Free Radicals

Antioxidant Functions of Copper

Mitochondria,84 increases the production of breath ethane85 and increases the susceptibility of tissues to lipid peroxidation.86,87 Lipid hydroperoxides and ethane are byproducts of lipid oxidation and the results of these studies indicate that lipids in membranous cellular components are subject to increased oxidation during Cu deficiency. Cu deficiency also increases the carbonyl content of the alpha and beta subunits of spectrin in erythrocyte membranes in rats88 and proteins with molecular weights of 90 kDa and 100 kDa in mitochondria of HL-60 cells grown in culture.89 Oxidation of proteins converts some of their amino acid side chains to carbonyl derivatives, and the presence of carbonyls is a marker of ROS-induced protein oxidation.90 Thus, the increase in protein carbonyl content is evidence that Cu deficiency increases the susceptibility of intracellular proteins to oxidative modifications by ROS. Low dietary Cu intake in rats has also been shown to increase the activity of...

Antioxidant Antiinflammatory Activity

Many classes of antioxidants and anti-inflammatories have shown chemopreventive activity in animal models (Wattenberg, 1978 Kelloff et al, 1995b Singh and Lippman, 1998a,b). Those with activity derived by inhibition of AA metabolism are among the most promising The first is the PG synthetic pathway, involving the enzyme PG H synthase (PHS). This enzyme has two activities - COX, which catalyses the formation of PGG2 from arachidonic acid, and hydroperoxidase, which catalyses the reduction of PGG2 to PGH2. To return to its native state, the hydroperoxidase requires a reducing cosubstrate procarcinogens, e.g. arylamino and arylnitro compounds, are such substrates. According to the model proposed, the carcinogens are activated (oxidized) during catalysis to free radicals and electrophiles that can form adducts with DNA and initiate carcinogenesis. This process can be stopped in four ways (1) at formation of PGG2 via inhibition of COX, (2) by inhibition of peroxidase activity, (3) by...

Hsp And Antioxidant Enzyme Expression In

There are a number of factors that provide evidence in favor of an imbalance between oxidants and antioxidants in DMD. A number of studies have examined the antioxidant status in DMD and found either decreased or increased (as well as normal) levels of antioxidants in the blood or the muscle, respectively, of patients suffering DMD (reviewed in ref. 17) (Table 1). When the products of lipid peroxidation were examined either in the blood or in the muscle, all studies (6 6) indicated increased lipid peroxidation (17). However, among 15 studies evaluating the results of antioxidant therapy (e.g., selenium, vitamin E, orgotein, allopurinol), only 3 showed a significant benefit in DMD (17). Using Western blotting and monospecific antibodies, we observed an increased expression of GSHP and catalase in muscle homogenates of certain patients with DMD (L. Bornman et al., submitted). Our results thus provide further evidence in favor of an oxidative load in DMD muscle fibers. The controversial...

Spirulina As An Antioxidant

Currently, S. platensis is gaining a tremendous attention not only for its nutritional values but also for its potential antioxidant properties. Experimental and epidemiolo-gical evidences suggest that oxidative stress characterized by excessive generation of ROS is a critical player in many pathological states including the inflammatory diseases, neurodegenerative diseases, atherosclerosis, cardiovascular diseases, diabetes mellitus, cancer, and reperfusion injury.108-112 Therefore, the therapeutic use of natural antioxidants appears to be promising in either prevention or protection or both from those diseases among humans. Many algal products appear to improve thenutritional quality of foods because of their ability to combat oxidative damage to cells.113 Spirulina and C-phycocyanin have been shown to protect against the oxidative stress-mediated pathological conditions.104'106'114'115 Studies have shown that Spirulina has potent antioxidant activity 105,106 and scavenges hydroxyl...

Mechanisms Of Antioxidant Activity Of Spirulina

Harmful free radicals such as superoxide anion (an ROS) hydroxyl, alkoxyl, and peroxyl radicals are produced in various tissues because of the partial reduction of some oxygen molecules in the mitochondria. In various tissues (liver, lung, brain) an electron transport chain from NADPH to water occurs (with insertion of one oxygen atom into xenobiotic substrates) that use cytochrome P450 as the electron acceptor. Here futile recycling of electrons in the absence of substrates produces the superoxide

Antioxidant Effects Of Spirulina

In Vitro and In Vivo Antioxidant Effects of Various Extracts of Spirulina The antioxidant properties of Spirulina and its extracts have recently attracted the attention of researchers (Table 5.1). In one of the earliest studies, Manoj et al.12 reported that the alcohol extract of Spirulina inhibited lipid peroxidation more significantly (65 inhibition) than the chemical antioxidants like -tocopherol (35 ), butylated hydroxyanisole, an antioxidant (BHA) (45 ), and beta-carotene (48 ). The water extract of Spirulina was also shown to have better antioxidant effect (76 ) than gallic acid (54 ) and chlorogenic acid (56 ). An interesting aspect of their finding is that the water extract had a significant antioxidant effect even after the removal of polyphenols. In another study, by Zhi-gang et al.,13 the antioxidant effects of two fractions of a hot water extract of Spirulina were studied using three systems that generate superoxide, lipid, and hydroxyl radicals. Both fractions showed...

Addition of Stabilizers Such as Antioxidants and Stabilization through the Use of Packaging

Often, the effect of oxygen can be eliminated by the addition of antioxidants. Oxidation of lovastatin in aqueous solution is inhibited by antioxidants such as a-tocopherol and butylated hydroxyanisole (BHA), as shown in Table 9.553 Similarly, the inhibition of the oxidation of cholecalciferol by a-tocopherol and ascorbic acid554 and the inhibition of the oxidation of NSC-629243 (an O-alkyl-N-aryl thiocarbamate see Scheme 49) by thioglycolic acid187 have been reported. The ability to inhibit oxidative photodegradation of benzaldehyde has been utilized as a measure of the antioxidant effects of polyhydric phenols.555 Pharmaceuticals are often stabilized by the utilization of packaging containing an antioxidant.556 For example, the photooxidation of cianidanol in the solid state was inhibited by lowering the concentration of oxygen with the use of an oxygen absorbent, as illustrated in Figure 132.402

Antioxidants

The damage caused by ROS to matrix and cellular proteins, lipids and nucleic acids and ROS mediated signalling contribute to the pathogenesis of ARDS.55 The thiol groups of glutathione concentrated in the lower respiratory tract normally provide physiological antioxidant protection. However, the concentration and activity of glutathione in broncho-alveolar lavage fluid of patients with ARDS is reduced.56 Intravenous administration does not reliably raise glutathione levels, but glutathione synthesis is stimulated by N-acetylcysteine (NAC) and procysteine (L-2-oxothiazolidine-4-carboxylate). Administration of these precursors increases plasma, erythrocyte, neutrophil, and BAL fluid concentrations of glutathione in patients with ARDS, although a complete effect may require 10 days of treatment.57 Early results of NAC therapy were promising, but several trials have found no difference in mortality, length of ventilatory support, or improvement in oxygenation in patients with established...

Host Risk Factors For Severity Of Illness

Sulfonamide treatment exacerbates the severity of illness caused by rickettsial infection. It is possible that sulfonamides increase oxidative stress, a pathogenic mechanism of cell injury in R. rickettsii infection in vitro. Glucose-6-phosphate dehydrogenase deficiency is associated with the occurrence of fulminant Rocky Mountain spotted fever in African-American males and has been reported in unusually severe cases of murine typhus and Mediterranean spotted fever. Glucose-6-phosphate dehydrogenase is a component of the antioxidant protective mechanisms, and its deficiency could result in increased damage secondary to oxidative stress. Fulminant Rocky Mountain spotted fever is associated with hemolysis whether or not the patient is deficient in glucose-6-phosphate dehydrogenase. The release of iron-containing hemoglobin from erythrocytes could exacerbate the reactions involving free radicals of oxygen that are hypothesized to play a role in tissue injury in spotted fever...

Oxygen Sensing And Gene Activation

The molecular basis for oxygen sensing has not been established and may differ between tissues. Current evidence suggests that, following activation of a hypoxic sensor , the signal is transmitted through the cell by second messengers which then activate regulatory protein complexes termed transcription factors.40 41 These factors translocate to the nucleus and bind with specific DNA sequences, activating various genes with the subsequent production of effector proteins. It has long been postulated that the hypoxic sensor may involve haem-containing proteins, redox potential or mitochondrial cytochromes.42 Recent evidence from vascular smooth muscle suggests that hypoxia induced inhibition of electron transfer at complex III in the electron transport chain may act as the hypoxic sensor .43 This sensing mechanism is associated with the production of oxygen free radicals (ubi-quinone cycle) that may act as second messengers in the activation of transcription factors.

Heterogeneity and Mitochondria

There is a good experimental basis to consider a possible involvement of mitochondria in ageing, mainly from data obtained in postmitotic tissues. Mitochondria are the major source of oxygen-free radicals in cells, which by their very nature are highly unstable molecules with an unpaired electron in the outer orbital, which can react indiscriminately with any organic molecules present in a cell. The main cause for increased mitochondrial production of free radicals is still unclear. One suggestion has been accumulation of mutations in the mitochondrial (mt) DNA (Harman 1972). Mitochondria, like telomeres, are highly susceptible to oxidative damage - and for good reasons. There is close physical proximity between the sites of reactive oxygen species production and the mtDNA. Moreover, there is relative inefficiency of the repair mechanisms in mitochondria and, unlike the nuclear genome, the mitochondrial genome is not protected by histones. Accordingly, mtDNA damage was found to be...

