Free Radicals

Dietary Fiber And Antioxidants

Recently, considerable attention has been focused on the role of dietary antioxidants (particularly vitamin E, carotenoids and vitamin C) in counteracting the formation of lipid peroxides and oxidative modifications of LDLs, which play an important role in the progression of atherosclerosis. Dietary fiber binds bile acids and increases formation of micelles in the intestinal lumen. It may lead to decreased absorption of fat-soluble vitamins. In experiments on the influence of dietary fiber components on absorption of vitamin A and P-carotene in animals, conflicting results were obtained (43, 44). It should be mentioned, however, that diets rich in plant foods and high in fiber are also rich in antioxidants such as vitamin C, tocopherols and tocotrienols, carotenoids and other phenolic compounds such as tannins with high antioxidative properties. If dietary fibers were to suppress the absorption of dietary antioxidants, such action of fiber would be compensated by a simultaneous rise...

Reactivity Toward Radical And Antioxidant Activity Of Ubiquinol

The reactivity toward radicals, as determined by chemical structure, is apparently the important factor in determining the antioxidant activity of the compound. The reactivity of ubiquinol toward radicals has been measured by several groups. Mellors and Tappel1 observed that ubiquinol-6 was as reactive as a-tocopherol toward diphenyl-p-picrylhydrazyl, while Naumov and Khrapova4 reported that the rate constant for the reaction of ubiquinol with peroxyl radical was smaller than that of a-tocopherol. Mukai and colleagues5 have measured the rate constant for the reaction of ubiquinol-10 and radical. Tsuchiya et al.6 have measured the relative reactivities of ubiquinol-10 and a-tocopherol toward peroxyl radical in the phosphatidylcholine liposomal membranes and found that a-tocopherol was more reactive that ubiquinol-10 by a factor of 4.8. A higher reactivity of a-tocopherol than ubiquinol toward phenoxyl7 and peroxyl8 radicals has been also reported by Foti et al. and Barclary et al.,...

Antioxidant Action In The Membranes

There are other factors that have to be taken into consideration with respect to the antioxidant action in the membranes and lipoproteins in heterogeneous aqueous dispersions. Coenzyme Q is not only present in the inner mitochondrial membrane, but in lipoproteins, plasma membranes, and all intracellular membranes and it is present largely in the reduced state.10 The antioxidant potency of a lipophilic antioxidant against lipid peroxidation in the membranes and lipoproteins is dependent not only on the chemical factors mentioned above, but also on physical factors such as local concentration and mobility within and between the membranes and lipoproteins. It has been shown, for example, that the efficacy of scavenging radicals in the membrane by a-tocopherol decreases as the radical goes deeper into the interior of the membranes1112 and the apparent antioxidant activity decreases accordingly.1314 a-Tocopherol is incorporated into the membranes in such a way that the active phenolic...

Antioxidant Properties Of Coenzyme Q Analogs

Many experimental data strongly suggest that short chain quinones, in their reduced form, can function as antioxidants by inhibiting lipid peroxidation in model systems10-14 and in biological membranes1015-19 (Table 10.2). Lipid peroxidation proceeds by a classic chain reaction mechanism that includes the three discrete phases of initiation, propagation, and termination (Figure 10.1). Initiation occurs when an oxidant of sufficient chemical reactivity abstracts a hydrogen atom from a polyunsaturated fatty acid (LH) producing an alkyl radical (L ) which, in turn, yields a lipid peroxyl radical (LOOO by a diffusion-limited reaction with O2. Once formed, LOO propagates

Newer Antioxidant Approaches

The role of ROS generation and the resulting oxidative damage mechanisms in secondary CNS injury is arguably one of the more established aspects of secondary CNS injury, based on findings that a multitude of free radical scavengers and LP-inhibiting antioxidants can reduce postischemic and or posttraumatic damage in preclinical stroke, TBI, and SCI models (Figure 2). Following the discovery and attempted development of PEG-SOD and tirilazad, discussed above, considerable interest shifted to a variety of very potent nitrone-based 'spin-trapping' agents (Figure 3). The prototype of this antioxidant class was a-phenyl-N-tert-butylnitrone (PBN), which was protective in animal models of stroke and TBI. However, limitations to its solubility led to the incorporation of two sulfonyl groups to improve aqueous solubility, forming NXY-059, which was extensively tested in ischemic and hemorrhagic stroke models followed by entry into clinical trials in ischemic stroke patients. NXY-059 has at...

The antioxidant paradox

While the oxidation of LDL by several oxidative enzymes is believed to be a key component driving the retention of mmLDL, foam cell development, and the progression of plaque, the levels of extracellular antioxidants have been found to be quite high within atheroma and approach those of normal human plasma. LDL contains significant quantities of a-tocopherol (vitamin E), a phenolic antioxidant that helps protect LDL from one-electron radical oxidation processes, and does not appear to be depleted in isolated oxLDL. Thus, LDL lipid peroxides and apoB protein oxidation products form even in the presence of a-tocopherol. These and other data challenge the conventional

Interaction With Other Antioxidants

The radical-scavenging antioxidants function not only individually but also cooperatively and sometimes synergistically with other antioxidants. The most well-documented interaction is the one between vitamin C and vitamin E.25 Vitamin C present in the aqueous phase, efficiently reduces the vitamin E radical located within the membranes and lipoproteins to regenerate vitamin E and to inhibit, if any, the chain initiation induced by the vitamin E radical. It has been observed that ubiquinol spares a-tocopherol during lipid peroxidation in solution and liposomal membranes2635 and low density lipoprotein.36-38 The regeneration of a-tocopherol from a-tocopheroxyl radical by ubiquinol in mitochondrial membranes has also been reported.3940 a-Tocopheroxyl radical can be reduced by ubiquinol, ascorbate, a-tocopheryl hydroquinone, and dihydrolipoic acid.41 The relative importance of these reducing compounds in the regeneration of a-tocopherol depends on their concentrations and the active...

Antioxidants as Monotherapy in Coronary Heart Disease

The clinical success of antioxidant-based therapies has been extremely limited.22 Several studies have explored the potential contribution that supplementation with antioxidant-based natural vitamins, such as vitamin C or vitamin E, might play in reducing cardiovascular risk, with inconsistent results. In primary prevention studies, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) trial followed subjects on supplemental vitamin E or vitamin C for 3 years. Supplementation with vitamin C or vitamin E did not reduce the progression of atherosclerosis compared to placebo. Instead, vitamin E appeared to produce a small disease-promoting effect. A recent examination of the combined data from secondary prevention trials treating over 81 000 patients with vitamin E concluded that vitamin E therapy produced no significant reduction in coronary events. Similar results were observed using vitamin E in combination with other antioxidants where the combination of antioxidant...

Antioxidants in combination therapy with statins

Several clinical studies have examined antioxidants in combination with various statins. However, no significant beneficial effects in coronary event reduction were achieved by adding vitamin E to simvastatin, pravastatin, or atorvastatin. Notably, in the secondary prevention HDL Atherosclerosis Treatment (HATS) trial, treatments with antioxidants such as vitamin E, vitamin C, and beta-carotene were compared alone or in joint therapy with a combination of simvastatin 3 and niacin 17. In contrast to the lipid-lowering effects and reduction in coronary events observed with the simvastatin niacin combination alone, antioxidants by themselves demonstrated no significant benefit in disease progression and coronary outcomes. However, the beneficial effects of simvastatin niacin on lipid lowering and disease progression were essentially negated when this combination was administered together with antioxidants. Thus, supplementation with antioxidants produced a significant negative outcome...

Low Density Lipoprotein Cholesterol Lowering Agents Synthetic Antioxidants

The synthetic antioxidant probucol 11 was identified in the early 1960s as a modest lipid-lowering agent. Probucol lowers plasma LDLc in both animals and humans, but it also profoundly reduces HDLc. In clinical testing, probucol lowers LDLc by up to 20 but can lower HDLc by as much as 20-30 . The precise mechanism by which probucol lowers LDLc and HDLc is unknown however, probucol is known to prevent the oxidation of LDLc both in vitro and in vivo. Probucol has shown favorable benefits in reducing restenosis in patients, but its effects on atherosclerosis have been variable. Probucol undergoes extensive metabolism and oxidative degradation75 to produce a variety of potentially toxic metabolites, including the spiroquinone 32 and the fe-quinone 33 (Figure 13), that have been implicated in causing QTc prolongation and fatal arrhythmia.76 Probucol 11 was approved in the US in the early 1980s, but, because of these safety concerns, it was voluntarily withdrawn from the US market in 1995,...

