Peripheral Oxidative Dna Damage And Antioxidants In Ad

The relationship between oxidants and antioxidants in various processes and disease states has been largely evaluated in recent years, and has been found to be strong, at least as far as certain molecules and peculiar conditions are concerned. A significant negative correlation between concentrations of serum carotenoids which are known to act as antioxidants and oxidized pyrimidines, however, was found in lymphocytes of healthy humans (Collins et al., 1998), suggesting that some nutritional factors may protect from oxidative DNA damage independently of the health status of the organism. In another interesting study, Lenton et al. (1999) showed that naturally occurring levels of intracellular antioxidants glutathione and vitamin C were negatively correlated with oxidative damage in human lymphocytes, as assessed by levels of 5-hydroxy-2'deoxycytidine (5-OH-dCyd) and of 8-oxo-dG. In particular, the strongest inverse relationship was found between glutathione and 8-oxo-dG, and on the...

Role Of Acetaldehydeprotein Adducts And Free Radicals

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

Free Radicals And Antioxidants

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

Clinical Box 51 Free Radicals and Aging

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

Alcoholic Liver Disease Role Of Free Radicals

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


According to the free radical theory of the aging process, antioxidants should help reduce some of the symptoms associated with cellular senescence. Experiments with mice and rats have failed to substantiate this claim. However, there is some evidence suggesting that antioxidants such as vitamin C and E may reduce the threat of Alzheimer's disease by dissolving beta-amyloid plaques (deposits). In addition, research on longevity genes (described in chapter 6) has shown that some of these genes code for proteins that minimize oxidative damage to cells and tissues. This could mean that the failure of previous experiments to substantiate the free radical theory may be the fault of the experimental procedure and, thus, not a true test of the theory.

Free Radicals

The role of free radicals is closely related to the rate-of-living theory and was originally proposed in the 1950s. Free radicals are molecules that have an unpaired electron, which makes them very reactive. One of the most important, the oxygen free radical, is a toxic exhaust produced by mitochondria during the very important metabolic process of oxidative phosphorylation. This process produces the ATP that cells need to survive. The oxygen free radical can remove an electron from virtually any molecule in the cell, including DNA, RNA, proteins, and the lipids in the cell membrane. When it does so, it triggers a chain reaction of destabilized molecules reacting with other molecules to form new free radicals and a variety of potentially dangerous compounds. Many gerontologists believe free radicals are directly responsible for cellular senescence and the aging of the animal as a whole. However, cells do not allow free radicals free rein. A special enzyme, called superoxide dismutase...

Methods In Enzymology

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

Alphatocopherol And Ethanol Consumption

Chronic alcohol consumption produces an increased breakdown oflipid-soluble vitamins such as hepatic alpha-tocopherol, possibly secondary to a marked increase in the formation ofhepatic alpha-tocopherol quinone, a metabolite of alpha-tocopherol formed by free radical reaction 82 , Since chronic ethanol consumption has been associated with compromised antioxidant status and an increase in lipid peroxidation, the significant decrease of vitamin E compared to other lipid-soluble antioxidants may contribute, at least in part, to enhanced hepatic lipid peroxidation seen in alcoholics. Besides vitamin E, other antioxidants such as vitamin C, glutathione and selenium are also strikingly decreased following chronic ethanol ingestion 83 . It is also interesting that chronic alcohol consumption significantly alters the distribution of alpha-tocopherol and gamma-tocopherol not only in hepatic tissue but in extrahepatic tissues as well 84 ,

Pathogen or Protector

Viewing amyloid-p and tau as antioxidants provides an explanation for the in vitro oxidative effects of amyloid-p (since all antioxidants are, by definition, also prooxidants dependent on environment) as well as the in vivo antioxidant properties of amyloid-p. Therefore, as we celebrate the 100th anniversary of Alois Alzheimer's original paper describing the pathological lesions, we find ourselves at a crossroads, namely, is the pathology a harbinger of disease or a protective response to the disease The latter would represent a major paradigm shift but, after 100 years, is it not about time

Evidence Suggesting A Role For Reactive Oxygen Metabolites In Ischemic Acute Renal Failure

Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors, and iron chelators protect against injury. Evidence suggesting a role for reactive oxygen metabolites in acute renal failure. The increased ROS production results from two major sources the conversion of hypoxanthine to xanthine by xanthine dehydrogenase and the oxidation of NADH by NADH oxi-dase(s). During the period of ischemia, oxygen deprivation results in the massive dephosphorylation of adenine nucleotides to hypox-anthine. Normally, hypoxanthine is metabolized by xanthine dehydrogenase which uses NAD+ rather than oxygen as the acceptor of electrons and does not generate free radicals. However, during ischemia, xanthine dehydrogenase is converted to xanthine oxidase. When oxygen becomes available during reperfusion, the metabolism of hypoxanthine by xanthine oxidase generates superoxide. Conversion of NAD+ to its reduced form, NADH, and the accumulation of NADH occurs during ischemia. During the...

Gastrointestinal Tract Including Carcinogenesis

The role ofROS in alcohol-associated gastric mucosal injury is underlined by the fact that oral administration of absolute alcohol to rats reduces glutathione and increases lipid peroxidation in the gastric mucosa 105 , Antioxidants, superoxide dismutase and hydroxyl radical scavengers prevent gastric lesions caused by alcohol, whereas inhibition of superoxide dismutase results in a deterioration 105 , It is interesting to note that the pretreatment of rats with allopurinol, a xanthine oxidase inhibitor, protects against haemorrhagic lesions due to alcohol which points to the involvement ofROS produced by xanthine oxidase in the gastric mucosa 106,107 , However, controversial results have also been published by using a stomach perfusion model with 30 alcohol 108 , In any event, cellular glutathione levels are believed to be indicators of oxidative tissue injury and it has been shown in experimental animals as well as in humans that alcohol decreases gastric mucosal glutathione...

Lipids And Cardiovascular Disease

The potential significance of these in vitro data needs to be discussed in relation to the prevention of atherosclerosis by ATC in vivo, although consideration need to be given to the possibility that other pharmacological preparations may be equally promising in reducing the oxidation ofLDL. Such candidates include analogues of tetronic acid (for example acid), which are able to inhibit hepatic membrane lipid peroxidation and LDL oxidation in vitro to a greater extent than Trolox 131 . Some authors have questioned whether blood levels oflipophilic antioxidants reflect the development of atherosclerosis 132 , In a comparison between patients with coronary heart disease and controls, gamma-tocopherol levels were significantly lower in patients with coronary heart disease, although in contrast no such differences were observed for ATC 132 , In other studies, patients with coronary artery disease (for example, angina or myocardial infarction) were shown to have lower serum ATC compared...

Discussion And Conclusions

Apart from vitamin C, flavonoids (Noroozi et al., 1998), co-enzyme Q10 (Tomasetti et al., 1999) and lycopene contained in tomatoes (Riso et al., 1999) have also been shown to exert protective effects against oxidative DNA damage, either decreasing DNA strand breaks (Noroozi et al., 1998) or increasing DNA resistance towards H2O2-induced oxidation (Riso et al., 1999 Tomasetti et al., 1999). Regarding antioxidant supplementation and its potential use in AD, it has been shown that a 20 week supplementation with a daily antioxidant mixture containing 100 mg vitamin C, 280 mg vitamin E and 25 mg p-carotene resulted in a significant decrease in endogenous lymphocyte DNA oxidative damage (measured with the comet assay) in 5059 year-old smokers and non-smokers (Duthie et al., 1996), suggesting that the positive effect of diets rich in fruit and vegetables on certain cancers may be exerted by dietary antioxidants (Miller, 1990 Negri et al., 1991 Steinmetz and Potter, 1991 Byers and Perry,...

Colonylevel defense

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

Ap Deposition And Cerebral Oxidation Are Both Closely Associated With Ad Pathogenesis

Increasing evidence has implicated oxidative stress in the pathogenesis of AD. Metabolic signs of oxidative stress in the neocortex of AD patients, oxygen radical-mediated damage of brain proteins, lipids and DNA, systemic signs of oxidative stress and the response of antioxidant systems have all been observed in AD (Mecocci et al., 1994 Hensley et al., 1995 Ceballos-Picot et al., 1996). A number of oxidative stress markers have been observed in association with amyloid plaques, neuritic plaques and NFTs, including 4-hydroxynonenal (Sayre et al., 1997), pyrraline and pentosidine (Smith et al., 1994b), 3-nitrotryosine (Smith et al., 1997b), AGE-modified tau (Smith et al., 1994b), redox active Fe (Smith et al., 1997a), neurofilament-related protein carbonyls (Smith et al., 1991), as well as elevations in Cu Zn-SOD (Pappolla et al., 1992), Mn-SOD (Furuta et al., 1995), catalase (Pappolla et al., 1992 Furuta et al., 1995), ferritin (Grundke-Iqbal et al., 1990) and elevated HO-1 (Smith et...