Reactive Oxygen Species and Exercise

Aerobic exercise is intrinsically linked to increased oxygen consumption. During exercise the body as a whole uses 10-fold more oxygen than at rest, while in muscle tissue oxygen consumption may increase by 50 to 100-fold 40 .Various studies have demonstrated a connection between this increase in oxygen consumption during exercise and the formation of reactive oxygen species (ROS). In addition it has been shown that macromolecular structures within the cell can be damaged by elevated ROS. In fact, oxidative stress contributes to the accumulation of somatic mutations and oxidative damage to mtDNA. This has been apparent in mitochondrial diseases 41 , tumorgenesis 42 , aging 43 , degenerative diseases 44,45 , and diabetes 46 . However, skeletal muscle not only has the ability to produce ROS, but also has an elaborate system to regulate these reactive molecules and prevent their damaging effects. The cellular antioxidant defense system includes the mitochondrial and cytosolic forms of...

Strength From Bonding And Structure

A covalent bond is formed when two atoms together bind two electrons, one of which belongs to one nucleus and the other electron belongs to the other nucleus. Each atom in the intact covalent bond would have an orbital with these two electrons oriented with opposite spins. Such a bond in a vacuum, if broken, would yield two free radicals. Not so for the weaker apolar and van der Waal's bonds. Such paired electrons are needed to satisfy the Pauli principle of physics. A consequence is that a covalent bond is much more stable than the two free radicals formed by splitting it. Such free radicals arising within a molecule in an aqueous environment would cause a water molecule to split in such a way that the OH would bind to one and the H to the other radical, eliminating the free radicals and forming only covalent bonds. It therefore follows that splitting a molecule's bond in an aqueous environment to create two molecules is easier than in the absence of water where forming free radicals...

Detoxifying Enzymes

The detoxifying power of a tissue can be better described by monitoring some enzymatic ratios. In particular, catalase SOD and GSH Px SOD ratios can be considered as an index of the tissue ability to counteract oxidative stress injury. When these ratios increase, this might indicate an activation of antioxidant enzymes system. When these ratios decrease, this may be indicative of a lower scavenging efficiency that might result in an increase of ROS levels and in a higher risk of oxidative damage17. In our experiments, in the control and hypotaurine-treated groups both the above ratios decrease, while in the taurine-treated group they increase after hyperoxia. These results might indicate that the presence of taurine enhances enzymatic scavenging efficiency when the tissue undergoes oxidative stress risk. This increased efficiency protects the tissue as shown by the ultrastructural analysis. In the untreated muscles, the scavenging efficiency is lowered under hyperoxia with the result...

Mitochondrial Content and Function During Aging

Further investigation is nevertheless needed to relate the series of events connecting defective mitochondria, muscle fiber breakage, and muscle atrophy. Answers may lie in the pivotal role that mitochondria play in reactive oxygen species (ROS) production and apoptosis regulation. An early proposal from Harman 119 suggesting that increased ROS could be involved in age-related alterations has been and is still thoroughly investigated, since mitochondria are both the source and the target of those byproducts. ROS production has generally been shown to be elevated in aged skeletal muscle 120, 121 , and it is known to damage mtDNA, organelle phospholipids, and proteins 122-124 . In contrast, results concerning the expression of antioxidants enzymes (e.g., MnSOD, glutathione peroxidase, catalase) activities are not altogether clear. Some studies show decreases, while others illustrate increases or no changes with aging 125-127 . Nevertheless, because of the general increase in oxidative...

Results And Discussion

The efficiency of ROS scavenging measured as a ratio between specific activities of catalase and SOD show some important modifications. Catalase specific activity markedly increased in methylene blue + light treated cells. SOD specific activity does not strongly change in any of the considered conditions, even if there is a little decrease when cells are stressed in the presence or in the absence of hypotaurine. The ratio catalase SOD doubles with respect to the control cells, indicating a positive response of the cells to oxidative stress. The ROS scavenging efficiency is increased even if it is not sufficient to avoid cell death. In the presence of hypotaurine this ratio does not change when cells are stressed and it is a little over the control. These results suggests that the protection by hypotaurine is not imputable to an induction of antioxidant enzymatic response.

Potential of Exercise to Attenuate Age Related Mitochondrial Dysfunction

In response to a bout of exercise, total oxygen consumption is increased by 10- to 15-fold in skeletal muscle and can ultimately result in an elevation in ROS production 135 . It has also been shown that the rate of production of ROS from muscle mitochondria from exercised rats was increased when compared to rested animals 120,136 . Several lines of evidence support the fact that exercise may be beneficial in attenuating an aging-induced ROS imbalance. Old animals that were submitted to an 8-week treadmill exercise program, or 1 year of swimming, were found to have reduced oxida-tive damage compared to untrained old rats, notably due to alterations in antioxidant defenses 137,138 . At the mitochondrial level, recent work from Leeuwenburgh's group has reported a 10 decrease in mitochondri-al hydrogen peroxide production 139 in animals resulting from lifelong voluntary wheel running. This may occur through the exercise-induced increase in mitochondrial content, a better redistribution...

Inflammatory mediators

Animal model work suggests that free radicals are fundamental to the tissue damage resulting from proinflam-matory stimuli and that antioxidants, including glutathione and superoxide dismutase, are important protective mechanisms. Similarly, in humans oxidant stress is increased and plasma antioxidant levels are reduced in patients with ARDS.55 67 Nitric oxide may play a role in septic lung injury as nitrotyrosine, a product derived from peroxynitrite, is found in increased amounts in patients with ARDS.68 The lipid mediator platelet activating factor (PAF) can activate both neu-trophils and platelets and administration can mimic many features of lung injury. Other mechanisms for the generation of barrier dysfunction during the inflammatory phase include pathological changes in the regulation of apoptosis. In this regard soluble Fas ligand (sFasL) has been shown to drive alveolar epithelial cell apoptosis in vitro, and to cause lung injury with increased airway cell apoptosis in vivo,...

Metabolic Functions

Could increase the risk for vascular disease. Majors quotes others that indicate elevated homocysteine may promote the oxidation of LDL and have the potential to increase free radicals.54 Moustapha et al. believe their research confirms that patients with elevated plasma homocysteine levels have a greater likelihood of developing thrombotic or atherosclerotic complications.55 Stanger et al., investigating the management of homocysteine, folate and B vitamins in treatment of cardiovascular and thrombotic diseases, reported that a plasma homocysteine concentration of 10 pmol l could produce a linear dose-response relationship for increased risk of cardiovascular disease. The researchers further stated that hyperhomocysteinemia, as an independent risk factor for cardiovascular disease, is thought to be responsible for 10 of the total risk.56

Attempts to enhance survival of transplanted dopamine neurons

Only about 5 of neurons in the SNc are dopaminergic, and only about 5-20 of grafted dopamine neurons survive transplantation (Kordower et al., 1998 Sortwell et al., 2004). Approximately 20-30 of mes-encephalic cells die during preparation of the tissue for transplantation probably due to ischemia or trauma associated with dissection and dissociation of the cells (Fawcett et al., 1995 Brundin et al., 2000a) and another 60-70 of cells die during the first week post-transplantation (Barker et al., 1996 Sortwell et al., 2000). Enhanced survival of transplanted cells would facilitate the logistics of performing a fetal nigral transplant procedure and could potentially yield enhanced clinical results. Considerable research has focused on ways of trying to improve this yield. Mesencephalic cell graft aggregates can be maintained in culture and exposed to agents such as antioxidants and trophic factors that promote their survival that promote their survival following transplantation (Meyer et...

Subclinical Mastitis As A Risk Factor For Motherinfant Hiv Transmission

Since subclinical mastitis was common among Bangladeshi women and was associated with poor infant, and possibly also maternal, health, we extended our investigations to other populations. Of Tanzanian women participating in a trial of food-based micronutrient supplementation, 13 at 1 month postpartum and 11 at 3 months had subclinical mastitis.11 Milk Na K ratio correlated with maternal plasma acute phase proteins. Biologically it seems more plausible that subclinical mastitis may result from systemic infection or inflammation than that a localised and subclinical inflammation can result in a detectable systemic inflammation. Systemic illness is common in the first few months postpartum16 and can increase permeability of other epithelia such as that of the gastrointestinal tract.17We also found in the Tanzanian cohort that supplementation of women during the last trimester of pregnancy and the first 3 months postpartum with vitamin E-rich sunflower oil, but not with vitamin A-rich red...

Changes Induced by Cytotoxic Therapy 10121 Anthracyclines

The earliest changes seen in cardiac myocytes after exposure to doxorubicin include swelling of the sarcoplasmic reticulum, and mitochondria with occasional nucleolar changes 6, 7 . Large vacuoles that probably distend SR displace mitochondria and contractile elements. Injuries to the mitochondria, SR and sarcolemma affect both calcium transport mechanisms and intracellular calcium concentrations. Those injuries, in concert with the actions of other potential mediators of anthracycline-induced cardiac damage (e. g. free radicals, prostaglandins, histamines and metabolites), result in the morphologic changes noted on endomyocardial biopsies taken from patients undergoing anthracycline therapy, as well as cell death 8,9 .

Signaling Pathways Implicated in Cell Intrinsic HSC Ageing

The free radical theory of ageing proposed by Harman in 1956 suggests that ageing, as well as age-related degenerative diseases, can be attributed to the deleterious effects that free radicals impose on a cell (Harman 1956 see Passos et al., this volume). Thus, long-lived cells run the risk of accumulating damage from oxidative stress as a result of normal metabolism, exposure to cellular toxins, and cellular stress. Ataxia telangiectasia mutated (ATM) is a protein kinase encoded by the ATM gene (Savitsky et al. 1995), which is mutated in the disease ataxia telangiectasia (AT). ATM functions by regulating telomere length, its primary role, and response to cellular damage (Wang et al. 2005). HSCs in ATM-'- mice, as expected, show signs of telomere dysfunction, increased cellular oxidant levels, and reduced numbers of HSCs. This dysfunction in the HSC compartment results in aplasia and severe anemia in mice as early as six months of age. Administration of the hydrogen peroxide...