New oral antiinflammatory antioxidants

AGI-1067 (succinobucol 44, Figure 15), a metabolically stable derivative of probucol, where the introduction of a monosuccinate ester group alters its overall in vitro and in vivo pharmacology, is a new oral antioxidant being tested in atherosclerosis. AGI-1067, like probucol, is a potent extracellular antioxidant but has an enhanced intracellular uptake capability compared to probucol. AGI-1067 inhibited intracellular ROS production whereas probucol had no effect and also inhibited proinflammatory gene expression in stimulated endothelial cells, including the expression of several proteins associated with atherosclerosis VCAM-1 and MCP-1.93 In LPS-challenged mice, oral dosing with AGI-1067 reduced VCAM-1 and MCP-1 mRNA levels. In LDLr 7 mice, AGI-1067 reduced aortic atherosclerosis by 49 in the absence of a lipid-lowering effect.94 Like probucol, oral dosing with AGI-1067 inhibited restenosis in phase II trials, but an important antiatherosclerotic effect was observed in the...

The Multiple Actions of Carvedilol Antioxidant Properties

A different potential explanation for the extraordinary cardioprotective effects of carvedilol in models of cardiac ischemia and infarction surfaced in the literature. At that time, Weglicki and colleagues suggested that the antioxidant properties of some antihypertensive drugs, including some beta blockers at extremely high doses, could provide cardioprotection by inhibiting the generation of toxic oxygen free radicals.15 Although the antioxidant actions of the beta blockers studied were far too weak to be therapeutically relevant, this work triggered a series of experiments in our laboratory by Yue, a biochemist with interests in 'redox' (oxidation-reduction) reactions and drugs that inhibit oxygen free radical formation. He investigated carvedilol in experimental systems of oxygen radical formation, primarily in cell membranes from the brain, and demonstrated that carvedilol was an extremely potent antioxidant. Most importantly, these antioxidant actions of carvedilol were of...

Carbon Tetrachloride May Alter The Hepatic Contents Of Antioxidants

Chronic CCl4 administration is known to induce cell necrosis by increased oxidative stress,46 and repeated injections of CCl4 initiate the fibrogenic process in the liver and may result in cirrhosis.47 Administration of vitamin E prevents CCl4-induced liver necrosis and cirrhosis, which supports the role of reactive oxygen species in liver damage associated with CCl4.48 CCl4 is metabolically activated by cytochrome P450 to form CCl3 free radicals, which initiate lipid peroxidation in the cell and decrease cellular ubiquinol-10.49 Kishi et al. demonstrated that administration of ubiquinone supplement attenuated CCl4-induced cell necrosis.49 In a study in which rats were exposed to diethylnitrosamine (DEN) as initiator, followed by repeated injections of carbon tetrachloride (CCl4)

Effects Of Exercise On CoQ And Antioxidant Potential Serum Antioxidant Potential Despite the lack of changes in the concentration of serum ubiquinol-10, the concentration of serum antioxidant potential increased by 22 (832 29 p,mol l vs. 1018 47 p,mol l) during the 31-km exhaustive run in the 8 endurance athletes, and by 16 (1165 39 p,mol l vs. 1355 36 p,mol l) during the marathon run in the 22 keep-fit runners.30 The increase in serum antioxidant potential during the exercises was explained at least in part by a simultaneous rise in the concentration of serum alpha-tocopherol. Serum alpha-tocopherol rose by 29 and 7 during the 31-km run and marathon, respectively.30 Also, both preexercise and postexercise concentrations of serum antioxidant potential and serum alpha-tocopherol correlated significantly in the keep-fit marathoners (r 0.47, 95 confidence intervals 0.064 to 0.75 and r 0.52, 95 confidence intervals 0.13 to 0.77, respectively).30 In another study, a simulated half-marathon run increased the serum antioxidant...

LDL Antioxidant Potential

Several years of intensive endurance training is associated with reduced circulating minimally oxidized LDL the veteran athletes had 37 lower LDL fraction diene conjugation than the matched controls.16 In that study, the veteran athletes also tended to have 17 higher LDL antioxidant potential than the controls (p 0.056, NS), however, no differences were seen in concentrations of serum ubiquinol-10.16 Other studies have also reported normal concentrations of LDL antioxidant potential in endurance athletes and keep-fit runners.30,33 Limited information is available concerning the concentration of LDL ubiquinol-10 in athletes, although coenzyme Q is considered to be the most potent antioxidant of LDL cholesterol.38,39 A 10-month exercise training program for sedentary subjects increased the ratio of LDL antiox-idant potential to LDL cholesterol by 16 in men and by 11 in women.17 The decreased ratio was caused by reduced concentration of LDL cholesterol. The concentration of LDL...

Use Of CoQ To Enhance Antioxidant Potential In Athletes

25.3.1 Serum Antioxidant Potential There is limited information available concerning supplementation of coenzyme Q in order to enhance antioxidant potential in athletes. In general, supplementation of coenzyme Q is shown to increase ubiquinol ubiquinone content in muscles, but the results on athletes do not confirm this.34,44-46 Also, absence of increase of coenzyme Q after supplementation is seen even in concentration of serum ubiquinol-10 in athletes.33 The expected increase in serum ubiquinol concentration after coenzyme Q supplementation is known to depend not only on the level of serum baseline ubiquinol concentration and amount and duration of supplementation used, but also on the vehicle in which the coenzyme Q is administered. Obviously, the best way to administer the coenzyme Q is to use plant oil capsules. In one antioxidant cosupplementation study, endurance athletes consumed in a randomized single-blind order, either a combination of antioxidant supplements (antioxidant...

Antioxidant Vitamins Generally Vitamins A C and E

Among all categories of dietary supplements, antioxidant vitamins were among those used most frequently by a large group of people with MS who were surveyed through a study at the Rocky Mountain Multiple Sclerosis Center (the full results of this survey may be seen at Antioxidant vitamins include These vitamins act on free radicals, chemicals that can damage cells in the brain and other organs of the body. For years, it has been proposed that free radicals may play an important role in aging, aging-related diseases, and many other conditions, including MS. Antioxidants have various actions on the immune system and nervous system some of these effects could be beneficial for people with MS. Specifically, free radicals may play an important role in MS using antioxi-dants to decrease the harmful effects of free radicals may be beneficial. In MS, one type of immune cell, the macrophage, injures the myelin coating on nerve cells by releasing free radicals....

Food additives the antioxidants butylated hydroxyanisole and butylated hydroxytoluene

To preserve quality and to prevent loss of nutritional value, the addition of antioxidants to food containing fatty acids has a long tradition. Two well-known antioxidant food additives are butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) (see Figure 18.2).

Iron Overload Depletes Hepatic Antioxidants

Iron has been used as a model substance in the studies of oxidative liver damage, since iron is known to increase the production of free radicals and enhance oxidative stress.24,25 In humans, the most common diseases with iron overload are genetic hemochromatosis and transfusional iron overload. Genetic hemochromatosis is an inherited disorder of iron metabolism in which excess iron is absorbed via the gut and deposited in parenchymal organs, predominantly the liver.26,27 With time, deposition of intracellular iron in hepatocytes results in lipid peroxidation of cellular membranes, impairment of mitochondrial functions, leakage of lysosomal enzymes, and finally iron-induced necrosis (called sideronecrosis).26 Once sideronecrosis has occurred, Kupffer cells and lipocytes will become activated and collagen synthesis increased,28 eventually leading to fibrosis, cirrhosis, and an increased risk for the development of hepatocellular carcinoma.29-31


Several studies have proposed various antioxidants as anti-AGE agents, including vitamin E (167), N-acetylcysteine (168), taurine (169), a-lipoic acid (170), penicillamine (171), and nicarnitine (172). Also, pyruvate is a potent scavenger of ROS such as H2O2 and O2- that also minimizes the production of OH by the Haber-Weiss reaction. Additionally, it inhibits the initial reaction of glucose with free amino groups that results in Schiff base formation, as documented by in vitro data (173,174). Despite the existing data, however, further studies are needed to establish the effectiveness of treatment with antioxidants as a strategy in reducing AGE levels.