Sundry Biochemical Actions

What eventually amounted to a breakthrough in establishing the mechanisms of aminoglycoside toxicity came from observations that aminoglycoside antibiotics elicited the formation of reactive oxygen species (ROS free radicals) in isolated renal mitochondria31 and that a radical scavenger was able to protect from the auditory side effects of kanamycin.32 At the time, however, these observations were challenged by other studies failing to link free radicals to nephrotoxicity33 or to confirm radical scavenger protection against aminoglycoside ototoxicity.34 Although more evidence emerged that antioxidants could limit ototoxicity and that free radicals were generated in tissues exposed to aminoglycosides,10'35'36 there appeared to be considerable reluctance to accept reactive oxygen species as causal agents in aminoglycoside toxicity. One of the stumbling blocks was the unresolved question of how aminoglycoside antibiotics could participate in single electron transfers and...

Devising New Treatments For Parkinson Disease Through Research On Animal Models

The current problem for treating PD lies in the lack of therapies that can provide a long-term benefit in the absence of disabling complications. Devising novel efficacious treatments for the future is an important goal for both preclinical and clinical investigators in the Parkinson field. New therapeutic options can be classified in three main categories (1) neuroprotective treatments, which aim at halting the neurodegenerative process at the basis of PD. For example, investigators are attempting to counteract the degeneration of DA neurons through intracerebral delivery of trophic factors (Gill et al. 2003 Grondin et al. 2003) or systemic administration of antioxidants (Shults 2002 Mandel et al. 2003) (2) restorative treatments, which aim at restoring the integrity of the damaged nigrostriatal system by intracerebral transplant of DA-producing cells (Lindvall and Hagell 2000 Bjorklund et al. 2003), or by delivery of viral vectors encoding DA-synthesizing enzymes (Kirik et al....

ERWPt suppress the augmentation of intracellular ROS induced by PMA as well as ascorbic acid2phosphate ASA2P

ASA-2P suppress the transformation foci under the condition of 0.2 g ml-1 of MCA initiation from day 1 to day 3 and 100 ng ml-1 of PMA promotion from day 6 to day 21 (data not shown). ASA-2P is a stable antioxidant, and suppressed Balb c 3T3 two-stage cell transformation in promotion stage15. The treatment of ERW with 1 ppm of Pt nanoparticles suppressed cell transformation stronger than 100 M ASA-2P (data not shown). To evaluate the intracellular ROS scavenging effect of ERW Pt, intracellular ROS was induced by the PMA treatment for 15 min and determined by using DCFH-DA and flow cytometer (Figure 2). ASA-2P, ERW, Pt nanoparticles and ERW Pt significantly reduced excess intracellular ROS induced by PMA treatment. We have revealed that ERW contains a small amount of Pt nanoparticles as active hydrogen donors and ROS-scavengers2'5. These results suggested that ERW Pt acted as antioxidant in the cells and suppressed tumorigenesis.

Oxidative stress response

Q10 is well known strong anti-oxidants. 8-OHdG is well known oxidative DNA damage as a marker. We evaluated 8-OHdG concentrations change in our process. Q-Media supplemented with 500 micro-mol L is expected antioxidant effect, but no-effect for 8-OHdG concentrations tendency and cumulative cell density. SPR with Q-Media was indicated higher than without Q-media, it was similarly data by Q10 Tween-80.

Compensatory Responses

Intracellular oxidative balance is tightly regulated and therefore, in the face of stress, an upregulation of compensatory mechanisms would be expected in AD. One of the first reports of oxidative stress in AD came from the finding of pentose phosphate pathway induction in AD (Martins et al., 1986). Reducing equivalents in the form of NADPH are essential to maintain oxidant defenses. Later findings of induction of the NADPH-requiring enzyme heme oxygenase-1 (HO-1 Smith et al., 1994b Premkumar et al., 1995), the rate-limiting enzyme required for transforming prooxidant heme to anti-oxidant bilirubin, substantiated the view of active antioxidant defense in AD. Since HO-1 induction is synchronous with t accumulation in neurons (Takeda et al., 2000a,b), reduced oxidative damage in neurons with t accumulation may be a part of this antioxidant response. Another consequence of increased NADPH generation is increased glutathione and free sulfhydryls. The latter are specifically increased in...

Results And Discussion 31 Effect of Qi0 in the medium

We screened substances using YB2 0 cell-lines. We found SPR was enhanced in Q10 Tween-80 additive media supplemented with 50 micro-mol L. On the other hand, Tween-80 additive media was not affected to SPR. Q10, also known as Ubiquinone is applied for healthcare or other uses. Q10 is a lipid soluble compound that inhabits the inside of inner mitochondrial membranes, where it functions as an integral part of the electron transport chain as well as an efficient endogenous lipophilic strong antioxidant. In addition, it has been known that addition of Q10 to cell culture media promotes growth of several cell lines, such as HeLa cell and murine fibroblast cell or bovine embryo cell.

Oxidative and Nitrative Stress

Reactive oxygen species (ROS) such as superoxide and hydroxyl radicals are known to mediate reperfu-sion-related tissue damage in several organ systems including the brain, heart, and kidneys 17 . Oxygen free radicals are normally produced by the mitochondria during electron transport, and, after ischemia, high levels of intracellular Ca2+, Na+, and ADP stimulate excessive mitochondrial oxygen radical production. Oxygen radical production may be especially harmful to the injured brain because levels of endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase, glutathione , and antioxidant vitamins (e.g.,alpha-tocopherol,and ascorbic acid) are normally not high enough to match excess radical formation. After ischemia-reperfusion, enhanced production of ROS overwhelms endogenous scavenging mechanisms and directly damages lipids, proteins, nucleic acids, and carbohydrates. Importantly, oxygen radicals and oxidative stress facilitate mitochondrial transition pore...

Murine Aids Maids And Micronutrient Deficiency

LP-BM5 Murine leukemia virus (MuLV) infection of C57BL 6 mice causes a disease that has many features in common with human AIDS, in particular abnormal lympho-proliferation and severe immunodeficiency. Thus, this murine AIDS (MAIDS) model is useful for evaluation of antiviral agents as well as deficiency in antioxidant micronutrients such as selenium (Se), vitamin A, vitamin E, zinc (Zn), cooper (Cu), and glutathione. In one study using MAIDS, the effect of Se as sodium selenite was used to evaluate immunological and oxidative effects. The results indicated that Se treatment inhibited splenomegaly, which is characteristic of chronic murine AIDS. In addition to detecting abnormal immune function, oxidative imbalance possibly existed in the MAIDS model, as lipid peroxide increased significantly in the spleen and whole blood glutathione peroxidase (GSH-Px) activity decreased markedly. Se supplementation had a good protective effect 54 , In another study using MuLV, ethanol administration...

Nonpharmaceutical Approaches Albumin

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

Tocopherol neuropathy

Vitamin E deficiency results from abetalipoproteinemia (Bassen-Kornzweig Pathogenesis Syndrome), fat malabsorption states (cystic fibrosis, biliary atreasia), or a familial defect of the tocopherol transport protein. Tocopherol is a free radical scavenger and probably functions as an antioxidant to maintain nerve membrane integrity.

Chemical Enhancers and Inhibitors of Carcinogenesis

Hydrogen peroxide in the diet enhances carcinogenicity in MNNG-initiated rainbow trout (Kelly et al., 1992). Fish fed H2O2 had increased levels of the mutagenic DNA adduct 8-hydroxy-2'-deoxyguanosine, which is an indication of oxidative DNA damage. Vitamin E, an antioxidant, did not have a significant effect in this study.

Degenerators of cells

Aydos et al.478 underlined the particularly detrimental effects of nicotine on germ cells, peritubular structures and Sertoli cells. The germ cells were degenerated, and spermatids retained excess cytoplasm and accumulated electron-dense lipid droplets in the cytoplasm. Moreover, the results of Aydos et al.478 proved that the acrosomes in rats exposed to nicotine were irregular and abnormally configured. It is not difficult to interpret these results as evidence of active nicotine toxicity. Moreover, this chronic toxicity is reported also by Sener et al.479, who have studied aqueous garlic extract as an antioxidant. In this research, male Wistar albino rats were injected with nicotine, which led to increased collagen contents in tissues. Although Sener et al.479 reported the aqueous garlic extract was a protector of rat tissues, there is evidence of nicotine-induced oxidative damage. Nicotine toxicity has been studies also on None of these studies question the symptoms of acute and...