Bioartificial Organ Rejection

Initiates the cellular and humoral immune response. The former leads to activation of cytotoxic cells, macrophages and other cells of the immune system. These cells must be prevented from contacting grafted tissue, a requirement relatively easy to meet. More difficult is keeping out components of the humoral immune response. These include cytokines, for example, interleukin-1, which can have detrimental effects on beta cells, as well as the antibodies formed as a response to the antigens, which have leaked across the barrier. In addition, there may always be some antibodies already present in the antibody spectrum of the blood serum which correspond to cell surface antigens (e.g., major histocompatibility complexes) on allo- or xenografts. Antibodies produced during preexisting autoimmune disease, such as type I diabetes, might also bind to surface antigens on allogeneic cells. Finally, macrophages and certain other immune cells can secrete low-molecular weight reactive metabolites of...

Basal Lamina And Schwann Cell Myelination

Facing the basal lamina and a surface facing the lumen or the axon, respectively (Bunge and Bunge 1983). In vitro co-cultures of rat dorsal root ganglion (DRG) neurons, seeded with Schwann cells, demonstrated that with the addition of serum and ascorbic acid, triple helical collagen could form, a basal lamina could be assembled, and myelination could proceed (Carey et al. 1986 Eldridge et al. 1987 Eldridge et al. 1989). Later, similar studies showed that partial myelination could be achieved in the absence of serum and ascorbic acid, as long as a defined medium (B27) containing antioxidant was provided (Podratz et al. 1998 Podratz et al. 2004). In this system, although myelin was formed in the absence of basal lamina, laminin was still present around Schwann cells (Podratz et al. 2001). This suggests that laminins themselves, but not the assembly of a complete basal lamina, are required for myelination. This conclusion is supported by several examples in vivo, where myelin can be...

Pathophysiologic Changes Induced by Cytotoxic Therapy

Alkylating agents, such as the nitrosoureas, are known to cause late onset pulmonary fibrosis. The pathology of the fibrosis noted after nitrosourea therapy demonstrates less inflammation than bleo-mycin-induced fibrosis, but consistency in Type I depletion and Type II hyperplasia with excess collagen deposition. The formation of free radicals and lipid peroxidation of phospholipid membranes may also be the mechanism by which cyclophosphamide and mitomycin damage the capillary endothelium 25 . Permeability increases, resulting in interstitial edema. Hyaline membranes form as plasma proteins, and fluid enters the alveoli through the denuded epithelium. Type I pneumocytes swell, become necrotic and are replaced by cuboidal cells. Proliferation of fibroblasts then occurs. This process may evolve slowly, with fibrosis increasing over a period of years. Interstitial pneumonitis (either the desquamative type that appears to be an earlier stage or the usual type with fibrinous exudation,...

Oxidative Stress And Mitochondrial Toxicity Caused By Nrtis

As mentioned above, energy depletion from altered mtDNA replication in NRTI toxicity is a logical consequence (3,4,8,9,17-21). Furthermore, it follows that related events of oxidative stress also impact on energetics and mtDNA replication. Oxidative stress is defined as an imbalance between the production of reactive oxygen species (i.e., superoxides, hydrogen peroxide, lipid peroxides, hydroxyl radicals, and peroxynitrite) and the cellular antioxidant defenses that prevent damage from those moieties (22). Mitochondria are a logical target for oxidative stress, based on their ability to generate reactive oxygen species, and mitochondria may be primarily involved in oxidative stress associated with HIV therapy. Chronic zidovudine (ZDV) treatment induces oxidative damage of skeletal muscle in mice (13).

Department of Plant Physiology Faculty of Agricultural Biotechnology Agricultural University of Athens Iera Odos 75

The volatile oils of sage are chemically complex mixtures, often containing in excess of 100 individual components (Waterman 1993, Hay and Waterman 1993), although terpenoid molecules predominate. They have low boiling points and can be recovered from the plant tissues by steam distillation. In addition to flavouring foods, volatile oils can also act as antioxidants and preservatives against food spoilage, while a broad range of applications in aromatherapy and health care has been observed during the last fifteen years (Hay and Waterman 1993).

Figure 5 Carcinogen damage to DNA

Include 8-hydroxydeoxyguanosine (formed by the hydro-xylation of guanine bases), which is considered to be a mutagenic lesion in DNA, and believed to be formed by attack of the DNA by highly reactive free radicals. Free radicals are a common product of a number of chemical carcinogens, which either carry an unpaired (and so-called radical) electron on the molecule, or are formed from oxygen (oxygen free radicals) via metabolism. Hydro-xylations and other more extensive radical damage may result in the loss of bases and the creation of abasic sites, either apurinic or apyrimidinic. Free radical attack of DNA is also responsible for the formation of genotoxic strand breaks in the DNA. These can be formed at either one strand or may span both sides of the sugar--phosphate backbone resulting in a double-strand break.

Potential Mechanisms Of Nrtiinduced Mitochondrial Toxicity

Evidence has been mounting that the pathology of NRTI-induced defects of electron transport may, to some degree, be mediated by reactive oxygen species, which damage cellular proteins, lipids, and mtDNA itself, possibly causing a vicious cycle leading to progressive worsening of mitochondrial function. ZDV has been shown to increase mtDNA oxidized guanosine levels (28,29). Two recent studies supported a potential role for oxidative stress in NRTI-induced mitochondrial dysfunction (30,31). The first study showed that supplementation with the antioxidants, vitamins C and E, prevented the ZDV-induced increase in the level of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine, a good marker for oxidative damage to mtDNA (30). In addition, in ZDV-treated animals, vitamins E and C were able to prevent ZDV-induced histological mitochondrial damage. The second study demonstrated that these antioxidants were able to reverse d4T-induced oxidative stress in mice (31). These studies provide an incentive...

Water Insoluble Organic Solvents and Solids

Oleic acid is the common name for (Z)-9-octadecenoic acid and is a nearly colorless liquid at room temperature. Vitamin E is the common name for d-a-tocopherol, is an oily liquid at room temperature and is also an antioxidant (Constantinides etal., 2004 Constantinides etal., 2006). Propylene glycol esters of fatty acids such as propylene glycol laurate and propylene glycol monolaurate (LauroglycolTMFCC) can be used alone or as a co-surfactant. The medium-chain diester of propylene glycol (LabrafacTMPG) is a clear liquid for soft gelatin capsule formulations. The glycerol monoesters of oleic acid (PeceolTM) and linoleic acid (MaisneTM35-1) are liquid solvents that can be the oily phase of SEDDS formulations.

Mitochondria and Common Disorders

Mitochondrial dysfunction is increasingly recognized as an important factor contributing to common human diseases, including neurodegenerative disorders, diabetes, heart failure, and cancer (Fig. 2). These diseases are almost always connected with a progressive reduction of mitochondrial oxidative capacity and energy production, but also with the increased oxidative damage to the cells. Oxidative damage to the cells is mainly caused by reactive oxygen species (ROS) or reactive nitrogen species (RNS). ROS are the main byproducts of oxidative phosphorylation in mitochondria and it is primarily formed as superoxide (O2 ). There are at least 9 known sites were ROS are produced in the mitochondria, but the sites at complex I and complex III in the respiratory chain are considered the most important 44 . Originally it was estimated that between 2 and 4 45 of the electron flow gave rise to ROS but now it is believed that in fact it is closer to 0.2 under physiological conditions 46 . ROS...

Recent Advances since the Edmonton Protocol

Marginal mass islet model in mice, as well as antioxidant therapy with nicotinamide, vitamin D3, pentoxiphylline or cholesterol lowering agents pravastatin or simvastatin, have all demonstrated positive impact in the pre-clinical setting, and suggest a potential role in future clinical trials designed to improve islet engraftment.

ROS Mitochondria and Aging

Olipin content decreases with age in heart, liver, and brain mitochondria 79 . Finally, mtDNA is highly susceptible to oxidative damage and several studies have shown higher age-dependent levels of 8-hydroxy 2-deoxyguano-sine (8OH-dG) in mtDNA relative to nDNA 80 . Today, ROS- and ROS-induced damage to different cellular compartments are widely recognized as a possible cause of aging. Caloric restriction (CR), the most widely accepted experimental intervention for increasing lifespan in laboratory animals, also leads to decrease in the amount of ROS produced as well as oxidative damage to proteins, DNA, and lipids in the cell. It has been proposed that the decrease is most likely due to a reduction in ROS produced from complex I 81 . Another correlative link comes from the comparison of the rate of ROS production from isolated mitochondria in a variety of species with varying lifespans. In this case, ROS production and lifespan are inversely correlated 82 . Furthermore, the level of...

Chemical Structure And Isomers

The term vitamin E refers to the group of eight molecules having antioxidant activity, including four tocopherols, a, p, y, 8 and four tocotrienols, a, p, y, 8 (Figure 13.1).3 The four tocopherols share a common saturated phytyl tail, but differ in the number of methyl groups on the chromanol ring. The tocotrienols differ from the tocopherols in that they have an unsaturated tail. Of these eight naturally occurring forms, a-tocopherol has the greatest antioxidant activity and is the most prevalent form found in the body.3 Synthetic vitamin E consists of eight a-tocopherol stereoisomers that are distinct due to differences at the three chiral centers of the phytyl tail.4

Biochemical and physiological role of PPOs and PODs

Also the nutritional value of food products, in particular their content of nutraceuticals, may be affected by PPO-action, as many compounds with putative antioxidant properties, such as flavonoids, may be utilised by PPOs as substrates (Martinez and Whitaker, 1995 Van Rensburg et al., 2000). Additionally, the action of PPOs may lead to depletion of natural antioxidants such as vitamin C in food products. Vitamin C serves as a shuttle between catechols and quinones that are formed as a result of PPO-action, and is thus consumed in this process (Fig. 12.1 Espin et al., 2000d). Vitamin C, Other antioxidants Vitamin C, Other antioxidants

Attenuation Of Oxidative Damage To Dna By Taurine And Taurine Analogs

Abstract Taurine has been suggested to have cytoprotective actions via a number of different mechanisms. The role of taurine in protecting DNA from oxidative damage has received only limited attention. The aim of the present studies was to test the hypothesis that taurine might act to attenuate oxidative damage to DNA caused by free radicals generated by iron-stimulated catecholamine oxidation in the presence of H2O2. Calf thymus DNA (100 g tube) was exposed to a reaction mixture containing ferric chloride (60 M), H2O2 (2.8 mM) and L-dopa (100 M). Taurine and taurine analogs were added simultaneously to determine their effects to prevent oxidative damage to DNA. The reaction was carried out for 1 hour at 37 C and terminated by rapid freezing in an ethanol dry ice bath. The DNA was precipitated with ethanol and subsequently hydrolyzed with formic acid under vacuum. The hydroxylated bases were separated by HPLC and detected electrochemically. All experiments were replicated a minimum of...