Carbazol antioxidant

Over the next decade, compelling data were generated in a variety of in vitro and in vivo experimental systems that highlighted novel and unusually effective cardioprotective properties of the drug that resulted in part from the beneficial hemodynamic effects emanating from beta blockade and alpha blockade, and in part from the unique antioxidant, antiapoptotic, and antiproliferative properties of the molecule. Based on these extensive studies, the highest levels of corporate and R&D management at SmithKline Beecham took the brave, risky, controversial, and highly innovative decision to support long-term clinical trials of carvedilol in patients with congestive heart failure, for whom such drugs remained contraindicated. The importance of this decision cannot be overstated given the dogma prevalent at the time that such a drug might actually harm patients, as well as the resulting concerns related to liability and the view that the commercial value to the corporation after taking such...

Stroke and nervous system trauma

The incidence of stroke in the USA approaches 700000 per year, the majority occurring in the elderly. Of these, 90 are 'ischemic' involving a thromboembolic blockage of a brain artery impairing cerebral blood flow and oxygenation, causing infarction of the brain region. The remaining 10 of strokes are 'hemorrhagic' involving intracerebral hemorrhage where blood is released into the brain parenchyma producing brain damage by triggering brain edema leading to secondary ischemia and subarachnoid hemorrhage where the blood is released into the subarachnoid space. There are about 30 000 aneurysmal subarachnoid hemorrhages and 1.5 million cases of TBI each year in the USA, and 11 000 new cases of SCI each year with an overall prevalence of 250000. Most cases of TBI and SCI occur in the second and third decades of life. Given the incidence, limited treatment options, and disabilities resulting from stroke, TCI, and SCI, there has been considerable effort over the past 20 years to identify...

Dietary Guidance For Complex Carbohydrates

There is growing acceptance that isolated carbohydrates provide different physiological responses than whole foods. Thus, it is difficult to study complex carbohydrates since they must be fed in their refined state. It is then difficult if not impossible to generalize the results to the unrefined complex carbohydrates fed in their native state. This is compounded further by the fact that many other nutritional ingredients cloud the physiological results of the experiment. If an exciting physiological response is seen with intake of a whole grain high in complex carbohydrate the question arises as to the true origin of the response is it due to the carbohydrate, a specific component of the carbohydrate or an associated substance such as an antioxidant, phytoestrogen, trace mineral, and so on.

Discharge And Home Healthcare Guidelines

ARDS is defined as noncardiogenic pulmonary edema that occurs despite low to normal pressures in the pulmonary capillaries. Many theories and hypotheses are currently under investigation. Patients with ARDS are characterized as having high-permeability pulmonary edema (HPPE) in contrast to cardiogenic pulmonary edema. In ARDS, the alveolar-capillary membrane is damaged, and both fluid and protein leak into the interstitial space and alveoli. Recent research has focused on possible mediators of the membrane damage, such as neutrophils, tumor necrosis factor (TNF), bacterial toxins, and oxygen free radicals, among others. The onset of symptoms generally occurs within 24 to 72 hours of the original injury or illness.

Inflammatory Response in Cardiac Surgery

We will briefly review briefly the inflammatory response evoked by cardiac surgery. (Fig. 1.1A.) The interaction of blood with the cardiopulmonary circuit activates complement following commencement of cardiopulmonary bypass, leading to the formation of anaphylatoxins C3a and C5a mainly via the alternative pathway. P-selectin is expressed on endothelial surface as a result of endothelial cell exposure to C5a.21 Endothelial cells, activated by C5a, adhere to neutrophils. Adherent neutrophils release cytotoxic proteases, and oxygen-derived free radicals that are responsible for tissue damage, resulting in capillary leak. Proinflammatory cytokines are released in response to cardiopulmonary bypass and tissue hypoxia. Levels of interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor rapidly increase following commencement of cardiopulmonary bypass. Cytokines are mainly deployed in the venous microcirculation and act as stimulants for neoangiogenesis. Another form of...

Alteration in Oxidative Stress

Increases of oxidative stress by metabolic derangement has long been reported in diabetic states and proposed to cause vascular complications (44,59,63,64). In diabetic states, induction of oxidative stress could be as a result of the increased production of superoxide anion via the induction of NADPH oxidase and mitochondrial pathway decreases of superoxide clearance lipid and protein modification and the reduction of endogenous antioxidants such as ascorbic acid, vitamin E, and glutathione. that400 IU per day of vitamin E failed to show difference in cardiovascular outcomes and diabetic nephropathy (76). However, we have reported that oral vitamin E treatment at a dose as high as 1800 IU per day appears to be effective in normalizing retinal hemodynamic abnormalities and improving renal function in type 1 diabetic patients of short disease duration without inducing a significant changes in glycemic control (77). At this dose, vitamin E is capable of inhibiting PKC activity (74)....

Conjugations with Glutathione 506371 Glutathione and glutathione transferases

Glutathione reacts in a variety of ways, one of which is its redox capacity. Indeed, GSH can reduce peroxides (a reaction catalyzed by glutathione peroxidase) and organic nitrates in its GSSG form, glutathione can oxidize the superoxide anion radical. Of major significance in detoxification reactions is the capacity of GSH (and other endogenous thiols including albumin) to scavenge free radicals, in particular radical oxygen species (e.g., R , HO , HOO , ROO ). As such, glutathione and other thiols have a critical role to play in cellular protection.116 The reactions involved are highly complex and can be simplified as follows

Vascular Contractility and Blood Flow

Hemodynamic abnormalities such as blood flow and vascular contractility have been reported in many organs of diabetic animals or patients, including the kidney, retina, peripheral arteries, and microvessels of peripheral nerves. In the retina of diabetic patients and animals with a short duration and without clinical retinopathy, blood flow has been shown to be decreased (119-123). One possible explanation for the decreased retinal blood flow in early stage of diabetes is as a result of an increase in vascular resistance at the microcirculatory level induced by PKC activation. We have reported that the decreased retinal blood flow can be mimicked by intravitreous injection of phorbol esters, which are PKC activators (78). Furthermore, decreases in retinal blood flow in diabetic rats have been reported to be normalized by PKC inhibitors (90). In addition to the retina, decreases in blood flow have also been reported in the peripheral nerves of diabetic animals by most investigators...

Coenzyme q and the plasma membrane redox system

Several studies have shown the presence of significant amounts of CoQ at the plasma membrane of eukaryotic cells such as hepatocytes3,14 and Saccharomyces cerevisiae,4 which indicates an important role in the biochemistry and physiology of the plasma membrane. Several possibilities have been proposed to explain this presence a storage for transfer to other compartments or blood serum,3 a role as an antioxidant within the lipid bilayer,8 and finally, acting at the plasma membrane as an intermediate electron carrier across the membrane as it does in mitochondria.51

In Vitro Toxicological Models And Methods Commonly Used In Drug Discovery

It is well known that many toxic agents can be metabolized to reactive metabolites that can in turn react with glutathione, enzymes, nucleic acids, lipids, or proteins 30,31 . These reactive intermediates are electrophilic metabolites or free radicals that are generated during the metabolism of a broad range of chemical structures. Reactive metabolite formation is considered necessary but not sufficient in immune-mediated idiosyncratic drug reactions 32 . There are several rapid in vitro methods to detect and measure the generation of such reactive intermediates. For example, high-throughput assays for identifying pharmaceutical compounds that produce reactive metabolites have been developed. These methods involve incubating drug candidates with a liver microsomal drug metabolizing enzyme system in the presence of glutathione and detecting glutathione conjugates via mass spectrometry 33-36 . In a recent review biotransformation-related causes of toxicity were identified to account for...

Role Of Plasma Membrane CoQ In The Control Of Cell Growth Differentiation And Apoptosis

Cell population is based on the equilibrium among proliferation, differentiation, and cell death. Although antioxidants including CoQ can stimulate cell proliferation in serum-limiting conditions83,84 (see above), a likely function of antioxidant CoQ in extramitochondrial membranes is the prevention of apoptotic program development, resulting in the maintenance of cell population.17 Mild oxidative stress has been related to the development of cell death by apoptosis,88 and Bcl-2, which is one of the main antiapoptotic proteins, acts through an antioxidative pathway suppressing lipid peroxidation developed after the apoptotic signal.81 Serum or growth factor withdrawal is a way to initiate apoptosis that courses through an increase of peroxidation levels in membranes.89,90 Consistent with their ability to reduce levels of lipid peroxidation, addition of antioxidants, including CoQ, to cultures in the absence of serum results in enhanced protection against cell death.17,19,20,80...