Mutants Who Live Longer

There are many indications that aging is accompanied (or perhaps even caused) by an increase in the oxygen danger. For instance, ischemia of isolated mouse heart damaged the cardio-myocite nuclear DNA much stronger if the heart was obtained from 22- to 24-month-old mice than from 6- to 7-month-old ones 208 . The traditional point of view is that the age-related sensi-tization to the oxidative stress is a consequence of occasional injuries resulting in disregulation in the antioxidant system in an old organism. The phenoptotic concept, however, takes into account an alternative possibility assuming that such a disregulation is specially induced to realize the suicide signal which comes from, e.g., intracellular sensors measuring the telomere length. If it were the case, the paradoxical observation of the Pelicci's group would be explained.

Zinc Modulates Sod Neurotoxicity A Molecular Insult Linking Ad To Familial

The altered reactivity of Zn-less SOD allows it to be reduced by cellular reductants (like GSH) which then donate an electron to O2 to generate O2 , which then reacts with NO to form the strong prooxidant, peroxynitrite. Thus, if SOD1 loses Zn2+, its dismutase catalytic activity is diminished while it simultaneously abnormally develops tyrosine nitration activity mediated by O2 formed at the Cu2+ catalytic site (Crow et al., 1997). The Beckman group proposed that the O2 formed by Zn-deficient SOD1 might not be released as a free intermediate, which could explain why excess SOD1 fails to slow disease progression in FALS SOD1 transgenic mice (Bruijn et al., 1998). Like Ap (Cuajungco et al., 2000), Cu-loaded SOD1 is neurotoxic at micromolar concentrations in cell culture when not bound to Zn2+ (Estevez et al., 1999). Hence, SOD1, while being traditionally thought of as an antioxidant, has the capacity to become strongly pro-oxidant as a consequence of diminished zinc binding....

Group I Polypeptides Keeping The Killers In Check

The effects of these group III Bcl-2 family members are inhibited by group I family members, including Bcl-2, Bcl-xL, and Mcl-1. Over the years, several different explanations for the antiapoptotic effects of these polypeptides have been proposed. First, it was suggested that group I polypeptides inhibit apoptosis by binding and neutralizing group II polypeptides, especially Bax (80,108,109) or Bak (110). The identification of Bcl-xL mutants that fail to bind Bax or Bak but still inhibit apoptosis (111) cast doubt on this model, at least as a universal mechanism of apoptosis inhibition. Second, it was proposed that Bcl-2 prevents apoptosis by increasing the antioxidant capacity of cells (112). Observations that place apoptosis-associated increases in reactive oxygen species downstream of caspase 3 activation (113,114) cast doubt on this model. Third, it was suggested that Bcl-2 prevents apoptosis by inhibiting the release of calcium from endoplasmic reticulum stores (115-119)....

Oxidative Dna Damage In Ad

When oxygen free radicals some of which are highly reactive molecules able to damage all cellular key components, including proteins, lipids and nucleic acids react with and damage DNA, oxidized bases are formed, of which at least 20 are known to date. One of these bases, 8-hydroxy-2'deoxyguanosine (8-oxo-dG), is a reliable marker of oxidative stress to DNA, and can be measured by HPLC with electrochemical detection, a sensitive and specific method of assay (Floyd et al., 1986). As cited above, this technique has allowed the observation of an age-dependent increase in the levels of 8-oxo-dG in DNA extracted from cerebral tissue of human healthy subjects aged 42-97 years, both in nuclear DNA (nDNA) and in mitochondrial DNA (mtDNA). The latter showed a higher susceptibility to oxidative damage compared to nDNA (Mecocci et al., 1993), a difference that might be explained by a number of factors, including the proximity of mtDNA to the inner mitochondrial membrane (where enzymes of the...

The Antimalarial Mode Of Action Of Artemisinin And Derivatives

There is now an increasing amount of experimental evidence which suggests that the antimalarial mode of action of artemisinin, 1 and related compounds, 2-6 is a two-step process. In the first, artemisinin is activated by interacting with the haem residue which remains following the digestion of haemoglobin by the malaria parasite the result of this process is the production of highly reactive free radicals. In the second step, the reaction of artemisinin-derived free radicals with various molecular components of the parasite leads to the disruption of normal metabolic processes and parasite death. The evidence supporting the above will now be critically discussed in some detail. The discovery that deoxyartemisinin, 7 which lacks the endoperoxide group is devoid of antimalarial activity clearly showed that the presence of this group is essential for activity (Anon. 1982). The well established observation that iron causes the catalytic decomposition of peroxides to yield free radicals,...

Pharmacological approaches to cerebral protection after cardiac arrest

Free radicals Oxygen-derived free radicals have been implicated in the production of ischaemic neuronal damage. During both ischaemia and reperfusion the natural free radical scavengers are depleted. In certain experimental settings exogenous free radical scavengers (desferrioxamine, superoxide dismutase, and catalase) have been shown to influence an ischaemic insult to the brain, suggesting a potential use for these drugs, although no clear role in clinical practice has currently been defined.

Chronic Abdominal Pain

The etiology of the pain is multifactorial and, in general, is not well understood. Factors include continued alcohol consumption that results in local release of oxygen-derived free radicals, diminished pancreatic blood flow and tissue acidosis, perineural sheath destruction with exposure to various nociceptive agents, and elevated pancreatic duc-tal and parenchymal pressures. The initial therapy for pain in all of these patients should be nonoperative and includes recommendations for the cessation of alcohol intake, and the administration of oral analgesic agents.

Uva Uvb and Sunscreens

Whether or not sunscreens help to protect against skin cancer remains unproven. As the sale of sunscreen has risen in recent decades, so has the incidence of skin cancer. Indeed, recent studies have shown that people who use sunscreens have a higher incidence of basal cell carcinoma than people who do not, while data relating malignant melanoma to sunscreen use are still contradictory and inconclusive. Some of the chemicals used in sunscreens damage DNA and generate harmful free radicals when exposed to UV chemicals such as para-aminobenzoic acid (PABA) (now discontinued), zinc oxide, and titanium dioxide. The jury is still out, however, on how sunscreens react on and with the skin authorities cannot say with certainty, yet, whether sunscreens provide any protection or do any harm. Not enough data are available yet on older people who have used sunscreen their entire lives. Given the uncertainty about their effectiveness, it is best not to assume that sunscreens protect you from skin...

Acute Renal Failure Cellular Features of Injury and Repair

Although ischemic acute renal failure (ARF) is likely the result of many different factors, much tubule injury can be traced back to a number of specific lesions that occur at the cellular level in ischemic polarized epithelial cells. At the onset of an ischemic insult, rapid and dramatic biochemical changes in the cellular environment occur, most notably perturbation of the intracellular levels of ATP and free calcium and increases in the levels of free radicals, which lead to alterations in structural and functional cellular components characteristic of renal epithelial cells 1-7 . These alterations include a loss of tight junction integrity, disruption of actin-based microfilaments, and loss of the apical basolateral polarity of epithelial cells. The result is loss of normal renal cell function 7-12 .

Toxicities Linked To Descriptors For The Overall Properties Of The Molecule

Sections 2.1-2.3 summarize the weight of evidence that links specific structural fragments (toxicophores) to adverse outcomes. Literature evidence linking overall molecular properties and adverse outcomes is less prevalent. One approach is to examine the link between overall physicochemical parameters and toxic endpoints and has been the subject of an excellent recent review which discusses the physico-chemical parameters commonly associated with toxicity endpoints 62 . Lipophili-city , usually described by the octanol-water partition coefficient, (log P) or the calculated value, (clog P) appears to be the most general requirement in quantitative structure-toxicity relationships (QSTRs) reflective of the link between lipophilicity and access to tissue and cell compartments through membrane permeability and lipophilicity driven non-specific binding to hydrophobic protein sites or membranes. This paper also highlights the literature evidence linking lipophili-city to metabolism,...

Morphological and cytological changes that occur with drying

Myrothamnus flabellifolia, anthocyanin levels increased significantly in dried tissues, helping to mask chlorophyll and reduce damage by free radicals (Sherwin and Farrant, 1998 Koonjul et al., 2000). Photoprotection by mechanisms associated with the production of zeaxanthin has also been demonstrated (Casper et al., 1993 Eickmeier et al., 1993).