Development And Validation Of Countermeasures

In the area of nutrition, four studies are targeted at countermeasures. Two relate to countermeasures against in-flight renal stone formation with the objective of developing a dietary intake (fluid and electrolytes) and urine electrolyte excretion profile to predict the probability of renal stone formation. A third study is focused on vitamin E as an antioxidant, and the fourth on protein-energy balance. All of these studies are appropriate. There is a need to minimize the risk of renal stone formation. Oxidative damage has been implicated as a factor in chronic ground-based disease states such as cancer and atherosclerosis, so a study of the use of vitamin E as an antioxidant is relevant. The energy balance study is targeted at elucidating the mechanisms of the inability to maintain energy balance in flight.

Regulation Of Caspase Activity

Two prominent triggers of neuronal apoptosis that may play central roles in an array of neurodegenerative disorders are reactive oxygen species and calcium36,37. Exposure of cultured neurons to agents that induce calcium influx through plasma membrane channels (e.g., glutamate) or calcium release from endoplasmic reticulum (eg, thapsigargin) can induce apoptosis, and drugs that suppress calcium influx can prevent neuronal apoptosis38,39. Similarly, agents that induce oxidative stress (e.g., Fe2+ and amyloid b-peptide) can induce neuronal apoptosis, and antioxidants prevent such cell death40.

Ergogenic Effects Of Vitamin E

While exercise-induced damage could be the result of ultrastructural damage, impaired excitation-contraction uncoupling72 or central fatigue,71 evidence that oxidative damage by ROS mediates skeletal muscle damage is accumulating.70,74 Damage to skeletal muscle cell membranes by ROS, specifically lipid peroxidation, can impair cell viability, leading to necrosis and an acute-phase inflammatory response.74 75 ROS may play a central role in the etiology of skeletal muscle damage via oxidation of ion transport systems, leading to disruption Ca2+ homeostasis, impaired mitochon-drial respiratory control, distortions in signal transduction pathways and ultimately cell dysfunc-tion.76 Therefore, protection from ROS by antioxidants such as vitamin E could abrogate muscle damage caused by exercise. Creatine kinase (CK) is an intramuscular enzyme that is markedly increased in the plasma following damaging exercise including both prolonged and eccentric activity.80 Due to the invasive nature of...

Considerations And Future Recommendations

There are a number of explanations for the inconsistent findings with regard to antioxidant protection in exercise. In addition to differences in the modes, duration and intensity of exercise, there were large discrepancies in the types and amounts of antioxidant supplements provided and in the duration of supplementation. Probably the most important explanation for the inconsistent results in the oxidative stress studies, especially in those with similar protocols, is the different assays used to assess lipid peroxidation. As discussed previously, assays such as TBARS (MDA), breath pentane and conjugated dienes are susceptible to artifact and are often not specific enough to accurately assess lipid peroxidation in complex mixtures such as plasma.2 F2-IsoPs, on the other hand, are chemically stable, specific end-products of free-radical catalyzed lipid peroxidation.59 When handled appropriately (samples flash frozen in liquid nitrogen immediately and stored at -70 C) F2-IsoPs are a...

Summary And Conclusions

While supplementation with vitamin E alone appears to be effective in attenuating lipid peroxidation induced by aerobic endurance type exercise,3548-52 its effects on strength training seem to be limited.53 The effects of vitamin E in combination with other antioxidants on exercise-induced oxidative stress are less conclusive. A primary influence on results of these studies has been differences in the assays used to assess lipid peroxidation. Using the most reliable lipid peroxidation marker available, F2-IsoPs, supplementation with vitamins E and C clearly prevented increases in lipid peroxidation observed in the placebo group following a 50 km ultramarathon.24 On the other hand, studies using LDL susceptibility to oxidation as a marker of oxidative stress have yielded conflicting results protection13 or no effect.27 Studies at high altitude have involved more complex antioxidant cocktails and have yielded mixed results due to the use of multiple lipid peroxidation assays of varying...

Mitochondrial Encephalopathy Lactic Acidosis and Strokelike Episodes

About 80 percent of MELAS patients exhibit a heteroplasmic A to G point mutation in the dihydrouridine loop of the tRNA Leu(UUR) gene at mt3243.y Two other mutations in the same gene, at mt3250 and mt3271, have been identified in the remaining cases. Ihe MELAS3243 mutation alters the dihydrouridine loop of the tRNALeu(UUR) gene and changes a nucleotide at the binding site for a nuclear DNA encoded transcription termination factor. It is hypothesized that the mutation reduces the binding affinity of the transcription termination factor. Another possibility is that this mutation impairs protein synthesis by interfering with polypeptide chain elongation. Ihe cerebral infarcts are nonvascular, owing to transient dysfunction of oxidative phosphorylation within parenchyma. Areas of neuronal loss, demyelination, and astrocytic proliferation are found in the infarct-like brain areas. PET studies show reduced cerebral metabolic rates for oxygen but normal glucose utilization. Mitochondrial...

Various Transporter Defects Hartnups Disease

Menkes' disease, an X-linked disorder in which insufficient intestinal absorption of copper leads to deficiency of copper-requiring enzymes, is now known to be due to a gene located at Xq13.3. y The gene product belongs to a highly conserved family of cation-transporting ATPases, which function in the transport of ions across cellular and intracellular membranes. The low serum copper levels, the high tissue levels (particularly intestinal mucosa, except liver), and studies from patients' cultured cells strongly suggest that the basic pathogenetic defect is the failure of a plasma membrane pump that usually extrudes copper from cells or the failure of a pump that ordinarily transports copper into an intracellular organelle-like endoplasmic reticulum. Deficient activity of copper-requiring enzymes explains the symptoms and signs. Deficiency of dopamine beta-hydroxylase, critical to the catecholamine synthesis pathway, may be related to autonomic abnormalities due to decreased...

Mitochondria and Reactive Oxygen Species

The important role of redox signaling in the regulation of physiological responses is underscored by the apparent dysregulation of physiological responses in various disease-related oxidative stress conditions. Excessive levels of reactive oxygen species (ROS) may be generated by mechanisms that produce ROS accidentally in an unregulated fashion. This includes the production of ROS by the mitochondrial electron transfer chain, the quantitatively most important source of ROS in higher organisms. These chemical species are characterized by the presence of an unpaired electron on the oxygen atom that can promptly react with virtually any biomolecules. Thus, mitochondrial structures are particularly susceptible to oxidative damage as evidenced by lipid peroxidation, protein oxidation, and mitochondrial DNA mutations 11 . ROS have been implicated in many pathological conditions, in particular in the aging process. Indeed, the free radical theory of aging has a long history and it has been...

Description of the Kit

Each vial contains the freeze-dried, sterile components under nitrogen atmosphere in a multidose vial. 99mTc-Na-pertechnetate used for labeling must be free from any oxidizing agent, using a solution of 0.9 sodium chloride (saline) as diluent. No bacterio-static agents are present in kits. In order to prevent oxidative reactions, kits are purged with nitrogen gas, the amount of tin reducing agent might be increased, and or antioxidants might be added (Saha 1998).

Chemoprevention Of Tobaccorelated Cancer

Some of the other compounds which have been shown to inhibit lung carcinogenesis by NNK include butylated hydroxyanisole, an antioxidant used in food preservation, (+)-limonene, a constituent of orange juice and other citrus products, and diallyl sulfide, a constituent of garlic. Inhibition of NNK carcinogenesis has also been observed in animals treated with green and black tea, as well as its major polyphenolic constituents. Inhibitors of lung tumorigenesis induced by BaP include -naphthoflavone, butylated hydroxyanisole, ethoxyquin, diallyl sulfide and mjo-inositol. It seems likely that properly designed combinations of some of these inhibitors will be effective chemopreventive agents against lung cancer in humans.

Endogenous Antigenotoxins

Evidence is increasing that DNA damage can occur as a result of normal cellular functions. There are three main sources of DNA damage. (1) many cellular processes require or consume oxygen. Sometimes oxygen and other small molecules such as hydroxyl (OH) groups become electron deficient and may escape normal cellular pathways such as those of the respiratory chain, and these oxygen radicals can react with DNA and may cause mutations or cancer. (2) A second very important source of oxygen radicals in the body is the normal burst of free radicals generated by neutrophils, in order to kill bacteria, viruses, etc., entering the body, as part of the normal defence against such intruders. (3) In the normal metabolism of endogenous or exogenous molecules, often very reactive metabolites are formed intracellular by cytochrome P450-mediated reactions. Sometimes such metabolites may be mutagenic or carcinogenic and need to be further metabolized or detoxified by appropriate endogenous systems....

Viiiinfections Hsp And Atherosclerosis

It is possible that a third variable may be associated with both infections and atherosclerosis, and that hsps might be the missing link between these conditions. For instance, infections can stimulate endothelial cells to overexpress hsps, directly or indirectly, by released cytokines and free radicals pathways. Infections trigger the immune system to induce T cells and antibodies specific for bacterial hsp 65, which in turn may bind to surface-expressed hsp 60 on the endothelium via cross reaction.

Acidosis and Hyperglycaemia

Injury.19 While the general consensus is that preischaemic hyperglycaemia is deleterious, in some studies it has been shown to delay the onset of ischaemic Ca++ influx from the ECF and potentiate reextrusion of Ca++ following recirculation. These findings may reflect the modulatory effects of the type of ischaemia (focal versus global), its duration and extent and the completeness of the ischaemic insult.1020 It is thought that acidosis enhances production of reactive free radicals, causes oedema, aggravated tissue damage and delayed seizures and prevents recovery of mitochondrial metabolism.1419 However, it still remains to be fully established whether exaggerated intra-ischaemic acidosis enhances postischaemic production of reactive oxygen species (ROS).