Conclusions and perspectives

Central molecule in the extramitochondrial antioxidant machinery. A delicate balance between proox-idant and antioxidant activity of CoQ is maintained by the equilibrium between one- and two-electron quinone reductases, and its relationship with other hydrophilic and lipophilic antioxidants.

Changes in raw materials during storage and processing and in food during manufacture preparation and storage

Ascorbic acid has an enediol structure, in which the double bond is conjugated with a carbonyl group. Due to this structure, it has both acidic and (strong) reducing properties. The natural form is the L-isomer. The D-isomer has about 10 of the activity of the L-isomer. The latter is used as food antioxidant.

Gathering Food from the Wild

In recent years it has become obvious that food and medicine are closely linked a food plant may be used for medicine, and vice versa. Moreover, eating food from the wild is not simply an essential response in times of famine or food shortages, or an easy way to obtain primary nutrients, but more often a complex evolutionary process, involving different aspects of the relationship between humans and their natural environment. Non-cultivated gathered food plants are often weedy and grow in environments disturbed and managed by man. In addition, eating these plants provides many micronutrients and phytochemicals that are now known to play a central role as antioxidants in the prevention of various illnesses, especially age-related diseases.

Comparison Of Direct Radical Scavenging Effects Of Vitamin E And Coenzyme Q

Thus, both vitamin E and reduced coenzyme Q act as direct chain-breaking antioxidants by donating an H-atom to reduce peroxy- and or alkoxy-radicals However, the chemical reactivity of ubiquinols with peroxyl radicals in organic solvents is slightly lower (k 3.4 X 105 M-1s-1) than the reactivity of tocopherols (k 33.0 X 105 M-1s-1) ( 10, 11, 12 , see also chapter 3 in this volume). Since concentrations of free ubiquinols in membranes are roughly equal to or lower than those of vitamin E38,39 and their concentration in LDL is roughly 10-20 that of vitamin E,40 it is likely that vitamin E is more efficient as a chain-breaking antioxidant. Indeed, effectiveness of direct peroxyl radical scavenging or antioxidant activity of long-chain ubiquinols (e.g., CoQ10 and CoQ9) in membranes in vitro is lower than that of vitamin E.31 This again raises the question as to whether direct radical scavenging is in fact an important function for CoQ in antioxidant protection.

Coenzyme Q Facilitates Vitamin E Recycling

Another possibility for the antioxidant function of coenzyme Q is its interplay with vitamin E resulting in electron transport-driven recycling of vitamin E. The one-electron redox potential for ubiquinol ubisemiquinone E70 (QH2 Q0 -0.24V is more negative than that for tocopherol tocopherol phenoxyl radical E70 (T-OH T-OO 0.48V 41 suggesting that ubiquinol may reduce the vitamin E phenoxyl radical (formed when vitamin E quenches a peroxyl radical), thus regenerating vitamin E radical.313742 In rat liver microsomal membranes, NADPH-dependent electron transport caused transient disappearance of vitamin E phenoxyl radical ESR signals (produced by lipoxygenase lino-lenic acid or UV-light) due to reduction of the radical by electron transport.31 Most importantly, this effect was dramatically enhanced when exogenous CoQ homologues were added to the incubation system to facilitate reduction of the vitamin E phenoxyl radicals. Similarly, succinate-driven reduction of vitamin E radicals in...

Molecular Actions Of Vitamin E During Lipoprotein Lipid Peroxidation

Is primarily dependent on their content of bisallylic hydrogen atoms. Cholesteryl esters contain threefold more bisallylic hydrogens than phospholipids and as such are the major lipid substrates for peroxidation in LDL (Table 9.1). LDL lipid peroxidation is generally held to proceed, and to a certain extent cause, the oxidation of apo B33 and oxidized lipid possess various proatherogenic activities.8,34 Therefore, understanding the molecular events involved in LDL lipid peroxidation and how antioxidants prevent this process may provide important information in designing antioxidant strategies to attenuate oxidative modification of lipoproteins in vivo and perhaps atherosclerosis. Importantly, however, certain oxidants (e.g., HOCl35 and peroxynitrite31) directly oxidize apo B independent of lipid peroxidation. Therefore, different antioxidant strategies may be required to adequately protect both lipoprotein lipid and protein moieties from oxidative modification in vivo. Studies in...

Raloxifene and Lipids

Estrogen increases HDL cholesterol levels and decreases LDL cholesterol levels in humans39,171 as well in animal models of atherosclerosis, partly because of estrogen receptor-mediated upregulation of the hepatic LDL receptor.172 In ovariectomized rats, raloxifene treatment has been shown to reduce serum total cholesterol concentrations,97,173 and this reduction correlates with the extent of raloxifene binding to the estrogen receptor.97,173 These results are not surprising for a 'nonsteroidal antiestrogen,' as the original observations for clomiphene analogs and tamoxifen show (see 8.08 Tamoxifen). Raloxifene may also have cardioprotective effects because of its antioxidant properties. This is important since oxidative modifications of LDL have been implicated in atherogenesisis.174 Raloxifene also appears to have a favorable effect on lipid parameters in postmenopausal women. In the published European trial,78 treatment with raloxifene in a dosage of 30, 60, or 150 mg day_ 1...

New Research Areas

Antiapoptotic agents (e.g., caspase inhibitors), anti-inflammatory agents (e.g., minocycline 87), bioenergetic enhancers antioxidants (e.g., creatine, coenzyme Q, lipoic acid, dicholoroacetate, cystamine), excitotoxic anatgonists (e.g., riluzole 88, remacemide 89), histone deacetylase inhibitors (sodium butyrate and suberoylanilide hydroxamic acid), and transcriptional inhibitors (e.g., mithramycin 90) have all been examined in the R6 2 mouse model of HD and have shown some benefit.84 Some of these agents have been advanced to clinical trials (Table 2). Aggregation inhibitors are also a target.85

Unmet Medical Needs

Since the approval of riluzole, at least 10 therapeutic approaches which showed promise in preclinical models have been tested in the clinic but have failed or shown equivocal results (such as for insulin-like growth factor-1). These include neurotrophic factor replacement strategies (ciliary neurotrophic factor, BDNF glial-derived neurotrophic factor, and insulin-like growth factor-1), glutamate NMDA receptor antagonists (topiramate, dextromethorphan) or putative glutamate modulators (gabapentin, lamotrogine, N-acetylcysteine), antioxidants (vitamin E), MAO glyceraldehyde phosphate dehydrogenase inhibitors (selegeline), and mitochondrial transition pore blockers (creatine).86'87'95 Insulinlike growth factor-1 has shown improvement in quality of life and benefit in ALS patients.97

Comparison With Other Surface Modalities

With the proliferation of a- and b-hydoxy acids, various retinoids, numerous antioxidants, microdermabrasion, and numerous peels, it would be the height of arrogance to describe my particular regimen. Every practitioner in the field will find his or her favorites. I would, however, propose a simple Resurfacing Ladder which may help place these methods in a useful context for both practitioners and patients.

Superoxide dismutase mimetics

Increased oxidative burden contributes to the pathophysiology of ALS with advanced glycation end-products, markers of lipid peroxidation (4-hydroxy-2-nonenal-histidine, crotonaldehyde-lysine), and markers of protein glycooxidation localized to motor neurons of ALS patients. A number of free radicals, including superoxide and nitric oxide, likely cause damage to motor neurons via the formation of peroxynitrite and subsequent nitration of tyrosine residues on proteins (e.g., neurofilaments), which are central to neuronal function. Spinal cord tissue from ALS patients has increased levels of 3-nitrotyrosine and 3-nitro-4-hydroxyphenylacetic acid, both products formed through the action of peroxynitrite. EUK-8 94 and EUK-134 95 demonstrated a benefit in the ALS mouse model. Given prophylactically, they delayed disease onset.107 AEOL-10150 96 is a manganese porphryrin catalytic antioxidant that decomposes biological oxidants such as peroxinitrite via its ability to cycle between Mn(III)...