DNA Structure Inspires New Theories

Gerontologists of the second epoch quickly realized that the genetic code and the events of protein synthesis gave them, for the first time, testable theories of the aging process. The first, proposed by Deham Harman in 1956, was the free radical theory, and the second, proposed by Leslie Orgel in 1963, was the error catastrophe theory. Both of these theories (described in chapter 2) suggest that aging is caused by errors in biosynthesis, due either to free radicals or to inherent error frequencies associated with transcription and translation. In either case, according to the theories, the result is a buildup of dysfunctional proteins that damage normal cellular functions, thus reducing cell viability with time. The error catastrophe theory was first tested on bacteria, experimental organisms introduced to gerontology during the early years. To further test this theory and the free radical theory, gerontologists of the

Body Architecture

How long can an individual cell be expected to survive There are cells and structures in the living world which can survive a very long time, such as bacterial spores or many plant seeds. These are in a highly dehydrated state, and they essentially have no respiration or metabolic activity. Cells in an active animal are very different as they contain a high proportion of water and they also depend on energy from respiration. Under these conditions, innumerable chemical reactions are occurring. Many of these comprise the wide range of activities characteristic of any living cell, but some provide background 'noise' which can interfere with those normal activities. In particular, respiration generates oxygen free radicals (often abbreviated to ROS - reactive oxygen species). These are short-lived but highly reactive. During their very short lifetime they can damage DNA, proteins, or lipids in the cell membrane. As we shall see later, the cell has defenses...

Exposure to Red Tide Planktons

The mechanisms by which various algal blooms kill fish must be as varied as the number of major algal groups. Although the morphological and physiological changes above would be stressful enough to kill fish, it still remains possible that they are the consequences of still a more primary action of the plankton on the fish. The work of Oda and colleagues (Oda et al., 1992a,b) clearly show that superoxide radicals and hydroxyl radicals are generated from C. marina. The cytolytic action of free radicals (see Dean, 1987) and the possible consequence of breakdown in ionic and osmotic homeostasis in the cells that make up the surface of the gill epithelium has been suggested as a primary process by which this red tide organism begins the degradative processes which can lead to the death of the fish (Oda et al, 1992b). While Yang and Albright (1992) suggested that death from exposure to C. concavicornis is due to suffocation as a result of impaired O2 uptake, Yang (1993) has also shown that...

Oxidative stress and anhydrobiosis

Whether oxidative stress is a cause or an effect of desiccation sensitivity has yet to be resolved due to a large body of conflicting evidence in the literature. The core of the problem is two fold. From a physiological point of view, Hendry (1993) argued that attempts to correlate free radical processes with desiccation tolerance must be done in relation to the characterization of other desiccation-induced damage. This must be done in order to assess whether free radicals generated during drying are a cause or an effect of the loss of viability. Echoing the earlier review of Gutteridge and Halliwell (1990) and Leprince et al. (1990), he pointed out that free-radical-mediated injury can occur before or after the time of death during drying (Hendry, 1993). Thus, great caution should be exercised in ascertaining whether oxidative stress plays a role in desiccation-induced injury and loss of desiccation tolerance. Oxidative injury in both animals and plants generally results from...

The Student Year SE Severin and VA Engelhardt

Obvious the pK of carnosine is about 7, so carnosine neutralized H+ produced by glycolysis and allowed the muscle to accumulate lactate without risk of acidification of the tissue. Paradoxically, Severin did not accept this explanation, deciding that pH buffer function is too primitive for a compound which was the main subject of his studies for so many years. He continued his search for carnosine function even after 1978 when Effron and coauthors reproduced Severin's phenomenon,'' replacing carnosine with Tris buffer. In his studies, Severin addressed himself to quite different aspects of biochemistry, trying to find a place for carnosine in various metabolic processes or mechanisms of their regulation. After all, Severin's pupils described an antioxidant effect of carnosine. In certain rare cases, it proved to be a neuro-transmitter. Some other functions of this dipeptide were found by Russian and foreign biochemists, which confirm once more the statement that the majority of cell...

Theories Of Senescence

Reactive radicals of nitrogen (nitric oxide and derivatives such as pero-xynitrite) and of oxygen (superoxide anion, hydrogen peroxide, hydroxyl radical) can inflict considerable damage on macromolecules (proteins, nucleic acids, complex lipids), give rise to carcinogens (e.g., nitrosamines), and trigger (or sometimes prevent) apoptotic death of cells such as macrophages and vascular epithelial cells. There are mechanisms for scavenging and antagonizing those highly reactive species of molecules and for repairing damage caused by them. However, unless such mechanisms are absolutely effective, damage inflicted by free radicals may accumulate, even in a self-potentiating or exponential manner. There is evidence that the efficiency of mitochondrial electron transport and energy-generating processes deteriorate with age, resulting in increased appearance of oxidizing free radicals (26,27). Moreover, antioxidant resistance declines with age (28,29). Thus, the free radical and nitric oxide...

Modalities That Escape Classification As Antipruritic Interventions

Other therapeutic modalities that have been used to treat the pruritus of cholestasis include flumecinol, ligno-caine, antioxidants, and androgens, and are stated here for completion. Ursodeoxycholic acid (UDCA) is a drug approved to treat PBC. UDCA treatment may be associated with some improvement in pruritus by virtue of the impact it has on the liver disease per se. The effect of UDCA as a specific antipruritogen has not been studied and based on clinical trials of UDCA in PBC, it is uncertain however, the choleretic effect of UDCA may have a beneficial impact on the pruritus by the presumed enhanced biliary excretion of pruritogen(s). Exacerbation of pruritus upon start

Environmental Factors

Photosensitivity is seen in the majority of SCLE patients. UV light can induce the release of inflammatory mediators such as IL-1, TNF-a, IL-10 and oxygen free radicals at the level of the epidermis and dermis. In addition to natural light, cutaneous LE lesions have been provoked by exposure to psoralen with UVA (Dowdy et al. 1989 McGrath et al. 1990), UVB via unshielded fluorescent light (Rihner and McGrath 1992 Kuhn et al. 2001), radiation therapy (Balabanova et al. 1997), and even photocopier light (Klein et al. 1995). In addition, many drugs which have been reported to induce SCLE lesions often have photosensitization as a side effect of their use. Several researchers have used standardized phototesting protocols which involve exposing specific patches of skin to precise amounts of UVR or natural light in order to demonstrate photosensitivity in these patients (Sanders et al. 2003 as reviewed in Kuhn et al. 2001). One such study was able to diagnose...

Cardioprotective Effect Of Moderate Wine Drinking

There is evidence that moderate wine consumption protects against CAD. Two studies linked the beneficial effects of moderate drinking only to wine 13,14 , Red wine contains several flavonoids and phenolic compounds with significant antioxidant properties. The protection effects against atherogenesis suggested that antioxidants in wine might play a role through modification of LDLs 15 , However, it seems unlikely that the cardioprotective effects are due solely to the antioxidant properties of these compounds, since the orally ingested phenolic antioxidants may not reach sufficiently high plasma levels to affect the oxidizability of LDL in humans 16 , Moreover, the majority of epidemiological studies have shown that all alcohol beverage types (beer, wine, and distilled spirits) confer some cardioprotective effects 17 , supply phytochemical isoflavenoids, vitamins which have powerful antioxidant effects. These effects include inhibition oflow-density lipoprotein oxidation as well as...

Extended Mitochondria as Intracellular Electric Cables

Facilitate energy supply of the cell core since very fast A 2H+ transmission substitutes for slow diffusion of respiratory substrate and O2 (or ADP, phosphate, and ATP) in cytosol crossed by intracellular membranes and cytoskeleton structures. Moreover, it allows a very large cell like a myocyte to operate in such a fashion that oxygen is present only in a narrow peripheral zone, the major part of the cell being anaerobic. This might create a line of antioxidant defense for the cell 119 .

Prospects for the Future

Bradley Hyman

Strategies are being developed to ameliorate the neuro-toxicity caused by abnormal metabolic products and prevent processes that lead to cell death. A large number of clinical trials are underway, both industry and government (NIA-ADCS) sponsored studies, with widely-used drugs (e.g., antioxidants, anti-inflammatory agents, statins, vitamins and folate) that might reduce the risk ofAlzheimer's disease. Intensive studies are underway on multiple fronts, from basic science to genetics to drug therapy to care giving.