Myocardial Ischemic And Reperfusion Injury

In the clinical scenario, the antecedent of most myocardial damage continues to be a combination of two phenomena termed ischemia and reperfusion. A regional ischemic event occurs in the heart when the blood supply to an area of functioning myocardium is interrupted, usually due to the formation of a thrombus within the lumen of a coronary vessel. If the thrombus reaches a critical mass, an occlusion forms, depriving the viable tissue of nutrients. Since the ischemic tissue attempts to function without incoming blood flow, detrimental metabolic by-products accumulate within the tissue. For example, high-energy phosphate-producing glycolytic pathways lead to the formation of lactic acid under anaerobic conditions. On restoration of flow to the ischemic area, oxygen is delivered into the tissue. The reintroduction of molecular oxygen to a previously ischemic region of the heart can lead to profoundly damaging effects (6). This damage results, in part, from the generation of...

The Role Of Oxidative Stress In Aging

Asecond focus of aging in the CNS is oxidative stress and the mitochondrion. Reactive oxygen species (ROS) are oxidants that, if unrestricted, can cause oxidative damage to the mitochondria, cellular proteins, lipids, and nucleic acids. ROS are the normal byproducts of cellular metabolism in the mitochondrion. Free radicals are chemical species with a single unpaired electron, which is highly reactive. The majority of free radicals that damage biological systems are oxygen radicals and other ROS, which are byproducts formed in the cells of aerobic organisms. The generation of mitochondrial ROS is a consequence of oxidative phosphorylation, a process that occurs in the inner mitochondrial membrane and one that involves the oxidation of NADH to produce energy. Under normal circumstances our natural antioxidant defense systems detoxify the superoxide anion by the mitochondrial manganese (Mn) superoxide dismutase In the aging brain as well as in the case of several neurodegenerative...

The Role Of Microglia In Aging

It has been proposed that the increase in brain microglial activation may be one of the early events that leads to oxidative damage. Activated microglia release radicals such as superoxide and nitric oxide.44 Microglia derived radicals, as well as their reaction products hydrogen peroxide and peroxynitrite, can harm cells and these products have been shown to be involved in oxidative damage and neuronal cell death in neurological diseases.45 Microglial cells are equipped with efficient antioxidative defense mechanisms. They contain high concentrations of gluthatione, the antioxidative SOD enzymes, catalase, glutathione peroxidase, and glutathione reductase, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-regenerating enzymes.45 When the production of ROS is prolonged, the endogenous reserves of antioxidants become exhausted and result in cell damage.

Therapeutic Interventions For Inflammation And Oxidative Stress In Aging

Were overshadowed by the implications of long-term NSAID usage on the digestive and cardiac system.74 A possible result of this finding was a shift away from manufactured pharmaceuticals and a shift towards a natural occurring source of supplementation. Supplementation of diets with antioxidants can be viewed as a way to support the internal antioxidant system in order to help deter an exacerbation of proinflammatory cytokines. A great natural source of antioxidants are fruits and vegetables. Researchers have used an in vitro assay of oxygen radical absorbance capacity (ORAC) to determine which fruits and vegetables contain the highest oxidative fighting capacity.75 Experiments using dietary interventions with fruit and vegetable supplements (blueberry, strawberry, spinach, and vitamin E) high in ORAC activity have resulted in successful amelioration of such age-related declines as muscarinic receptor sensitivity, noradrenergic modulation of cerebel-lar Purkinje neurons, calcium...

Applications In Proteomics

Often a combination of techniques is advantageous. For example, optical (UV visible absorption) spectroscopy is useful where the protein is expected to contain a chro-mophoric prosthetic group. EPR spectroscopy is particularly useful to establish the correct insertion of transition metal ions and or stable free radicals 12 .

Squamous Cell Carcinoma

Transport of tobacco-associated carcinogens across the oesophageal lining. It may also impair the ability of the liver to detoxify carcinogens. In contrast, there appears to be a strong protective effect between the consumption of antioxidant vitamins and fresh fruits in areas at high risk for SCC.

General Properties and Metabolic Functions

Manganese superoxide dismutase is the major antioxidant in mitochondria. The importance of this enzyme was demonstrated by the finding that the deletion mutation of the manganese superoxide dismutase gene in mice resulted in death within 5-21 days of birth.66 Severe mitochondrial damage occurred in these rats that was attributed to the increased presence of reactive oxygen species. The importance of this enzyme for protection against oxidant stress has also been demonstrated by studies with animals or cells that overexpress manganese superoxide dismutase. For example, this overexpression has been shown to prevent alcohol-induced liver injury in rats,67 attenuate myocardial injury following ischemia and reperfusion,68 protect lung epithelial cells against oxidant injury69 and protect against apoptotic cell death.70 In addition, high dietary manganese protected against heart lipid peroxidation in rats fed high amounts of polyunsaturated fatty acids.71 Physiological stress, including...

Effects of Carbon Monoxide on Brain Functions

By competing with sites that generally bind NO, CO may lead to an increase in free levels of NO. By itself, NO is a potent activator of guanylate cyclase and can participate in vasodilation. On the other hand, NO is very reactive and could stimulate the production of related free radicals, which can cause cellular damage often observed as nitroty-rosylation of proteins. Damage due to the generation of free radicals can be either to the cell or the blood vessels, depending on where NO is being dissociated from heme. Thus, even at relatively low concentrations, CO can produce oxidative stress and subsequent cell death. Using animal models, oxidative damage in rats has been observed with CO levels at 1,000 ppm for 40 minutes or as little as 50 ppm for 1 hour. These exposures are sufficient to cause an increase in nitrotyrosine and nitrosylated proteins (Ischi-ropoulos et al., 1996 Thom, Fisher, Xu, Garner, & Ischi-ropoulos, 1999). It was suggested that since CO does not modify the...

Conclusions And Implications

Many, but not all, of the nutrients are better utilized by the body if they are consumed as a component of food. Unfortunately, many people do not consume nutritionally adequate diets and these individuals would benefit from taking vitamin-mineral supplements. It appears prudent for all adults to take vitamin supplements, according to a scientific review and clinical applications paper published in 2002 in the Journal of the American Medical Association.13 Athletes are encouraged to consume a nutritionally adequate diet and should consider, based on their dietary intakes and general state of health, whether they should take a multivitamin-multimineral supplement. Some evidence, though not conclusive, exists that the needs of athletes for antioxidant vitamins may be higher than of the typical population.

Studies Of Spirulina In Druginduced Toxicities

Cisplatin is a highly effective chemotherapy drug. Unfortunately, it can be associated with kidney toxicity, resulting in severe and often irreversible renal failure. Several recent studies have investigated the ability of Spirulina to protect rats from cisplatin-induced nephrotoxicity. In one of these studies S. fusiformis was given orally at doses of 500, 1000, or 1500 mg kg body weight from 2 days before until 3 days after the injection of cisplatin.18 Administration of this alga was associated with marked amelioration of the cisplatin-induced changes in kidney morphology and significant, dose-dependent reduction of markers of renal dysfunction, such as serum creatinine and blood urea nitrogen. In addition, Spirulina reduced lipid peroxidation in the kidney and partially reversed the cisplatin-induced decrease in the levels of reduced glutathione and the activity of the antioxidant enzymes SOD and catalase. Gentamicin is an antibiotic used for the treatment of serious gram-negative...

Factors Underlying Circadian Dependent Susceptibility To Light Induced Retinal Damage

Retinal cell loss in diseases such as Retinitis Pigmentosa occurs through an apoptotic process.1 The mechanism of this cell loss is not completely understood. Models that allow for the study of conditions in which the retina is susceptible or resistant to retinal damage help to elucidate the mechanism underlying the cell death. One model that is used to study retinal cell loss is the light induced retinal degeneration (LIRD) model.2 Intense light exposure leads to rhodopsin bleaching2 and is the trigger for the subsequent photoreceptor cell degeneration, as blocking the regeneration of rhodopsin prevents photoreceptor cell death.3 Oxidative stress is also involved in retinal degeneration,24-7 and the administration of natural or synthetic antioxidants prior to light exposure prevents the subsequent cell loss.7-13 Many factors can influence the extent of light induced damage including prior light history of the animals, age, genetics, and diet.4 814 The extent of LIRD is also dependent...

Mitochondrial DNA Mutations and Aging

Furthermore, the amount of ROS produced by embryonic fibroblasts from mtDNA mutator mice was normal, despite severe respiratory-chain dysfunction. Antioxidant defences were unaltered in adult tissues of mtDNA mutator mice. Moreover, no differences could be detected in the amount of oxidative damage to proteins and DNA and aconitase enzyme activity, a common marker for oxidative stress, was normal in mtDNA mutator mice. Our results thus challenge the direct role of ROS in the aging process, as there was no link between oxidative stress and the premature aging phe-notypes in mtDNA mutator mice 76 .

Spirulina And The Innate Immune System

In contrast to whole Spirulina, perfusion of mouse liver with C-phycocyanin was associated with a concentration-dependent decrease in phagocytosis by Kupffer cells, the resident macrophages in the liver.9 There has also been a report that phy-cocyanin inhibited the respiratory burst associated with neutrophil phagocytosis.10 It is not clear, however, whether phycocyanin suppressed phagocytosis or rather neutralized the resulting reactive oxygen species through its ability to scavenge free radicals, which was demonstrated in this and other studies.10,11 In addition, it has been reported that phycocyanin induced a murine macrophage cell line to undergo apoptosis.12 Inflammatory responses are accompanied by markedly increased production of reactive oxygen species. Oxidative stress, in turn, induces the transcription of numerous genes encoding proinflammatory mediators or the enzymes producing them. Both Spirulina and phycocyanin can scavenge peroxyl, hydroxyl, alkoxyl, and superoxide...