Chemistry And Biochemistry Of Coenzyme Q Analogs

Mammalian membranes contain coenzyme Qn (CoQn) homologues with long isoprenoid chains (Q10 for humans and Q9 and Q10 for rodents), which are the major nonprotein components of the bioen-ergetic system of mitochondria.1 Aging and several degenerative diseases are associated with a decline in the normal levels of CoQ10, hence, CoQn supplementation has been introduced as a potential therapy to ameliorate energy deficiencies associated with these pathophysiological states.1-4 Nonetheless, the beneficial effects of CoQn supplementation cannot be altogether separated from its well-known antioxidant potential (see section 10.2).

Pathophysiology of Photosensitivity in Lupus Erythematosus

Bennion and Norris (Bennion and Norris 1997) have also discussed in depth the role of UV irradiation in the induction of cytokine mediator release and adhesion molecules in the epidermis and dermal vessels. Recent studies have demonstrated that adhesion molecules are not only induced secondary to cytokines (TNF-a, IL-1) but also directly through transcriptional activation. This activation occurs by formation of transcriptional factors such as activator protein-2 in a single oxygen-dependent mechanism (Grether-Beck et al. 1996). Growing evidence suggests the link between UVA sensitivity and free oxygen radical formation (Krutmann 2000). Chemicals with the ability to scavenge free radicals may, therefore, be of special potential

Pharmacological Properties And Therapeutic Potential Of Coenzyme Q Analogs

Coenzyme Q10, due to its bioenergetic capacity and or antioxidant activity, has been widely used in the prophylaxis and therapy of a wide variety of pathological states,1-3 38 although it has remained uncertain whether its deficiency is the cause or the effect of the disease state itself. On the contrary, Idebenone is currently administered to ameliorate cognitive status in patients with clinical history of stroke, Alzheimer's disease, and multiinfarct dementia.39-41 Idebenone has been reported to improve cerebral energy metabolism,39,42 to decrease excitotoxic neuronal degeneration,43 and to stimulate nerve growth factor synthesis.39,44 Idebenone also appears to minimize platelet formation of thromboxane45 as well as the toxicity of oxidized low density lipoprotein to endothelial cells.46 In so doing, idebenone inhibits platelet aggregation and contributes to the maintenance of vascular wall integrity and functions. The mechanism by which IDB exerts its pharmacological effects...

Background Information

Polyacrylamide gels form after polymerization of monomeric acrylamide into polymeric polyacrylamide chains and cross-linking of the chains by N,N'-methylenebisacrylamide. The polymerization reaction is initiated by the addition of ammonium persulfate, and the reaction is accelerated by TEMED, which catalyzes the formation of free radicals from ammonium persulfate. Because oxygen inhibits the polymerization process, deaerating the gel solution before the polymerization catalysts are added will speed up polymerization deaeration is not recommended for the gradient gel protocols because slower polymerization facilitates casting of gradient gels.

Lessons Learnt from Past Clinical Trials of Neuroprotective Agents

Firstly, the discovery of the first generation of neuroprotective agents, which included glutamate receptor antagonists, calcium channel blockers, and antioxidants, occurred prior to the elucidation of an adequate understanding of the intricacies of the targeted secondary injury mechanisms. In each case, knowledge of the time course and interrelationships of these events and their therapeutic windows for effective treatment intervention was lacking. In the case of reactive oxygen mechanisms, knowledge of the key ROS species and their sources and cellular targets was inadequate to guide the design of optimum antioxidant neuroprotective new compound entities. Secondly, the preclinical efficacy testing of new compound entities was, in some cases, woefully inadequate, and even naive. In contrast, it is now realized that several issues need to be addressed in preclinical evaluations in order to guide the design of clinical trials. These include

Prevention of Mitochondrial Dysfunction

Evidence has begun to accumulate that the particular ROS formed by mitochondria is peroxynitrite. NO is present in mitochondria, and a mitochondrial NOS isoform (mtNOS) has been isolated, Although probably playing a key physiological role in mitochondria, dysregulation of mitochondrial NO generation and the aberrant production of the toxic metabolite peroxynitrite appear to play a role in many, if not all, the major acute and chronic neurodegenerative conditions.66 Exposure of mitochondria to Ca2 +, which renders them dysfunctional, results in peroxynitrite generation, which in turn triggers mitochondrial Ca2 + release (i.e., limits their Ca2 + uptake or buffering capacity).67 Both peroxynitrite forms, ONOO- and ONOOCO2, deplete mitochondrial antioxidant stores and cause protein nitration. The relatively long half-life of peroxynitrite in comparison to other short-lived ROS also allows for mtNOS-derived peroxynitrite to diffuse between cells.

Electroblotting Of Proteins For Sequence Analysis

For preparing gels choose an acrylamide concentration such that the protein will migrate as a sharp, tight band with an Rf between 0.2 and 0.8. Casting a gel in advance allows complete polymerization, reduces the amount of oxidants and free radicals, and minimizes the possibility of blocking the N terminus or other amino groups of the protein. Thioglycolate scavenges remaining free radicals and oxidants in the gel.

Overview Of Coenzyme Q Biosynthesis

Coenzyme Q (ubiquinone or Q) is a prenylated benzoquinone lipid that functions in the electron transport chains of mitochondria in eukaryotes and plasma membranes in prokaryotes. Coenzyme Q is redox active and plays an important role as a lipid soluble antioxidant. In general, cells rely on de novo synthesis for their supply of Q,12 and much progress has been made in the characterization of Q biosynthesis. It was work with Rhodospirillum rubrum, that allowed Karl Folkers and colleagues to identify the key Q-biosynthetic intermediates.3 Elegant studies by Gibson and colleagues with Q-deficient mutant strains of Escherichia coli (containing mutations in the ubiA -ubiH genes)4 enabled the steps of E. coli Q biosynthesis to be identified and ordered as shown in Figure 12.1. Biosynthesis begins with formation of a polyisoprenoid tail that contains a variable number of isoprene units (designated as n) depending on the species, and 4-hydroxybenzoic acid. After their covalent linkage to form...

Reversedphase Peptide Separation At The 5 To 500pmol Level

Mobile-phase solvent A 0.1 (v v) trifluoroacetic acid (TFA Pierce) in Milli-Q water (TFA sold for protein sequencing may not be suitable because some manufacturers add antioxidants that can generate artifacts) Mobile-phase solvent B 0.07 to 0.1 (v v) TFA (Pierce) in acetonitrile or 1- or

Science Medicine and Leadership Win Out The Pendulum Swings in Carvedilols Favor

In addition, the other properties of carvedilol, namely its antioxidant actions, could also provide added benefit inasmuch as oxygen radicals were known to be potent activators of signaling pathways that have a short- and long-term negative impact on cardiac cell growth and survival. In particular, the emergence of apoptosis as a primary mechanism of cardiac cell death43 and remodeling in heart failure mediated in part by intracellular redox imbalance potentially expanded as we had successfully demonstrated in animal studies the potential benefits that this drug might have in heart failure beyond its adrenergic pharmacology. Thus, carvedilol could inhibit apoptotic cell death through modulation of expression of the Fas receptor, which is a cell surface receptor that activates a cell-death-signaling pathway.44-47 Additionally, carvedilol was also shown to possess antiproliferative actions on vascular smooth muscle cells and anti-inflammatory actions through its ability to inhibit...

Freeradical Polymerization

Free-radical polymerization begins with the formation of a free radical (a process called activation) and the subsequent combination of this free radical with a monomer. Free radicals are formed by the decomposition of a chemical (the initiator). The method of decomposition depends on the nature of the initiator. Possible initiators include benzoyl peroxide and Camphoroquinone. Benzoyl peroxide decomposes to free radicals at approximately 50 C or higher in a process called thermal activation. Excessive temperatures should be avoided during the early stages of thermal activation, because some monomers vaporize at temperatures near 100 C, with subsequent formation of porosity in the resultant polymer. Thermal activation results in greater contraction on cooling than with other activation methods and is therefore usually avoided for provisional restorations. Camphoroquinone decomposes to free radicals in the presence of both an aliphatic amine and blue light energy this...