Mitochondria and ROS in Apoptosis Mitochondrial Suicide Mitoptosis

The question arises why the mitochondrial intermembrane space is used by the cell to hide the suicide proteins like AIF or cytochrome c. In 1996, I suggested that the answer may be found if we take into account ROS 173 . To form a very large amount of ATP (in a 70 kg man, 40 kg ATP is produced per day), mitochondria convert to H2O about 0.4 kg O2 per day. If the O2 production is equal to 1 of the O2 consumed, this gives 4 g per day. For sure, this amount is quite sufficient to damage all our DNA and, hence, to kill us. To avoid such a danger, mitochondria must form much lower O2 amounts and antioxidant systems of organisms must effectively detoxify the O2 formed. Really, mitochondria are equipped with a multifaceted mechanism minimizing the ROS danger. According to our data 174 , it includes (i) lowering of O2 inside, and in vicinity of, mitochondria (ii) a A 2h+ decrease below the level critical for reverse electron transfer from CoQH2 to O2 in Complex I as well as for inhibition of...

Mice and

Fibroblast Cells From Mammal

Confirmed that normal cells from a range of species with different maximum longevities, have a range of repair efficiencies, that it, there is a direct correlation between repair capability and longevity. One study is of particular interest, because the cells were taken from the outer layer of cells of the lens of the eye. These cells are, of course, directly or indirectly exposed to sunlight, so they have a specific need for this repair mechanism. It turns out that the cells which have the longest exposure to sunlight ie. through the animals' lifespan, also have the most efficient repair. For six species, with maximum lifespans ranging from 3 to 40 years, the correlation was excellent. The levels of enzymes involved in other aspects of DNA metabolism, have also been shown to be correlated with maximum longevity. There is also evidence that damage to DNA from oxygen free radicals is greater in shorter lived species, which probably means that the defences against free radicals are more...

The Role of Damage Response Pathways in Stem Cell Aging

Fasl Induced Calcium

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

Maintenance of the Body

The power-houses in each cell are small organelles which produce energy from respiration. This process depends of course on a continual supply of oxygen, and an energy source such as glucose. During respiration some short-lived reactive components are produced as a by-product. These are known as oxygen free radicals, or ROS. These are neither molecules nor atoms, in the usual sense, and they have a transient existence. In fact, their survival ends when they react with some cellular component, that can be DNA, protein or lipid. The reaction often produces an abnormal or defective product, for example, an oxidized amino acid in a protein, or a peroxide in a lipid component. In the case of DNA, the reaction changes a single normal component to one which is abnormal. Because there are so many DNA components per cell, even the alteration of a very small fraction can amount to several thousand defects in every cell everyday of our lives. It is not surprising that organisms have evolved...

Feed Related Disorders in Aquaculture

Lipoid liver disease, a significant problem in farmed fish, is usually linked to rancidity (auto-oxidation) of fats in fish feeds (Roald et al., 1981 Saraiva et al., 1986). Clinical and pathological correlates include reduced haematocrit, an abundance of ceroid laden macrophages in visceral organs, and an enlarged pale, friable liver due to macrovesicular lipidosis. Oxidant damage occurs when free radical production overwhelms the free radical scavenging enzyme system of the animal (Winston, 1991). Systemically, free radicals damage cellular membranes. Damage to red blood cells leads to anaemia (Moccia et al., 1984) and ceroidosis results from breakdown products of dead cells. So called 'acute-on-chronic' episodes can occur, during which large portions of tissue, often the fatty liver, undergo an acute oxidation stress and necrosis. Oxidant stress can also promote other diseases. Manifestations of 'pancreas disease', a condition of farmed Atlantic salmon early in their first sea water...

Stroke Neuroprotective Clinical Trials Lessons from Past Failures

Given these past failures, the focus has shifted towards expanding the therapeutic time window, improved patient selection, the use of brain imaging as a selection criterion, combination acute stroke drug treatments, use of validated rating scales to assess functional end points, and improved stroke trial design and organization 127,130 . A number of new neuroprotection trials are currently underway or in the planning stages. These include trials of the free radical spin trap agent NXY-059 (now in phase III trials), intravenous magnesium, the antioxidant ebse-len, the AMPA antagonist YM872, and the serotonin antagonist repinotan 131-133 . With the insights gained from prior neuroprotective trials, it is anticipated that one or more of the impending trials will prove successful.

General Contraindications to Liver Transplantations

Special consideration should be given to the young infant who presents with liver failure. Some of the causes of liver failure in this age group can be treated with medical therapy. For instance, chelation and antioxidant therapy are now used to treat neonatal hemochromatosis. Albeit the rate of survival with medical therapy is only 30 to 40 , but that may be similar to survival after OLT in neonates.

Causes Of Electrolyte Derangements In Acute Renal Failure

Renal Failure Degree

Micronutrients in acute renal failure (ARF) antioxidative factors. Micronutrients are part of the organism's defense mechanisms against oxygen free radical induced injury to cellular components. In experimental ARF, antioxidant deficiency of the organism (decreased vitamin E or selenium status) exacerbates ischemic renal injury, worsens the course, and increases mortality, whereas repletion of antioxidant status exerts the opposite effect 45 . These data argue for a crucial role of reactive oxygen species and peroxidation of lipid membrane components in initiating and mediating ischemia or reperfusion injury. In patients with multiple organ dysfunction syndrome and associated ARF (lightly shaded bars) various factors of the oxygen radical scavenger system are profoundly depressed as compared with healthy subjects (black bars) plasma concentrations of vitamin C, of -carotene, vitamin E, selenium, and glutathione all are profoundly depressed, whereas the end-product of lipid...

The Paraquat Model Of Parkinson Disease

Investigators have hypothesized that paraquat toxicity depends on oxidative damage. In vitro, paraquat treatment caused oxidative damage, including ROS production, glu-tathione depletion, and lipid peroxidation. Antioxidant treatment prevented paraquat toxicity (Chun et al. 2001 Li and Sun 1999 Mollace et al. 2003 Osakada et al. 2003 Schmuck et al. 2002 Yang and Sun 1998a Yang and Sun 1998b). In vivo, directly injecting paraquat into the substantia nigra caused lipid peroxidation (Mollace et al. 2003). The source of this oxidative damage may be paraquat itself, as paraquat can undergo redox cycling and become a reac-

Treatment of Olfactory Disorders

Fect of aLA is well described both in experimental animals and in humans (for review see 257 ). It is known to stimulate the expression of nerve growth factor, substance P, and neuropeptide Y 258-260 . It enhances motor nerve conduction velocity as well as microcirculation 261, 262 . Further, due to its potent anti-oxidative effects, aLA also has neuropro-tective capabilities indicating that aLA is suited to treat neural damage involving free radicals 263 . Preliminary work has already indicated that it may be useful in post-URTI olfactory loss when administered at a dose of 600 mg d over a period of 4-7 months 136 . Other encouraging pilot studies have been performed with the NMDA-antagonist caroverine 135 administered at a dose of 120 mg d for 4 weeks. Potential mechanisms for the hypothesized effect included reduced feedback inhibition in the olfactory bulb as a consequence of NMDA-antagonistic actions, or antagonism of an excitotoxic action of glutamate.

The Modulation of Longevity

Antioxidants have become particularly popular, especially in the U.S.A., and these include Vitamin E and Vitamin C, and also carotene. Their efficacy is related to the strong view, which in some quarters is a belief, that the major cause of ageing is the damage produced by oxygen free radicals. If this is so, then antioxidants should be effective in reducing this damage, a conclusion that has been widely accepted by the public at large. The facts are not always easy to obtain. Lifespan experiments have been done with experimental animals provided with a diet containing one or more antioxidants in comparison to untreated control animals. Early reports suggested that life-extension was achieved, but those have not been repeated. A recent experiment carried our in Alec Morley's laboratory in Adelaide, demonstrated absolutely no effect of vitamin E on the longevity of mice. It is a reasonable presumption that other experiments that gave negative results have never been published, and...

Electron paramagnetic resonance EPR

Only systems that contain non-paired electrons will give an EPR signal. Pairing gives zero net electron magnetic moment. Since a paired spin system is energetically favourable, chemical bonding normally results in molecules that have no unpaired electrons and, hence, no EPR signal occurs. Exceptions to this rule are transition-metal ions, free radicals and free electron centres such as those produced by high-energy irradiation of macromolecules. Free radicals produced in biological systems usually cannot be detected by EPR because of their short half-life times, resulting in low steady-state concentrations. Spin labels are stable free radicals. The unpaired electron belongs to the nitroxide group, which is flanked by quaternary carbon atoms of methyl groups, protecting the radical from recombination and accounting for the high stability of the label. The EPR spectra of nitroxide spin labels have a three-line nitrogen hyperfine structure and are environmentally sensitive. The variety...