Effect Of Spirulina On Fatty Liver

NASH develops for various reasons, and proceeds by several poorly understood biochemical mechanisms. The causes of steatosis may involve the reduced synthesis of very low density lipoprotein (VLDL) and elevated levels of hepatic triacylglycerols, because of the reduced levels of fatty acid oxidation or an increase in the amount of lipids that circulate to the liver. As lipids accumulate, lipid peroxidation is likely to occur in the presence of free radicals, causing cell damage, which results in inflammation. These changes will activate HSCs, causing fibrosis, cirrhosis, and portal hypertension, if NASH is advanced, up to 40 of NASH patients develop liver fibrosis or 5-10 cirrhosis.92 A recent study indicated that patients with fatty liver disease should be encouraged to take vitamin E and C supplements.98 This treatment was claimed to be safe and affordable. Patients were randomly prescribed either oral vitamin E (600 IU day) plus vitamin C (500 mg day) or ursodeoxycholic acid (10 mg...

Selective Activation Of Rodent Liver Progenitor Cells

Oval cells can also be induced by placing animals on a CD diet containing 0.05-0.1 ethionine (Fig. 4), a low-toxicity protocol with very low mortality (Shinozuka et al., 1978 Sirica and Cihla, 1984 Lenzi et al., 1992 Hixson et al., 1996). Interestingly, a CD diet with or without ethionine destroys the acinar pancreas. This causes the activation of ductal progenitor cells that, for unclear reasons, differentiate into hepatocytes instead of acinar cells (Fig. 5). Ethionine in a CD diet (CDE) appears to act indirectly to cause DNA damage (Rushmore et al., 1986) by elevating levels of reactive lipid peroxidation products, free radicals, and reactive oxygen species. Ethionine is also known to cause changes in gene expression by altering DNA methylation patterns (Shivapurkar et al., 1984), which, in turn, alter differentiation and or growth regulatory pathways. In addition, there is evidence that a CDE diet may decrease growth inhibitors and increase growth stimulators, a shift that could...

Exogenous Antigenotoxins

Aflatoxin Biosynthesis Pathway

The fat-soluble vitamin E is a naturally occurring mixture of several tocol derivatives among which a-tocopherol is the most biologically active. The basic function of vitamin E in all living organisms is as an anti-oxidant in protection against oxidative damage of hydro-phobic molecules or structures, generated either by free radicals or by radical-inducing radiation. Thus, by preventing radical-induced damage, vitamin E was shown to be an antimutagen or antigenotoxin in many experimental studies.

Spirulina In Adaptive Immune Responses

It also remains to be established how phycocyanin exerts biological activities in vivo since proteins are generally broken down into individual amino acids or small oligopeptides before absorption. The phycocyanobilin chromophore, however, structurally resembles the bile pigment bilirubin, which can be absorbed from any part of the small or large intestine as long as it remains unconjugated. This would suggest that the phycocyanobilin part of phycocyanin is mainly responsible for the antioxidant and anti-inflammatory effects seen after oral administration of phycocyanin. This is supported by the observation that this chromophore accounts for much of the radical scavenging and antioxidant properties of phycocyanin and Spirulina.41

Hsp Function In Muscular Diseases

HO and ferritin are stress proteins with an interesting potential for radical scavenging. Degradation of heme by HO results in the production of the antioxidant bile pigments bilirubin and biliverdin (29). Subsenquently, ferritin is induced by the iron released during heme catabolism, leading to an improved iron storage and thus decreasing iron-catalyzed free radical reactions. Nath et al. (30) provided evidence that the induction of HO, coupled to ferritin synthesis during myoglobin degradation, is a rapid effective antioxidant response which reduces mortality in rhabdomyolysis. HO and or ferritin may play essential roles in protecting DNA from oxidatively induced strand breaks or fragmentation (39). Although our results on HO expression in the myopathies examined are as for now unconclusive, we have yet to determine HO activity and ferritin expression. The important role iron may play in DMD by potentiating oxidative injury (reviewed in ref. 40) is supported by our above-mentionned...

Dietary Supplement Health and Education Act DSHEA and Spirulina

Spirulina is sold in health food stores and similar outlets as a dietary supplement. There appears to be a lack of understanding about their regulatory status. Until 1994 dietary supplements were regulated as foods by FDA. However, with passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA), Congress amended the food regulations to include several provisions that apply only to dietary supplements and dietary ingredients of dietary supplements. As a result of these provisions, dietary ingredients used in dietary supplements are no longer subject to the pre-market safety evaluations required of other new food ingredients or for new uses of old food ingredients. They must, however, meet the requirements of other safety provisions. FDA defines a dietary supplement as a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients a vitamin, a mineral, an herb or other botanical, an amino...

Antiinflammatory Activity Of Spirulina

Cyclooxygenase-2 (COX-2) has an important role in catalyzing the conversion of arachidonic acid to prostaglandins and other eicosanoids.37 The overexpression of COX-2 is associated with high levels of prostaglandin E2 (PGE2) that are observed in various malignancies of the colon, breast, lung, prostrate, skin, cervix, pancreas, and bladder.38 Excess prostaglandin levels cause inflammation, influence cell proliferation, and the mediation of immune suppression.39,40 Many investigations have confirmed that nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors can induce apoptosis in colon cancer cell lines and transformed fibroblasts.41,42 Phycocyanin, present in Spirulina, has been claimed to have a selectively inhibitory effect on COX-2.28 Restated, phycocyanin is a natural COX-2 inhibitor, which controls inflammation that is caused by the presence of the enzyme COX-2. Studies have been conducted to examine the involvement of phycocyanin in inducing apoptosis in tumor...

Spirulina As A Natural Therapeutic Intervention For Inflammation And Oxidative Stress In Aging

Spirulina, is a very interesting and promising source of phytochemicals that has also shown hopeful results in dealing with age-related changes. With both antioxidant and anti-inflammatory actions, Spirulina has the ability to supplement our internal anti-oxidant defense systems as well as control any excessive inflammation. The first known use of Spirulina as a dietary supplement came from the Aztecs more than 400 years ago. The Spanish conquistadors found the Aztecs drying the green growth, called tecuitlatl, from Lake Texcoco located near Mexico city. Today, Lake Texcoco is still plentiful in Spirulina. It has also been speculated that the Mayans specifically farmed Spirulina as a crop. Likewise, the Kanembu who live along lake Chad were found to be taking the growth form the lake and drying it for food (Ciferri and Tiboni, 1985). Classified as a cynobacteria (blue-green algae) Spirulina is abundant in phycocy-anin, which gives it a blue pigmentation. The large amount of...

Therapeutic Utility Of Spirulina In Diabetes Mellitus

Noncommunicable diseases are increasing to alarming proportions and gaining their hold over the developing countries. One of the noncommunicable diseases that has gained importance is diabetes mellitus because of its rising prevalence. Worldwide, the number of cases of diabetes is currently estimated to be around 150 million. This number is predicted to double by 2025, with the greatest number of cases being expected in China and India.3 The rising prevalence of diabetes and its associated complications place a high burden on the health care systems. The major therapeutic goal in diabetic patients therefore, is to optimize blood glucose control in order to improve the well-being of the patients and reduce the risk of diabetes-induced complications. The recent years have witnessed a renewed interest in identifying probiotics, antioxidants, neutraceuticals, and designer foods that can be used as alternative therapies for sustaining and managing health. This prompted us to assess the...

Table 9 Aspects of chemoprevention at major cancer target sites3

Steroid 5-reductase inhibitors (e.g. finasteride) retinoids (e.g. 9-c s-retinoic acid) RAMBA antiproliferatives (e.g. DFMO, DHEA analogues) differentiating agents (e.g. vitamin D analogues) antioxidants (e.g. vitamin E, selenium, lycopene) GSH-enhancing agents (e.g. oltipraz) antioestrogens (e.g. toremifene, tamoxifen, raloxifene and other SERMs) aromatase inhibitors (e.g. vorozole) antiandrogens (e.g. leuprolide, flutamide) angiogenesis inhibitors (e.g. linomide) signal transduction regulators (e.g. soy isoflavones), Anti-inflammatories (e.g. lipoxygenase inhibitors, selective COX-2 inhibitors)

Interaction Of Selenium With Other Nutrients

Vitamin E and Se function as synergistic antioxidants, and many of the signs and symptoms of a double deficiency of these two nutrients can be prevented or will be improved by supplementation with either nutrient.22 Beck et al.32 reported that vitamin E deficiency increased the cardiac pathology associated with Coxsackie B3 infection in mice, especially in mice fed diets high in menhaden oil as opposed to lard, for dietary fat. Work by Beck et al.30,32 on the effects of both Se and vitamin E deficiency on myocardial injury from the Coxsackie B3 virus supports the possibility that both nutrients influence the development of Keshan disease. Selenium also works synergistically with ascorbic acid as an antioxidant. Selenium-dependent thioredoxin reductase helps protect the cell from oxidants and catalyzes the regeneration of ascorbic acid from dehydroascorbic acid. 56 However, in regard to selenium absorption, Robinson et al. reported that when sodium selenite was taken orally, a light...

Effects Of Selenium On Athletic Performance

Most research in the area of Se and exercise has focused on the role of Se in the antioxidant enzyme GSHPx which, using GSH, converts H2O2 to water. Whole-body and especially muscle oxygen uptake increases sharply during intense physical exercise leading to increased oxidative stress.61 This oxidative stress may be related to production of ROS such as superoxide in the mitochondria during exercise. Superoxide, when acted on by superoxide dismutase (SOD), produces H2O2, which can then be converted to water by GSHPx or catalase. In tissues that experience ischemia during exercise, reperfusion and reoxygenation contribute to a burst of ROS production. When biomembrane polyunsaturated fatty acids are acted on by ROS under aerobic conditions, a peroxidative chain reaction occurs leading to increased excretion of ethane and pentane in expired air and The only human study in which subjects were in less than optimal Se status was conducted by Edwards et al.69 Subjects also had intermittent...