Age Related Macular Degeneration

The main unmet medical need is that there is currently no accepted medical therapy to treat dry AMD. Based on epidemiological studies many cases of dry AMD could be prevented by reducing cigarette smoking for example, almost 30 000 cases of AMD in the UK could be attributed to smoking.23 The role of oxidative stress in disease pathology suggests the advisability of antioxidant, carotenoid, and vitamin supplementation. One difficulty with dry AMD is that, as a largely asymptomatic and slow-developing disease, it is frequently the case that significant morphological damage (RPE cell and photoreceptor death) has occurred before the patient experiences visual deficit and thus is aware of the disease. On the positive side, a therapy that even just significantly slowed AMD progression in an elderly population might be sufficient to mostly preserve visual acuity for the rest of a patient's life.

Strategies to improve cell productivity

Rosmarinic acid and related phenolics are natural antioxidants found as secondary metabolites in spearmint (Mentha spicata) and other plant species. These phenolic secondary metabolites have diverse food-processing and nutraceutical applications. Since natural cross-pollination results in plant-to-plant variation in the level of phenolic metabolites, tissue-culture-based techniques are essential to isolate elite antioxidant-producing clonal lines. Tissue-culture-based selection techniques to isolate high ros-marinic acid and phenolic-producing clonal lines from a heterogeneous bulk seed population of spearmint have been developed by Al-Amier and colleagues (1999).

Micronutrients 1231 Vitamins

Excessive vitamin intake can lead to a variety of toxic effects. In a number of cases, vitamin-induced toxicity is well-known. In other cases, vitamins are only slightly toxic or rather harmless. Although the vitamin content of the diet usually does not lead to toxic effects, it will be of increasing importance to take care of the standards set for vitamin intake in view of the recent trend of vitamin supplementation and fortification. In addition, vitamins are more and more used in processed food as naturally occurring antioxidants instead of synthetic antioxidants. Daily intakes of the antioxidant vitamin C (L-ascorbic acid) up to 1 g did not lead to toxic effects. The harmless use of vitamin C is also shown by Figure 12.2. There is a relatively wide margin between the RDA and the toxic dose. If high doses were taken over a long period of time, however, vitamin C appeared to induce toxic effects. Well-known adverse effects after doses as high as 1 g or more are gastrointestinal...

Coenzyme Q Administration And Peroxidation Products

Based on the antioxidant role of CoQ, several approaches have been followed in trying to correlate CoQ administration and the extent of peroxidative damage. Myocardial dysfunction associated with lipid peroxidation is known to occur after reoxygen-ation of hypoxemic hearts in the immature piglet subjected to cardiopulmonary bypass (CPB). Morita et al.,38 tested the hypothesis that CoQ10, administered before the onset of reoxygenation on cardiopulmonary bypass, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after CPB. It was found that CPB without hypoxemia caused no oxidative damage and allowed complete functional recovery. Hearts that were reoxygenated after hypoxemic CPB lasting 30 min showed a progressive increase in conjugated diene levels in coronary sinus blood after reoxygenation and a reduced antioxidant reserve capacity resulting in severe postbypass dysfunction. Conversely, CoQ10 treatment avoided the increase in conjugated diene levels,...

Figure 32 Affinityselection mass spectrometry as a means of screening compound libraries to identify agents that bind

X-Ceptor on nuclear hormone receptors, and so on. Such foci can lead to fascinating developments consider mitochondria, for example. Mitochondria are cytoplasmic organelles involved in calcium regulation, cell death, energy production, free radicals, and metabolism. They are cellular powerhouses, functioning as the batteries, generators, and engines of cells. Almost all cellular activity involves mitochondria, so they are essential to human life. In many ways, mitochondria function like a cell within a cell, and they house proteins derived from two genomes, the nuclear genome, inherited from both the mother and the father, and a small mitochondrial genome, inherited in almost all cases only from the mother. Whereas the mitochondrial genome has only 37 genes, nuclear DNA encodes thousands of mitochondrial proteins. Mitochondria play a critical role in human health and disease, and mitochondrial dysfunction has been linked to more than 75 diseases, including major diseases of...

Evidence for Apoptosis in Motor Neuron Disease ALS and Related Disorders

The discovery of Cu,Zn-superoxide dismutase mutations as a cause for some cases of familial ALS has strongly supported a role for apoptosis since the effect of the mutation is to convert an antioxidant defense enzyme into a proapoptotic gene.134 Furthermore, other rare cases of familial ALS have been associated with NAIP mutations.135 This suggests that ALS may well be very similar to Parkinson's disease and late-onset AD in that a number of specific gene defects or allelic effects may be identified, accounting for 25 to 50 of familial cases. Environmental factors most likely interact with these genes to determine onset and character of illness. Many of the remaining cases may result from multiple genetic factors in combination with stronger and more adverse environmental or aging-related events. It is important to realize that the identified genes to date only account for a proportion of the familial ALS cases, and that most ALS cases (95 ) are sporadic.

Summary And Conclusion

Animal and human studies have convincingly demonstrated significant photopro-tective effects of ''natural'' and synthetic antioxidants when applied topically before UVA and UVB exposure. However, particularly with respect to UVB-induced skin damage, the photoprotective effects of most antioxidants were modest as compared to sunscreens. More successful in preventing such damage were appropriate combinations of antioxidants resulting in a sustained antioxidant capacity of the skin, possibly due to antioxidant synergisms. On the other hand, regarding photoprotective effects against UVA-induced skin alterations, which are largely determined by oxidative processes (75,189-192), topical administration of antioxidants might be particularly promising (193-195). In fact, topical application of antioxidants resulted in a remarkable reduction of UVA-induced ROS generation in mice (134), and diminished UVA-induced polymorphous light eruption in humans (178). Furthermore, topical application of...

Direct Wired Microarrays

The 100 site microarray is about 7 mm2 in size, with an active test site array area of about 2 mm2. The microarrays are fabricated from silicon wafers, with insulating layers of silicon dioxide, platinum microelectrodes and gold connecting wires. Silicon dioxide silicon nitride is used to insulate the conducting wires, but does not cover the surface of the platinum microelectrodes. The whole microarray surface is covered with several microns of a hydrogel (agarose or polyacrylamide) which serves as permeation layer. The permeation layer is impregnated with a coupling agent (streptavidin), which allows attachment of biotinylated DNA probes or other entities. The permeation layer allows current (counter ions) to flow to and from the microelectrode surface, and also serves to protect the DNA molecules from the adverse effects of the electrolysis products (H+, OH O2, H2, and free radicals), which are produced on the electrode surfaces when activated. (In...

Effects of Estrogen on Lipids and Lipoproteins

Estradiol at plysiological levels has an antioxidant capacity that is independent of its effects on serum lipid concentrations. Thus, administration of 17 -estradiol in postmenopausal women can decrease the oxidation of LDL cholesterol, which could enhance endothelial NO bioactivity (62). This antioxidant effect may be as a result of ER-mediated changes in the expression of genes for enzymes that regulate the local production and degradation of superoxide.

The Complexity of Sex Steroid Actions

The mechanism of action of both estrogens and progestogens on the vascular system is diverse and complex. Some of the estrogen actions, including those on the atherogenic lipoproteins, antioxidant activity and enhancement of endothelial function are unequivocally antiatherogenic. Some of these effects, however, may be partly negated by certain synthetic progestogens used in conventional HRT. On the other hand, the net clinical effect of the prothrombotic vs fibrinolytic actions of estrogens may vary depending on dose, route of administration, the state of the vascular wall and genetic factors, so that in certain circumstances the prothrombotic effects may predominate resulting to thrombosis.

Analysis of Oxidative Modification of Proteins

IMPORTANT NOTE Tissue collection and preparation must be carried out in buffers supplemented with antioxidants, such as 100 M diethylenetriaminepentaacetic acid (DTPA) and 1 mM butylated hydroxytoluene (BHT). The use of antioxidant buffers may be especially critical for the detection of trace amounts of oxidized products formed during aging or under oxidative stress. In addition, all buffers should be bubbled with nitrogen before use.

Studies in MS and Other Conditions

The biologic effects of the chemicals in marijuana, known as cannabinoids, have been extensively investigated. These chemicals bind to proteins in the central nervous system (CNS) that decrease nerve cell activity. These proteins are known as CB1 receptors. Theoretically, binding to CB1 receptors could decrease some multiple sclerosis (MS)-associated symptoms, such as pain and spasticity. Also, cannabinoids bind to another type of protein known as CB2 receptors. Binding to these proteins, which are present on immune cells, may mildly suppress the immune system and could thus potentially slow down the disease course in MS. Other effects of cannabi-noids, including antioxidant properties and inhibitory effects on a harmful process known as excitotoxicity, could also theoretically be beneficial for MS.