Mitochondria Evolution and Clinical Significance

MtDNA is very exposed to damage from free radicals normally generated in mitochondria by aerobic respiration. Yet unlike nuclear DNA, mtDNA has no effective mechanism for repairing damage. Therefore, it mutates about ten times as rapidly as nuclear DNA. Some of these mutations are responsible for rare hereditary diseases. Tissues and organs with the highest energy demands are the most vulnerable to mitochondrial dysfunctions nervous tissue, the heart, the kidneys, and skeletal muscles, for example. Mitochondrial myopathy is a degenerative muscle disease in which the muscle displays ragged red fibers,

Combination Therapy For Stroke

Radical scavengers, cyclohexamide, caspase inhibitors, or growth factors such as fibroblast growth factor (bFGF).74 Synergy is also observed with two different antioxidants,75 and with citicoline plus basic bFGF.76 Caspase inhibitors delivered with bFGF or an NMDA receptor antagonist have been shown to potentially extend the therapeutic window for thrombolysis with lower effective doses.77

Mechanistic Events in Necrosis

Evidence is accumulating to support the notion that necrosis, like apoptosis, is a mechanistic cell-death process. For instance, necrosis can also be induced by death ligands such as TNF and Fas, redox signaling pathways involving ROS generation, stress-activated protein kinases such as JNK and p38, and release of mitochondrial factors 77, 100, 104, 105 . Anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-xL delay or protect against necrosis induced by a variety of insults in different cell lines 77 . Recent studies conducted in our laboratory indicate that the transcription co-activator and stress-regulated protein lens epithelium-derived growth factor p75 (LEDGF p75) protects cultured mammalian cells from necrosis induced by tert-butyl hydroperoxide (unpublished observations). This protection appears to be mediated by transcriptional upregula-tion of antioxidant proteins. Death receptor-induced necrotic cell death under caspase-inhibition conditions appears to be...

Parkinson Disease

In 1957, after demonstrating a reversal of the reserpine effects (depletion of central monoamines) in rabbits and mice, Carlsson reported that approximately 80 of all brain-derived dopamine was localized within the basal ganglia. Hornykiewicz and Birkmeyer and Barbeau independently reported therapeutic benefit from levodopa, and PD became the first disease treated by neurotransmitter replacement (Duvoisin 1992). In 1983 an effort led by Langston determined that a group of intravenous narcotic users developed a profound Parkinsonian syndrome after self-injecting (MPTP), a meperidine analog (Ballard et al. 1985). The discovery of this compound led to the creation of animal models, and served as the observation leading to the Deprenyl and Tocopherol Antioxidant Therapy for Parkinson Disease (DATATOP) clinical trial, the initial study of the Parkinson Study Group.

Protective Factors

During the past decade, biological and epidemiological evidence has been adduced that estrogens, NSAIDs, and antioxidants might protect against the onset of AD. These possibilities are of great importance since a drug that is effective in delaying onset of the disease would make a major contribution in


While wine has been reported to contain antioxidants and substances which have effects on thrombosis, the overall epidemiological evidence from studies in diverse populations suggests that all types of alcoholic drinks are associated with lower risk of coronary heart disease. Although wine drinkers showed a lower risk of CHD events as well as cardiovascular and all cause mortality than beer and spirit drinkers, they have lifestyle characteristics which are markedly advantageous and much if not all of the wine-drinker's advantage can be attributed to these characteristics.

Vitamin E

Oxidant stress is commonly invoked as a mechanism that ties together the accumulation of fat in the liver with the hepatocellular injury of NASH. Vitamin E is readily available and a biologically effective antioxidant. For these reasons, vitamin E is commonly used as a potentially beneficial therapy for NASH. Unfortunately, the data linking oxidant stress as a cause of the necroinflammation in humans has been scant, and data supporting the use of vitamin E has not been impressive. In children, vitamin E usually causes enzyme normalization and perhaps histological improvement (Lavine, 2000). In adults, an antioxidant approach to therapy has been more disappointing, either due to a true lack of effectiveness or failure of specific antioxidants to effectively block oxidant stress where it can cause damage. Nonetheless, vitamin E is commonly recommended to patients with NAFLD because in typically recommended doses (400 to 800 IU daily), little if any harm is thought to occur and the...


There have been many attempts to prevent development of pre-eclampsia, e.g. with dietary vitamins, antioxidants and minerals, with no clear benefit found. The large international CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) trial failed to show universal benefit from low-dose aspirin, suggesting instead that aspirin may be beneficial in selected high-risk women.


One reason for the decreased selenium levels in HIV infected patients may have to do with the virus itself. The virus uses selenoproteins to regulate its replication, which deplete the Se levels of the host. Supplementation trials with individual antioxidants have shown improvement in immunological parameters and decreased evidence of lipid peroxidation when selenium is added 46 , Recent investigations indicate that supplementation with Se may help to increase the enzymatic defense systems in HIV-infected patients 47,48 , These studies help support the assertion that increased Se levels help to decrease morbidity and prolong survival in HIV infected hosts.

Water Stress

In the above context, drought tolerance is really desiccation avoidance. Because the mechanisms required to scavenge and sequester water may differ from those that enable the organism to exist without it, tolerance of drought does not necessarily imply tolerance of desiccation. None the less, both desiccation- and drought-tolerant organisms accommodate life at low water potentials ( -1 MPa). Mild drops in water potential (from -1 to about -3 MPa) coincide with a series of metabolic changes that make cells more tolerant of the water stress (Ingram and Bartels, 1996 Bray, 1997 Oliver et al., 1998 see Chapter 11). The products of these metabolic changes (antioxidants, low-molecular-weight carbohydrates, late embryogenesis abundant

Dietary Factors

Compared to soy isoflavones, the mechanisms through which tea polyphenols act are less well understood. The best recognized properties of tea polyphenols are their activities as antioxidants.92 These effects are believed to be the basis for the ability of tea preparations to inhibit hydrogen peroxide formation in mouse epidermis and 4-(methylni-trosamino) -1- (3-pyridyl) - 1-butanone (NNK) -induced 8-hydroxyguanosine formation in the mouse lung.93,94 Inhibition of various enzymes known to be involved in tumor promotion includes protein kinase C, lipoxyge-nase, and cyclooxygenase, and ornithine decarboxylase has also been reported.95-97 It has also been found that (-)-epigallocatechin-3-gallate and other tea polyphenols can inhibit phorbol ester-induced activation of AP-1, a transcription factor known to be involved in numerous

Therapy for ALD

Major advances have been made in our understanding of mechanisms of alcohol-induced liver injury, and these concepts are being translated into clinical trials. Moreover, we are now in a position to better understand some of the mechanisms of actions of some traditionally used therapies for ALD, ranging from steroids to antioxidant therapy.

Yellow Nail Syndrome

Yellow nail syndrome is an uncommon disorder of unknown aetiology, characterized by the triad of yellow nails, lymphoedema and respiratory tract involvement. Vitamin E at dosages ranging from 600 to 1200 IU daily can induce a complete clearing of the nail changes. Although the mechanism of action of vitamin E in yellow nail syndrome is still unknown, antioxidant properties of alpha-tocopherol may account for its efficacy. A 5 solution of vitamin E in dimethyl sulphoxide produced marked clinical improvement in a double-blind controlled study. The efficacy of topical vitamin E, however, still needs confirmation. Oral itraconazole, 400 mg daily one week a month for several months, or oral flucouazole, may be beneficial in some cases.

Albumin Infusion

Albumin infusion enhances red cell perfusion and suppresses thrombosis and leukocyte adhesion within the brain microcirculation, particularly during the early reperfusion phase after experimental focal ischemia 187 . Albumin also significantly lowers the hematocrit and by so doing improves microcirculato-ry flow, viscosity of plasma and cell deformability, as well as oxygen transport capacity. Albumin reduces infarct size, improves neurological scores, and reduces cerebral edema in experimental animals 188 . These effects may reflect a combination of therapeutic properties including its antioxidant effects, anti-apoptotic effects on the endothelium, and effects on reducing blood stasis within the microcirculation. Clinical trials to test the effects of albumin are now being organized.