Metabolic Functions Of Selenium

Since the discovery of cytosolic GSHPx, other selenoproteins including additional antioxidant enzymes have been identified in mammals. A distinct, glycosylated GSHPx has been found in the plasma and a membrane-associated enzyme, phospholipid hydroperoxide GSHPx (PLGSHPx) has been reported to be widely distributed in tissues.1011 While an exact function is not totally clear, selenoprotein-P is found in plasma and tissues and appears to have some antioxidant or selenium transport properties.1012 An additional enzyme that contains Se is Type I iodothyronine 5-deiodinase, which is the enzyme that catalyzes the removal of iodine from thyroxine (T4), converting it to 3,3,5-triiodothyronine (T3).10 The primary task of the Se-containing antioxidant enzymes is to protect cellular components from peroxidation by controlling the H202 and organic peroxide levels in aerobic cells.10 According to Ursini and Bindoli,13 both glutathione peroxidase enzymes will reduce peroxidic substrates such as...

Identity And Roles Of Vitamins And Trace Minerals

In general, trace minerals are required cofactors for function of numerous enzymes in almost every aspect of metabolism and physiology. Roles that directly influence physical performance include oxygen binding and transport, generation of cellular energy, hormone function, antioxidant status and muscular contraction.5-12 Molybdenum and fluoride are not considered to have roles that affect physical performance, and so are seldom considered or discussed. Of the ultratrace minerals that are not confirmed for essentiality, none have actions that would directly influence physical performance. However, boron and vanadium play roles in hormonal balance, which might influence results of training. Because of these roles and their use as dietary supplements in products designed to affect physical performance (ergogenic aids), their use should be considered.

Carcinogenblocking Activities Antimutagenicity

Vitamin C prevents the biosynthesis of carcinogenic -nitroso compounds. Other chemopreventive antioxidants such as vitamin E prevent the formation of nitrosamines GSH-peroxidases (GSH-Px) catalyse the reduction of hydrogen peroxide (H2O2) and organic hydroperoxides the antioxidant effects of selenium may be related to its function in the enzyme's active site. Although several studies show that the anticarcinogenic activity of selenium in mouse and rat mammary glands is not mediated by GSH-Px, in tissues such as colon, glandular stomach and skin, GSH-Px are thought to play a role.

Physiological Basis of Sleep and Wakefulness

Wakefulness may also have important biochemical effects on neurones which are compensated for by sleep. During wakefulness neuronal glucose utilization is more rapid, and intracellular stores of glyco-gen within astrocytes are consumed. This process is reversed during sleep so that glucose can be available for neuronal activity and to enable normal metabolic functioning during the next episode of wakefulness. Replenishment of other metabolites or removal of oxygen free radicals during NREM sleep may also be important.

Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College 1 Xian Nong Tan Street

The genus Salvia has a variety of more than one hundred species distributed in several regions in China. Thirty of them are used as traditional and folk medicines (Huang 1991). The dried root of Salvia miltiorrhiza, called Danshen, is one of the most well known traditional Chinese medicines among these species. It has the effect of promoting blood circulation and removing stasis, and is widely used for the treat ment of coronary heart diseases, cerebrovascular diseases, hepatitis, hepatocirrhosis, chronic renal failure, dysmenorrhea and neurasthenic insomnia. The chemical constituents of S. miltiorrhiza have been studied for more than fifty years. But the studies have mainly been focused on the lipophylic diterpenoid quinones. According to traditional Chinese medicinal prescriptions it is used as a decoction. Since the seventies injections of Danshen have been used for the treatment of angina pectoris, myocardial infarction and various types of hepatitis. So there should still be...

Pharmacology 11 The Biologicalpharmacological Activity Of The Salvia Genus

Until the discovery of antibiotics, sage was a frequent component of herbal tea mixtures, recommended in patients with tuberculosis to prevent sudation. The essential oil of sage is still employed in flavouring condiments, cured meats, liqueurs and bitters. Besides the usage as a flavouring and antioxidant agent, sage (S. officinalis L.) leaves exhibit a range of biological activities, i.e. antibacterial, micostatic, virustatic, astringent and antihidrotic (Anonymus, 1994). Sage was found to be an active ingredient in combined plant preparations for treatment of acute and chronic bronchitis. Animal studies show hypotensive activity and central nervous system (CNS) depressant action of sage extracts (Newall et al., 1996). Because of antimicrobial effects (Dobrynin et al., 1976 Cherevatyi et al., 1980 Farag et al., 1986) and tannin-based astringent activities of sage this is used as an active ingredient of dental-care preparations. It reduces growth of plaques, inhibits gingival...

Rare insight The protective effect of betacarotene that wasnt

Observational studies have consistently shown that people eating more fruits and vegetables, which are rich in beta-carotene, and people having higher serum beta-carotene concentrations have lower rates of cardiovascular disease and cancer.36 Beta-carotene has antioxidant properties and could thus plausibly be expected to prevent carcinogenesis and athero-genesis by reducing oxidative damage to DNA and lipoproteins. Unlike many other associations found in observational studies, this hypothesis could be, and was, tested in experimental studies. The findings of four large trials have recently been published.37-40 The results were disappointing and for the two trials conducted in men at high risk, smokers and workers exposed to asbestos, even disturbing.37,38 mortality, comparing the results from the six observational studies recently reviewed by Jha et al.36 with those from the four randomised trials. In observational studies we compared groups with high and low beta-carotene intake or...

Clinical Manifestations Of Mitochondrial Toxicity

Subjects with symptomatic hyperlactatemia should have their therapy modified or even temporarily interrupted. In fact, because of the concern regarding progression to lactic acidosis, most experts would recommend a temporary interruption of all ARV until patients are asymptomatic and lactate levels are back to normal levels. This may take several weeks to months. Management of such patients after the resolution of the serious hyperlactatemia is controversial. Two strategies have been adopted in this setting switch to potentially less mitochondrial-damaging NRTIs (such as replacing d4T with either abacavir or ZDV) or switch to an NRTI-sparing regimen. The latter option is probably safer but, unfortunately, a growing proportion of the HIV-infected population has already been exposed to all available classes of ARV and, therefore, lacks this option. Available data demonstrate a normalization of serum levels with substitution of d4T with either abacavir or ZDV (44,49,58). There is not...

Inflammatory reaction

Endothelial dysfunction is triggered by a lack of nitric oxide availability which leads to vasoconstriction. Intermittent hypoxia and reoxygenation lead to the production of oxygen free radicals (reactive oxygen species) which increase the oxidative stress on the endothelium. Sleep fragmentation itself appears not to be a significant factor.

Antiproliferative Activity via Signal Transduction Pathways

ODC induction by TPA is regulated at the transcription level. Regulation occurs in part via signal trans-duction events at the membrane. For example, PKC appears to be involved, as are diverse signal transduction intermediates induced by TPA, including PGs, other products of AA metabolism and free radicals. Chemicals that inhibit PKC and AA metabolism and those that scavenge free radicals also may inhibit the induction of ODC, hence they may be chemopreventives by this mechanism. In this regard, several of the PKC inhibitors, including glycyrrhetinic acid, inhibit ODC induction and tumour promotion in mouse skin. AA metabolism inhibitors also inhibit both ODC induction and TPA-promoted mouse skin tumorigenesis, as do free radical scavengers such as GSH, flavonoids and green tea polyphenols.

Mechanism of Cardioprotection by Ethanol

The cardioprotective effects of alcohol may be mediated through increased antioxidant levels (15). It has been established that phenolic flavinoids, which are found in the skin of the grape (and therefore are much more plentiful in red wine), are antioxidants that inhibit the oxidation of LDL (13). LDL, in its oxidized form, is believed to be much more atherogenic. The most important flavinols in red wine are thought to be quercetin, myricetin, catechin, and epi(gallo)catechin (13).

Calpain Activity And Expression In Experimental Allergic Encephalomyelitis

EAE is an autoimmune inflammatory disease induced in animals - most commonly rabbits, guinea pigs, monkeys, mice and Lewis rats - by injection of an emulsified suspension of whole CNS tissue, white matter, myelin, PLP or MBP, together with Freund's complete adjuvant (FCA)106-110. The animals progressively lose weight followed by development of paralysis at 10 to 12 days after challenge. Perivascular cuffing with infiltrating lymphocytes, monocytes and plasma cells, can be observed by light microscopy 106,109,111. Electron microscopic examination has shown lamellar separation and splitting of the major dense and intraperiod lines of the myelin lamellae followed by vesicular degeneration of myelin which is ultimately phagocytozed112,113. Blood-brain barrier permeability is increased in EAE, possibly by free-radicals produced by inflammatory cells since permeability is reduced by antioxidant enzymes in EAE114.

Vitamin E Supplementation In Exercise

In a number of studies, vitamin E supplementation has been demonstrated to reduce steady state concentrations of lipid peroxidation markers without affecting exercise-induced increases in oxidative stress.47,49,54,64 Compared with pre-supplementation, resting concentrations of breath pentane and plasma MDA were significantly reduced by 6 weeks' supplementation with 600 mg a-tocopherol, 1000 mg ascorbic acid and 30 mg P-carotene at rest, prior to and during a 30 min run.54 In trained cyclists, 400 IU vitamin E for 3 weeks reduced resting MDA levels by nearly half, but did not attenuate the increase in MDA caused by 90 min of cycling.64 Schroder et al.47 reported that supplementation with 600 mg vitamin E, 1000 mg vitamin C and 32 mg P-carotene for 31 days of a regular competition basketball season resulted in significant decreases in resting plasma lipoperoxide levels compared with the placebo group, suggesting that an antioxidant mixture might be helpful in preventing accumulation of...