Snitrosylation Analysis Of Cells Or Cell Lysates Using The Biotinswitch Method

The previously described methods are useful for S-nitrosylation analysis of individual immunoprecipitated proteins. The methods are not as well suited for analyzing general protein S-nitrosylation in cell lysates because many components in lysates, including proteins, nitrite, oxidants, and antioxidants interfere with the assays (Fang et al., 1998 Nagata et al., 1999 Fernandez-Cancio et al., 2001 Jourd'heuil, 2002 Zhang et al., 2002). Therefore, to assess general protein nitrosylation in cell lysates, it is recommended that either a biotin-switch or immunofluorescence assay (Alternate Protocol 2) be used.

MMP Induction by Distinct Reactive Oxygen Species

Following UVA-irradiation in addition to 'O2, both H2O2 and O2-appear to play a role in the induction of MMP-1 synthesis.67, 73 By contrast, following UVB-irradiation, in particular iron chelators are able to inhibit the up-regulation of MMP-1 mRNA levels by 60 . This points to the importance of the iron driven Fenton reaction with subsequent generation of OH. and lipid peroxides. Interestingly, inhibition of the Fenton reaction and lipid peroxidation by iron chelators, the vitamin E derivative Trolox, and scavenging OH. by DMSO or mannitol resulted in a significant reduction of lipid peroxidation and MMP-1 mRNA levels after UVB irradiation.94 These results imply potential antioxidant approaches for controlling tumor progression and aging. In fact, due to a pathologically leaky vasculature in tumor angiogenesis, erythrocyte extravasation with hemosiderin formation and release of free iron into the connective tissue is a common feature in tumor angiogenesis. Upon...

Dietary factors and the risk of cancer

As far as the role of dietary factors in the etiology of cancer is concerned, laypersons mostly think that contaminants and additives are the main risk factors. A well-known publication in which the contribution of dietary factors to the occurrence of cancer has been estimated is The causes of cancer written by Doll and Peto (1981). According to their estimates, the effects of contaminants and additives on the occurrence of cancer range from a decrease of 5 (due to a protective effect of antioxidants) to an increase of 1 to 2 .

Gian Paolo Littarru and Maurizio Battino Contents

The bioenergetic role of coenzyme Q (CoQ) in mitochondria as well as its essential role in other redox chains is well accepted. What is more often debated is its antioxidant function and the rationale leading to clinical administration. In spite of the suggestion that CoQ in mitochondria may be involved in oxygen free radical generation,1 evidence has been found that CoQ acts as an antioxidant both in vitro1,2,3,4,4* and in vivo.5 Thus, the reasons justifying the use of CoQ in different clinical conditions may arise both from improvement of cellular bioenergetics and antioxidant protection3,6 and we shall try to critically discuss whether its therapeutic effect can reasonably be ascribed to the former or the latter of its features.

Pharmacologic Highlights

Other Drugs Sedatives and acetaminophen are avoided because poor metabolism can precipitate encephalopathy. Aspirin is usually avoided because of the action on platelets, which can lead to increased bleeding. If ascites is present, diuretics, particularly aldosterone antagonists such as spironolactone (Aldactone), may be prescribed and, if ineffective, more potent loop diuretics may be added. Silibinin is a derivative of silymarin, an active ingredient in herbal preparations that possesses antioxidant properties its use may benefit liver disease management.

Heterogeneity Of Microglial Activation

The microglia-derived signals which induce PCD are either oxidants or stimulators of oxidative metabolism. Oxidative stress, which refers to the cytotoxic consequences of oxygen radicals, may be induced by free radicals themselves (O2, OH, H2O2, and NO).87-89 Alternatively, free radicals may either elicit reactive oxygen intermediates, i.e., oxygen species with unpaired electrons, or they may extract electrons from molecules. There is an increasing amount of experimental evidence that oxidative stress causes cell death during development, implying that similar mechanisms of cytotoxicity may be induced in several neurodegenerative disorders, e.g., trauma, stroke, and seizures. There is common agreement that the association of oxidative stress with excessive activation of glutamate receptors is a final common pathway for cell vulnerability in the brain. The agreement on the importance of oxidative stress includes those pathological situations which unavoidably lead to neuronal death....

Lowdensity lipoprotein oxidation modification and retention

Similarly, 5-LO and 15-LO also oxidize unsaturated fatty acids bound to surface PL, generating oxidized PL (oxPL) or oxidize polyunsaturated arachidonic acids found within or released from the mmLDL particle by the action of PLA2, creating a number of reactive fatty acid hydroperoxide species. These hydroperoxides act as a source of damaging free radicals by propagating radical chain reactions within the tissue. OxPL species are found in both early- and late-stage atheroma tissue, suggesting that they contribute to all phases of disease progression.19 The transformation of arachidonic acid by 5-LO initiates the leukotriene biochemical cascade (Figure 6) that produces the powerful

Epoxide hydrolases EC 3323

MEH38 is highly expressed in the liver and several steroidogenic organs and at more moderate levels in many tissues of man and other mammals. mEH is induced by phenobarbital, trans-stilbene oxide, Aroclor 1254, and by several other xenobiotics including many antioxidants such as ethoxyquin. mEH metabolizes many structurally diverse epoxides. Structural requirements for a mEH substrate are sufficient lipophilicity and lack of trans-substitution at the oxirane ring.39 mEH substrates include epoxides metabolically formed from drugs, such as carbamazepine and phenytoin, from occupational compounds such as styrene, and from environmental compounds such as polycyclic aromatic hydrocarbons.38 With respect to toxification detoxification it is important to note that epoxide hydrolysis - normally a detoxification reaction can be involved in overall toxification pathways in some predictable cases. The mEH-catalyzed hydrolysis of pre-bay epoxides metabolically formed from angular PAHs (e.g., the...

The atheroprotective effects of highdensity lipoprotein cholesterol

While excessive mmLDL plays an important proinflammatory role in atherosclerosis, HDL and its associated apoA-I exert a corresponding cardiovascular benefit through the RCT pathway and several other important protective mechanisms.16 HDL also has beneficial antioxidant and anti-inflammatory properties and improves endothelial dysfunction. HDL contains two antioxidant enzymes, paraoxonase and platelet-activating factor (PAF) acetylhydrolase (PAFAH), that not only inhibit the oxidation of LDL but also help degrade oxidized phospholipids within oxLDL. HDL and its associated apoA-I protect endothelial cells from damage induced by oxLDL. HDL also displays anti-inflammatory properties, since pretreatment of human endothelial cells with HDL inhibits the cytokine-induced expression of cell adhesion molecules.

Measurement Of Oxidative Stress

Depending on its redox status, coenzyme Q is oxidized and reduced at low potentials.19 This characteristic of coenzyme Q allows it to fulfill its pivotal role in the electron transport chain.20 In the circulation, coenzyme Q is mainly carried by lipoproteins,21 where it is predominantly present in the reduced form of ubiquinol (CoQ10H2). CoQ10H2 in LDL is, however, easily oxidized to ubiquinone (CoQ10). In fact, CoQ10H2 is the first antioxidant to be depleted when LDL is subjected to oxidative stress in vitro22 As CoQ10H2 is easily oxidized, the CoQ10H2 CoQ10 ratio may be used as a marker of oxidative stress to which circulating LDL has been exposed.22,23 This ratio may be measured by HPLC using a coulometric detector in an oxidation-reduction-oxidation mode as originally described by Edlund.19 CoQ10H2 is, however, unstable in whole blood or plasma, and this compound undergoes substantial oxidation within hours after the blood specimen has been obtained.24 This implies that reliable...

Nutrients antibodies secondary metabolites and vaccines

At present there is active research on flavonoid biosynthesis which is thought to possess health-promoting properties such as antioxidant, vasodilatory actions which may protect against cardiovascular diseases, particularly for one group such as flavonols (e.g., quercitin and kaempferol) and pigmentary flavonoids known as anthocyanins which play an important role in flower and leaf colour in plant. Attention is directed toward calchone isomerase, an enzyme involved in flavonol biosynthesis. Tomato fruits over-expressing constitutively Petunia calchone isomerase gene contained high levels of quercitin glycosides and moderate levels of kaempferol (Muir et al. 2001). This gene may be used to transform many fruit crops, reinforcing their natural red colour e.g., plum, grape, strawberry, and some Citrus sp. (e.g., orange, grapefruit).