Lipid peroxidation is increased during haemodialysis, because ofROS generation 188-190 , Paradoxically, total antioxidant capacity increases in patients undergoing dialysis due to high serum urate levels, although this decreases after dialysis, as does serum ATC 189 , Increased ROS generation has also been reported to increase apoptosis in leukocytes 191 . Potentially, this offers the interesting possibility of using either treatment of dialysis membranes with ATC


The concentration of ergothionine in stallion semen is relatively high at 0.03-1.0 mg ml-1 (Leone, 1954 Mann etal., 1956 Mann, 1975). Ergothionine is largely secreted by the ampulla glands and is apparent in the sperm-rich portion of an ejaculate. Its function is as an antioxidant, preventing the oxidation of, and protecting the integrity of, other biochemical components within seminal plasma. Ergothionine acts in a reducing fashion similar to the action of cysteine or ascorbic acid (components not found in stallion seminal plasma but present in other mammals), protecting spermatozoa from the immobilizing action of oxidizing and peroxidizing agents (Mann, 1975). It has been reported that the secretions of the ampulla may contain concentrations of up to 1 mg ml-1, though concentrations of 0.2-0.6 mg ml-1 are more common. The concentration of ergothionine in a semen sample may, therefore, be used as an indicator of the percentage contribution of ampullary secretions. Season is known to...


In beta thalassaemia major (homozygous state) there is an absence, or a reduced production of beta chains, and therefore an increased production of alpha chains.The alpha chains precipitate in the red cell precursors, leading to ineffective erythropoiesis and shortened red cell survival.The haemolytic anaemia leads to tissue hypoxia and excess erythropoietin production, with marrow expansion and extramedullary erythropoiesis. Iron overload secondary to increased iron absorption and recurrent transfusion is another major clinical problem. When the capacity of ferritin is exceeded, plasma iron generates free radicals, and tissue damage occurs because of the inability of antioxidant systems to cope.Thalassaemia is a quantitative haemoglobinopathy, as opposed to sickle cell anaemia, in which the defect is qualitative.

Figure 1519

A-D, Similarities and differences between oxidant-induced and halocarbon-cysteine conjugate-induced renal proximal tubular lipid peroxidation and cell death. The model oxidant t-butylhy-droperoxide (TBHP) and the halocarbon-cysteine conjugate dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxidation after 1 hour of exposure and cell death (lactate dehydrogenase (LDH) release) over 6-hours' exposure. The iron chelator deferoxamine (DEF) and the antioxidant N,N'-diphenyl-1, 4-phenylenediamine (DPPD) completely blocked both the lipid


Ursodiol has been traditionally used for its very positive effects on the hepatobiliary system. It has multiple mechanisms of action, including (1) acting as a chemo-preventive agent, in animal models, (2) acting as an antioxidant, and (3) inhibiting cellular proliferation and being cytoprotective. Two studies have demonstrated the chemo-protective effect of ursodiol in UC PSC patients, a subgroup of UC patients that has a 50 risk of colonic neoplasia after 25 years of UC. A retrospective study demonstrated that patients with PSC UC had a significant reduction in dysplasia (odds ratio, 0.18 95 CI, 0.05 to 0.61 p .005) (Tung et al, 2001). A second prospective study also demonstrated a similar risk reduction of neo-plasia in UC PSC patients who were taking ursodiol (Pardi et al, 2003). Whether ursodiol can prevent dysplasia in UC patients who do not have PSC, or prevent progression of dysplasia that is already present in UC PSC patients, remains to be determined.

Practical aspects

The composition and pH of the buffer should be accurate to 0.001 mol 1_1 and 0.01 pH units. Most methods rely on the sequential application of a series of buffer solutions of increasing pH and molarity, with the initial pH around 3.2. Sodium citrate or, preferably, lithium citrate buffers are used, which incorporate a detergent (BRIJ 35), an antioxidant (thiodiglycol) and a preservative


Harvesting can be undertaken up to three times per year whereby 20-30 cm long sections from the tops of the shoots are removed before the flower buds open. It is at this stage of development that the plant leaves contain the greatest amount of volatile oil, giving the herb its pleasant aroma and slightly bitter peppery taste with a subtle undertone of anise (Bremners, 1997 Thieme and Nguyen-Thi-Tam, 1972a, b), although the comments by Olszewska-Kaczynska and Suchorska (1996a) should be noted wherein they state that high levels of methyl chavicol resulted in an un-acceptably strong flavour. A number of other compounds present in the oil make for caution in their use as crude drugs. Tosi et al. (1991) cite the significant levels of photoactive thiophenes which may be toxic. Equally important, tarragon oil with an estragole (methyl chavicol) content of -60 exhibited genotoxicity as evaluated in the Salmonella typhimurium bioassay (Bianchi-Santamaria et al., 1993). In contrast, Zani et...


In recent phase II clinical trials coenzyme Q (CoQ), a component of the mitochondrial respiratory chain, showed multiple beneficial effects on PD patients (Beal 2003). In C. elegans, animals defective in the clk-1 gene (which normally produces a mitochondrial polypeptide involved in the synthesis of CoQ) exhibit an exogenous CoQ-required increase in longevity (Larsen and Clarke 2002). CoQ is involved in mitochondrial respiratory transport and fatty acid oxidation and it functions as an antioxidant (Trumpower et al. 1981 Frerman et al. 1988 Ernster et al. 1995). Exogenous CoQ, while retaining its antioxidant activity, does not completely repair the mitochondrial functions of clk-1 animals (Felkai et al. 1999). Oxidative stress experiments comparing neurodegeneration in wild-type versus post-larval CoQ-replete animals and CoQ-deficient animals may potentially reveal mechanisms of actions for toxins. Furthermore, contribu


Since no therapy yet exists for CBD that affects the neurodegenerative process, management must be tailored toward symptoms. Pharmacotherapy directed toward parkinsonism has been disappointing (29). Levodopa, dopamine agonists, and baclofen tend to have little effect on rigidity, spasticity, bradykinesia, or tremor. However, levodopa should be titrated upward as tolerated to at least 750 mg per day in divided doses on an empty stomach to provide an adequate trial. Some patients have noted significant improvement in parkinsonism but this rarely persists beyond several months. In those who do improve dramatically with levodopa therapy, one must question whether CBD is the underlying disorder, as levodopa-refractory parkinsonism is considered by many to be a characteristic feature of the CBS and CBD. Anticholinergic agents rarely improve dystonia, and their use is limited by side effects. Botulinum toxin can alleviate pain owing to focal dystonia. Central pain has been rare, but some...


Golovina et al. (1998) speculated that amphiphiles may have antioxidant properties that protect membranes from damage by free radicals generated during desiccation and rehydration. If so, imbibitional leakage may be a necessary trade-off for protection. Much work will be required before the importance of native amphiphilic compounds in desiccation tolerance can be determined, but amphiphiles are an intriguing new development in our understanding of desiccation tolerance.

Aging Theories

Aging theories cover the genetic, biochemical, and physiological properties of a typical organism, and the way these properties change with time. Genetic theories deal with speculations regarding the identity of aging genes, accumulation of errors in the genetic machinery, programmed senescence, and telomeres. Biochemical theories are concerned with energy metabolism, generation of free radicals, the rate of living, and the health of mitochondria. Physiological theories deal almost entirely with the endocrine system and the role of hormones in regulating the rate of cellular senescence.

Figure 1424

Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydrogen peroxide are produced during normal cellular metabolism. ROS are constantly being produced by the normal cell during a number of physiologic reactions. Mitochondrial respiration is an important source of superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycin-induced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis. Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH or NADPH oxidase enzymes in the plasma membrane that are capable of generating superoxide. Xanthine oxidase, which converts hypoxathine to xanthine, has been implicated as an important source of ROS after ischemia-reperfu-sion injury. Cytochrome p450, which is bound to the...


The liver is the major organ for metabolism of many drugs. This explains its susceptibility to drug-induced injury. Drug elimination involves three phases. In phase I, drugs are metabolized by cytochrome P-450 enzymes. This process may generate toxic electrophilic chemicals or free radicals. In phase II, these metabolites or the parent drug are conjugated with glutathione or glucuronide to improve water solubility. This permits excretion of the agents from the body in bile or urine. The route of elimination is mainly determined by excretory transporters in the hepatocyte canalicular and sinusoidal membrane (phase III). Electrophilic chemicals and free radicals are potentially toxic because they can covalently bind to proteins, lipids, and deoxyribonucleic acid (DNA) cause lipid peroxidation and deplete glutathione. Consequently, these effects may lead to hepatotoxicity in several ways, including (1) by directly causing loss of vital cell function (eg, mitochondria) and subsequent cell...