Oxidative Stress And Damage

Several studies have demonstrated exercise-induced DNA damage in individuals of all training levels sedentary,41 recreationally active144243 and trained athletes,41 4445 with some evidence that sedentary individuals experience greater damage than trained subjects.41 Furthermore, exercise of varying intensity and duration has been demonstrated to cause similar amounts of damage.1441-45 Due to the potential involvement of oxidative DNA damage in cancer development and age-related degenerative diseases,46 the ability of antioxidant vitamins like vitamin E to prevent such damage has been investigated. The three supplement regimens inhibited DNA damage, but the protocol providing 1200 mg vitamin E for 14 days prior to the exercise bout (test IV) had the greatest effect, suggesting that vitamin E can prevent exercise-induced DNA damage. In contrast, Mastaloudis et al. 37 reported that in trained subjects, prior supplementation with vitamins E and C (300 mg vitamin E and 1000 mg vitamin C...

Gloves as Barrier Protection

In many patients, ACD caused by glove exposure is secondary to exposure to rubber accelerators, antioxidants and vulcanizing agents used in NRL and nitrile glove production. These agents are added to shorten production time, optimize glove quality and reduce effects of weathering and aging of the glove 30 . Von Hintzenstern et al. 30 examined the frequency of rubber allergy during a 5-year period. Of the 55 of rubber-additive-allergic patients who had an occupational source of exposure, 84 were labeled as sensitized by glove exposure, as this was the only likely source of sensitization. The remaining 16 with occupational rubber allergy were sensitized by rubber products such as cables, rubber grips or tools, tires and latex-coated papers. The top 4 professions associated with glove additive allergy were health and laboratory services, homemaking, building industry and the metal industry 30 . The most frequent glove allergens are thiurams, carbamates and mercaptobenzoth-iazole....

Therapeutic Uses Of Spirulina

Spirulina and its active constituents have specific therapeutic uses beyond general nutritional values. In vitro and in vivo studies have shown that either Spirulina or its active constituent, C-phycocyanin is promising in chemoprevention and cancer protection,98 neuroprotection,99 antiviral action,100 cardiovascular protection,87 immunomodulation,101 hepatoprotection,102 anti-inflammatory action,103 antioxidant action,104 and protection against chemical- and drug-induced toxicities.87,105-107

Immune Activation By Spirulina

There have been a number of reports relating to the functions of Spirulina in rodents. Zhang et al.16 reported that the hot water extract of Spirulina showed significant hydroxy radical scavenging activity in mice. In another study, the methanolic extract of Spirulina showed weak antioxidant activity in rats.17 Several papers suggested that the relevant substance is phycocyanin in Spirulina.17,18 Using an experimental squamous cell cancer model of hamsters, administration of Spirulina extract has been reported to result in total tumor regression in 30 of animals.19 Intraperitoneal injection of a polysaccharide extract of Spirulina was shown to inhibit proliferation of ascitic hepatoma cells in mice.20 Calcium Spirulan, a polysaccharide isolated from S. platensis, inhibited lung metastasis of mouse B16 melanoma cells by intravenous administration.21 Hence, phycocyanin and water-soluble components, presumably polysaccharides, may be responsible for antioxidant and anticancer effects in...

Future Implications And Conclusion

On reviewing the antioxidant studies of Spirulina it can thus be concluded that Spirulina is a unique blend ofcarotenoids, zeaxanthin, polyphenols, phycocyanin, and polysaccharides as well as superoxide dismutase. With accumulating epidemiological interventions and clinical evidence regarding strong association between antioxidant intake and incidence of chronic diseases, Spirulina has a potential application in prevention and mitigation of cancer, heart disease, inflammation, and premature aging. An efficacious approach to protect the body against consequences of oxidative stress consists in improving the antioxidant nutrition. Scientific studies have shown that the synergistic action of a wide spectrum of antioxidants is better than the activity of a single antioxidant and that antioxidant from the natural sources have a higher bioavailability and therefore higher protective efficacy than synthetic antioxidants. Thus well-planned human trials of Spirulina and its important...

Drug Toxicity Studies

Drug-induced toxicity is almost invariably associated with oxidative stress in the target organ or tissue. This stems from a variety of sources, including increased generation of reactive oxygen species as an inevitable consequence of certain enzyme activities, the conversion of the drug itself into a radical or a compound able to generate radicals, and drug-induced inhibition of antioxidant enzyme activities. Spirulina contains a variety of antioxidants, including ascorbic acid (vitamin C), -tocopherol (vitamin E), j-carotenes, and phenolic compounds.7 Various aqueous or alcoholic extracts of this alga can scavenge a variety of radicals in vitro and exhibit antioxidant activity in vivo.7-10 Another constituent of Spirulina, phycocyanin, has been demonstrated to scavenge peroxyl,11 hydroxyl,12,13 alkoxyl,12 and superoxide radicals10 as well as peroxynitrite.14 There are also results suggesting that phycocyanin is capable of chelating iron,11 which can be a powerful pro-oxidant. It has...

Concluding Remarks

The available literature contains little information about the potential of Spirulina to influence the metabolism of pharmaceuticals. Given the widespread use of this alga for the purpose of enhancing immune function, studies addressing this issue are urgently needed. There are data showing that Spirulina can provide considerable protection from the renal toxicity associated with cyclosporine, gentamicin, and cisplatin, the cardiotoxicity of DOX, and the genotoxicity of cyclophosphamide and mitomycin-C in mice and rats. This protective effect seems to be mediated mostly by the ability of this alga to act as an antioxidant and to reverse the drug-induced inhibition of endogenous antioxidant enzymes. Other mechanisms involve the ability to reduce the levels of reactive nitrogen species, possibly by inhibiting inducible nitric oxide synthase, and the ability to prevent apoptosis by altering the expression of proteins that regulate the apoptotic process. Although these results are...

Genetic Pathways of Postmitotic Cell and Organismal Survival

Several years later, the rate of living theory of aging became synonymous with the oxygen radical theory of aging proposed by Denham Harman (Harman 1956 see also Passos et al., this volume). Harman reasoned that enzymatic reactions using molecular oxygen create, on occasion, O2 radicals. Harman hypothesized that lower levels of oxygen free radicals, by reducing enzymatic activities that utilized molecular oxygen (O2), would result in increased longevity. Not all mitochondrial ETC lesions increase longevity. The mev-1(kn1) mutation is probably the best example of a mutation that decreases mitochondrial activity, but does not increase longevity. The mev-1(kn1) mutation was identified in a genetic screen to identify mutations that resulted in worms that were more sensitive to the drug methyl viologen (Paraquat). Cells treated with Paraquat produce excess oxygen-free radicals. mev-1(kn1) mutant animals are hypersensitive to Paraquat, are short lived, and have reduced mitochondrial...

Methylphenyltetrahydropyridine

The cerebrospinal fluid (CSF) of affected patients contains decreased homovanillic acid levels similar to those observed in patients with Parkinson's disease. y Positron-emission tomography (PET) using 18F-dopa of asymptomatic drug users exposed to MPTP showed decreased dopa uptake, which suggests that the numbers of DA terminals and, by extension, the nigral cell bodies were decreased. The MPTP model of dopamine depletion has been helpful in mechanistic studies of the degenerative and regenerative potential of the nigrostriatal DA system. MPTP is metabolized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase B. MPP+ is then taken up into DA terminals, where it blocks complex I of the mitochondrial respiratory chain. This blockage may lead to adenosine triphosphate (ATP) depletion with secondary cellular demise due to energy crisis. The possibility that abnormalities in the respiratory chain could also lead to cytotoxic oxygen-based free radicals has also been put forward. y

Lipid Peroxidation and Free Radical Formation

Free radicals are reactive chemical species that damage DNA, denature structural and functional proteins and result in peroxidation of membrane lipids. Free radicals are formed as a consequence of several processes including phospholipase activation by cytosolic Ca++, transitional metal reactions which involve free iron, arachidonate metabolism and oxidant production by inflammatory cells. These processes result in the formation of superoxide radicals, which are protonated in the ischaemic environment of the ischaemic brain to produce highly reactive hydroxyl radicals. Normally aerobic cells produce free radicals, which are then consumed by free radical scavengers, e.g. a-tocopherol and ascorbic acid, or appropriate enzymes, e.g. superoxide dismutase. In states where enzymatic processes are disrupted (ischaemia) or hyperoxia occurs (reperfusion), there may be excessive production of oxidants, in particular superoxide, hydrogen peroxide and the hydroxyl radical. These highly reactive...

Nonenzymatic Oxidation of Drugs

The nonenzymatic autoxidation of catecholamines also plays an important role in the physiology and aging of the CNS. Dopamine, like most catecholamines, can be easily oxidized by molecular oxygen in physiological solutions (i.e., at neutral pH and in the presence of transition metal traces) (104). During autoxidation, both semiquinones and quinones are formed, and they react with molecular oxygen to produce reactive oxygen species. Numerous data suggest that the cytotoxicity of levodopa, a dopamine precursor used for long-term therapy of Parkinson's disease, is likely due to the action of free radicals formed as a result of its autoxidation (105, 106). Moreover, quinoid compounds derived from the autoxidation of endogenous catechols polymerize to form neuromelanin, which contributes to the vulnerability of dopaminergic neurons in Parkinson's disease (107). Finally, quinoids products can crosslink with neurofilament proteins (108) and with cysteine to form cytotoxic cysteinylcatechols...

Introduction

Vitamin C is a water-soluble vitamin for humans, primates and guinea pigs. Most other animal species can make ascorbic acid from the sugar glucose, but humans lack an enzyme necessary to convert glucose to ascorbic acid. Vitamin C exists in humans in two biologically active forms, ascorbic acid and dehydroascorbic acid. It is the ability to interconvert between these two forms that gives vitamin C antioxidant capabilities.6-10 Ascorbic acid has several important functions as related to physical activity. The vitamin has long been known to be necessary for normal collagen synthesis. Collagen, one of the most abundant proteins in the body, is a vital component of cartilage, ligaments, tendons and other connective tissue. Vitamin C is needed for the formation of the vitamin-like compound carnitine, which is necessary for the transport of long-chain fatty acids into the mitochondria. The fatty acids can then be used as an energy source. The neurotransmitters, norepinephrine and...