antioxidants may reduce free radical generation processes in reperfusion injury in AMI (Levy et al 1998).

Cardiovascular Disease

Vitamin E is most well known for its effects on the cardiovascular system, as it inhibits platelet aggregation and adhesion, smooth muscle cell proliferation, has an antiinflammatory effect on monocytes, improves endothelial function and decreases lipid peroxidation (Kaul et al 2001). It also modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins) (Munteanu et al 2004). Its ability to reduce oxidative stress both directly and indirectly as part of the antioxidant network is of particular importance because oxidation of LDL is a key process in atherogenesis, enhancing foam cell and early lesion formation (Terentis et al 2002). Since these early studies were published, newer intervention studies using vitamin E as a sole agent or in combination with other antioxidants have generally produced negative results however, a number of important factors could account for some of the inconsistent results (see...

Dietary Prostate Cancer Risk Factors

Antioxidant vitamins and minerals are of great current interest, not only as antiprostate cancer agents but also as anticarcinogenic agents in a broad sense. Antioxidants are potential anticancer agents because they bind free radicals, chemical entities that can damage DNA, create mutations, and lead to malignant transforma-tion.12 Two antioxidants are of special interest in the context of prostate cancer. Lycopene is a member of the carotenoid family of vitamins and is the major antioxidant in tomatoes and tomato products. It is concentrated in the prostate and may suppress prostate cancer growth.13 Observational studies have demonstrated inverse relationships between lycopene and or frequency of consumption of tomato products and prostate cancer risk.14 Moreover, prospective serological studies have shown that high circulating levels of lycopene predict low prostate cancer risk.15 Additional prospective dietary and serological studies are ongoing to confirm this relationship and...

Studies on health effects

A review ofthis evidence indicates that transport-related air pollution contributes to an increased risk ofdeath, particularly from cardiopulmonary causes. It increases the risk ofrespiratory symptoms and diseases that are not related to allergies. Experimental research indicates that the effects are linked to changes in the formation of reactive oxygen species, changes in antioxidant defence, and increased inflammation, thus providing some indication of mechanisms ofsusceptibility. Laboratory studies indicate that transport-related air pollution may increase the risk ofdeveloping an allergy and can exacerbate symptoms, particularly in susceptible subgroups. The evidence from population studies, however, does not consistently support this notion. While only a few studies have been conducted on the effects of transport-related air pollution on cardiovascular morbidity, they report a significant increase in the risk of myocardial infarction following exposure. Other studies and the...

Susceptibility to Genomic Injury Genomic Instability

Repair of DNA double-strand breaks is often inaccurate in the pre-leu-kemic Bloom's syndrome and in FA (Gaymes et al. 2002 Langland et al. 2002). Impaired response to oxidative stress has also been implicated in the pathophysiology of MDS. Defects in both glutathione transferase theta 1 (GSTTi) and NADPH quinone oxyreductase (NQOi) have been associated with an increased risk of myelo-dysplastic syndrome (Chen et al. 1996 Farquhar and Bowen 2003 Rothman et al. 1997). Glutathione is both an antioxidant and a cofactor for many antioxidant enzymes that are important in the metabolism of various toxins and carcinogens. NQO1 is another gene involved in antioxidant mechanisms. Mutations in this gene have been reported in association with benzene-induced bone marrow damage.