Although the pathophysiology of SRES is not fully understood, gastric acid and pepsin appear to play a dominant role in the development of the gastroduodenal lesions characteristic of this entity. Both increased stress and head injury are associated with increased gastrin-mediated acid production (Beejay and Wolfe, 2000). As with other acid-related disorders, SRES appears to result from an imbalance between aggressive and defensive factors. Normal mechanisms of gastric mucosal integrity depend on an intact microcirculation, which ensures an adequate supply of nutrients to the mucosa and, in conjunction with the mucous layer, neutralizes hydrogen ions and other locally noxious agents. Mucosal ischemia appears to be the critical factor in the pathogenesis of SRES. Critical illness is commonly associated with hypovolemia, the release of proinflammatory cytokines, and increased cathecolamines production, which in turn lead to splanchnic hypoperfusion (Fisher et al, 1995). Reductions in...


In many species, the concentration of citrate in the semen (5 to 50 mM) greatly exceeds that of the blood (0.07 to 0.12 mM).21 In humans, the peripheral zone of the prostate is the primary source of seminal citrate, while in the rat, citrate is secreted by the lateral and ventral lobes of the prostate as well as by the seminal vesicles.21,55 Because of its key role in the tricarboxylic acid cycle (TCA) and in fatty-acid synthesis, citrate is conserved rather than secreted by most tissues. In contrast, the human prostate is able to concentrate citrate in the pro-static fluid to levels of 24 to 130 mM (making it the predominant anion), compared to plasma extracellular concentrations of 0.1 mM.21 Mitochondrial aconitate hydratase activity (citrate catalyzed to isocitrate) is inhibited by chelation with Zn++ 21,58 the excess citrate then replaces Cl- as the primary anion utilized by the luminal sodium transporter (Figure 14-3).21,59 Replenishment of four carbon submits for the TCA cycle...

Radiation Modalities

Radiation works primarily by damaging DNA through the creation of free radicals. Cells may be killed directly, or die during mitosis when severely damaged DNA is unable to replicate. A differential effect on tumor versus normal tissue is achieved due mainly to better DNA repair mechanisms in the normal tissue. Radiation is often fractionated (given in many small doses) to take advantage of these differences in repair and to overcome tumor hypoxia. Hypoxia is common in malignant tissues and causes relative radioresistance, but decreases quickly as cells are killed following each treatment. Although the organ of origin of the malignancy is important, the cell type of origin also plays a role in the management of the patient. Most tumors of the GI tract are adenocarcinomas (ACs), but there are many other malignancies, including squamous cell carcinomas, lymphomas, and GI stromal tumors. Different cell types have different responsiveness to radiation or chemotherapy. The standard unit of...

Vitamin Deficiencies

Naturally occurring tocopherols, which require micel-lar solubilization for absorption, is the most abundant source of vitamin E activity. Vitamin E inhibits the oxidation of unsaturated fatty acids, prevents lipid peroxidation and it is a scavenger of free radicals. Vitamin E deficiency manifests itself with a neurological syndrome characterized by peripheral neuropathy, cerebellar degeneration, and abnormal eye movements. Retinal degeneration has been ascribed to vitamins E and A deficiencies alone or combined. In children the complications of vitamin E deficiency are more severe than in adults with cholestasis. Recommendations to treat deficiency of vitamin E include 2 to 20 IU of a-tocopherol by mouth daily, 100 mg twice a day or 10 to 25 IU kg d.


Vitamin Eisa fat-soluble vitamin, and compared to other fat-soluble vitamins, appears to be the least toxic in high doses. There are 8 different homologues (i.e., vitamers) of vitamin E, comprising 4 tocopherols (namely, D-alpha, D-beta, D-gamma and D-delta) and 4 tocotrienols (also D-alpha, D-beta, D-gamma and D-delta) 76 , In broad terms, vitamin E is often used synonymously with alpha-tocopherol although strictly speaking it encompasses all 8 vitamers. The tocopherols and tocotrienols differ with respect to their side chain the former is saturated whereas the latter is unsaturated. If the biological activity of alpha-tocopherol is assigned an arbitrary value of 1.00, then the beta, gamma and delta-tocopherols have a biological activity of 0.49, 0.1 and 0.03 respectively 76 , 1 mg of pure synthetic DL-alpha-tocopherol acetate has a relative biological activity of 0.76, compared to 1.03 for both D-alpha-tocopherol acetate and D-alpha-tocopherol succinate 76 , One international unit...

Cell Death Pathways

Pathways of cell death triggered by aminoglycosides (Figure 9.2) are complex and range from apoptosis to necrosis of the sensory cells in the inner ear.50 51 Oxidative stress and a high load of ROS have many downstream consequences. ROS readily oxidize cellular components, including proteins, lipids, and DNA, by virtue of a highly reactive unpaired electron. If the oxidative imbalance is too great to be neutralized by cellular antioxidant systems, specific signaling pathways are invoked in order to maintain homeostasis or to prepare for cell death. The regulation of these pathways, in turn, requires the concerted efforts of cellular response elements to stress, second messenger systems, protein kinases, and transcription factors.


Lysosomes And Peroxisomes Function

Peroxisomes (fig. 3.28b) resemble lysosomes but contain different enzymes and are not produced by the Golgi complex. They occur in nearly all cells but are especially abundant in liver and kidney cells. Peroxisomes neutralize free radicals and detoxify alcohol and other drugs. They are named for the hydrogen peroxide (H2O2) they produce in the course of detoxifying alcohol and killing bacteria. They break down excess H2O2 with an enzyme


There is a growing interest in the actions of estrogens as neuroprotectants against neurodegenerative diseases and acute brain damage caused by stroke. Estrogens exert their neuroprotective effects predominantly through antioxidant effects of steroids and attenuation of NMDA-receptor activation 98,99 . In in vivo studies, the neuroprotective effects of estrogens have been demonstrated in all acute cerebral ischemia scenarios and it has been shown that estrogens could have a longer therapeutic window that extends up to 6 hours after ischemic insult 100,101 . Evidence from both in vitro and in vivo studies suggested that the neuroprotective


Penumbra Anatomy

Apoptosis occurs via caspase-dependent as well as caspase-independent mechanisms (Fig. 1.3). Caspas-es are protein-cleaving enzymes (zymogens) that belong to a family of cysteine aspartases constitutively expressed in both adult and especially newborn brain cells, particularly neurons. Since caspase-dependent cell death requires energy in the form of ATP, apopto-sis predominantly occurs in the ischemic penumbra (which sustains milder injury) rather than in the ischemic core, where ATP levels are rapidly depleted 31 . The mechanisms of cleavage and activation of caspases in human brain are believed to be similar to those documented in experimental models of stroke, trauma, and neurodegeneration 32 .Apopto-genic triggers 33 include oxygen free radicals 34 , Bcl2, death receptor ligation 35 , DNA damage, and possibly lysosomal protease activation 36 . Several mediators facilitate cross communication between


Reverse Cholesterol Transport

Figure 5.11 Schematic of beneficial effects of HDL. Several studies have shown that HDL improves endothelial function. HDL attenuates expression of adhesion molecules such as vascular intracellular adhesion molecule-1 (VCAM-1) and E-selectin, as well as inflammatory cytokines such as interleukin (IL)-8 that promote leukocyte extravasation into the vessel wall. Infusion of HDL has been shown to increase nitric oxide synthetase activity and therefore nitric oxide bioavailability, which promotes vasodilatation. Other studies have shown that HDL inhibits endothelial apoptosis by the inhibition of typical apoptosis pathways, such as the activation of caspases, and activates protein kinase Akt, a mediator of antiapoptotic signaling. A growing body of evidence suggests that HDL exerts part of its antiatherogenic effect by counteracting LDL oxidation. HDL inhibits the oxidation of LDL and the formation of lipid hydroperoxides. Inhibition of LDL oxidation by HDL is also attributed to the high...


Injury to the pancreas has important metabolic consequences, due to its central role in endocrinological and nutritional homeostasis. Susceptibility of pancreatic tissue to damage by ROS may be due to the relatively low activities of endogenous antioxidant enzymes such as glutathione peroxidase, and comparatively low cellular levels of ATC 93 , Certainly, pancreatic islet cells are profoundly sensitive to vitamin E deficiency, as reflected by reduced Mn-superoxide dismutase and increased CuZn-superoxide dismutase activities, coupled with reduced insulin secretory function 94 , Pancreatic atrophy due to dietary selenium deficiency can be reversed by high-dose vitamin E supplementation 93 ,