Examples of risk assessment risk evaluation and risk management Additives and processing residues According to the general public, the toxicological risks associated with the intake of food additives and food processing residues are high. In particular, sweeteners, antioxidants, dyes, and preservatives are substances that have recently received large negative publicity.

Murine Models of Atherosclerosis

Both LDLr_ _ and apoE _ _ models have been further exploited by backcrossing with other knockouts or transgenic mice overexpressing specific proteins to create new transgenic models that have helped define many of the mechanistic components underlying this disease. As a result, the specific effects of both human proinflammatory, anti-inflammatory, oxidative, antioxidant, and redox-regulated proteins on the atherosclerotic process have been confirmed in animal studies.

Hypothetical Mechanism Of Myocardial Acquisition Of Tolerance To Ischemia And Reperfusion By

Phosphorylation.35 The ability of CoQ to afford myocardial protection is also attributed to its antioxidant and membrane stabilizing properties. However, there are controversial issues as to whether CoQ acts as an antioxidant or prooxidant.36,37 O2 can stem from a divergent single electron transfer from redox cycling ubisemiquinone. It has been demonstrated that exogenously added CoQ enhances O2 generation in isolated complex I (NADH-CoQ reductase) and III (CoQ-cytochrome c reductase).38 Other lines of evidence, which also support redox cycling of CoQ as an alternative site of direct oxygen interaction during respiration, were derived from the experiments showing that H2O2 release from decomposing O2 was inhibited after removal of CoQ from mitochondria, but was reestablished after reincorporation of added CoQ.39 Myxothiazol, which prevents the existence of ubisemiquinone at its outer binding center to the bc1 complex, inhibited mitochondrial O2 formation.40 Arguments against the role...

Oxidative and Nitrosative Stress in Diabetes Induced Vascular Dysfunction

Various neurohumoral mediators and mechanical forces acting on the innermost layer of blood vessels, the endothelium, are involved in the regulation of the vascular tone. The main pathway of vasoregulation involves the activation of the constitutive, endothelial isoform of NO synthase (eNOS) resulting in NO production (53). Endothelium-depen-dent vasodilatation is frequently used as a reproducible and accessible parameter to probe endothelial function in various pathophysiological conditions. It is well established that endothelial dysfunction, in many diseases, precedes, predicts, and predisposes for the subsequent, more severe vascular alterations. Endothelial dysfunction has been documented in various forms of diabetes, and even in prediabetic individuals (52,54-58). The pathogenesis of this endothelial dysfunction involves many components including increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol, and the subsequent activation of...

Oxidative and Nitrosative Stress in Diabetic Cardiomyopathy

There is circumstantial clinical and experimental evidence suggesting that increased sympathetic activity, activated cardiac renin-angiotensin system, myocardial ischemia functional hypoxia, and elevated circulating levels of glucose result in oxidative and nitrosative stress in cardiovascular system of diabetic animals and humans. Oxidative stress associated with an impaired antioxidant defense status may play a critical role in subcellular remodeling, calcium-handling abnormalities, and subsequent diabetic cardiomyopathy (75,89). Oxidative and nitrosative damage may be critical in the early onset of diabetic cardiomyopathy (74,75). Consistent with this idea, significant nitrotyrosine formation was reported in cardiac myocytes from myocardial biopsy samples obtained from diabetic and diabetic-hypertensive patients (74) and in a mouse model of streptozotocin (STZ)-induced diabetes (75). Perfusion of isolated hearts with high glucose caused a significant upregulation of iNOS, increased...

Coenzyme Q And Arterial Function

Radicals led to a similar impairment of bradykinin-induced vasorelaxation. The impairment of endothe-lium-independent vasorelaxation was not as profound as that of endothelium-dependent vasorelaxation, suggesting that the endothelium is particularly vulnerable to free radical burst during the reperfusion period. In this study, pretreatement with coenzyme Q10 protected endothelium-dependent but not endothelium-independent vasodilatory responses from ischemia reperfusion- and H2O2-induced injuries. Furthermore, the free radical burst during the reperfusion period, measured by lucigenin-enhanced chemiluminescence, was significantly reduced by coenzyme Q10 pretreatment, and thus the authors suggest that coenzyme Q10 protects the endothelium via a direct antioxidant mechanism.

Extramitochondrial coenzyme q in the defense against oxidative stress

Oxidative stress can be defined as the result of oxidative changes in the cellular redox status. This status is the consequence of the equilibrium between oxidants and physiological antioxidants. The main sources of oxidative stress are oxygen and its ROS. Extracellular ROS mainly come from the interaction between transition metal ions and oxygen in solution, or by the radiation-induced hydrolysis. The most important intracellular sources of ROS are oxygen-metabolizing organelles such as mitochondria and peroxisomes (see Kehrer and Smith for a in-depth review, Chap. 2 Nat. Antiox in health and disease). In addition to its role as an electron carrier in electron chains associated with membranes, CoQH2 is an important antioxidant that protects membranes from peroxidations.6,35 As covered in detail in a next section of this book, antioxidant properties of CoQH2 rely on a direct scavenging of initiators and lipid peroxyl free radicals, and its ability to regenerate other antioxidants....

Pathobiochemical Mechanisms Of Rejection Of The Transplanted Heart

The following pathobiochemical mechanisms could be involved in acute rejection development of the transplanted heart increased free oxygen radical production, diminished antioxidant defense activities, and damaged heart mitochondrial function. 21.3.1 Ffee Radicals Antioxidants There is a dynamic balance between reactive oxygen species (ROS) production and antioxidant defense systems. Uncontrolled ROS production induces structural and functional alterations of cellular membranes, damage of polyunsaturated fatty acids, proteins, and deoxyribonucleic acid. Each cell contains antioxidant systems that protect tissues from oxidative insults, cell necrosis, and apoptosis. Coenzyme Q10, alpha-tocopherol and beta-carotene belong to the nonenzymatic lipid-soluble antioxidants. Nutritional elements (Mg, Se, Zn, Cu) participate in the defense antioxidant FIGURE 21.1 Antioxidants in the cell (Gvozdj kov , A., Gvozdj k, P., Ateli r 2, 1997). FIGURE 21.1 Antioxidants in the cell (Gvozdj kov , A.,...

Coenzyme Q Semiquinone Radical Reduces Vitamin E Phenoxyl Radical

Electron transport in membranes is always accompanied by generation and release of superoxide, whose level may become very high under some conditions (e.g., during the oxidative burst of phagocytic cells, or in the presence of redox-cycling drugs).1446 Overproduction of superoxide creates prooxidant conditions, resulting in depletion of antioxidants and development of oxidative stress. The reaction (8.4) is reversible ubisemiquinone can undergo autooxidation yielding superoxide radicals.4950 This suggests that the ubiquinone ubisemiquinone redox-couple may exert either antioxidant or prooxidant effects depending on the steady-state concentrations of oxidized and reduced coenzyme Q, oxygen, and superoxide. It should also be noted that ubisemiquinone is formed every time reduced coenzyme Q acts as a direct chain-breaking antioxidant (Figure 8.1). Clearly, production of superoxide by an antioxidant molecule is not consistent with its protective antioxidant role. If, however, CoQ* and O -...

Volatile Headspace Analysis of Cryopreservation Injury in Shoot Tips

The following headspace protocol describes the detection of ethane, ethylene, pentane, and methane. Ethane, ethylene, and pentane are secondary products of lipid peroxidation, and the detection of these compounds during cryopreservation may indicate membrane damage (25,26). Ethylene and ethane are produced from the peroxidation of linolenic acid, and pentane from linoleic acid (27,28). A second, and usually more abundant, source of ethylene in plants is produced enzymat-ically (29) from 1-aminocyclopropanecarboxylic acid. An intact membrane is considered essential for 1-aminocyclopropanecarboxylic acid-dependant ethylene biosynthesis, and a reduction in ethylene production during in vitro plant cryop-reservation intimates that membrane damage has occurred (25). The growth-regulating effects of ethylene also influence growth and development, such as inhibiting in vitro shoot growth and promoting senescence (29,32), and these could impact postcryopreservation regeneration. Ethylene may...

Importance Of Nutrition In Alcoholic Liver Disease

Nutrition is of great importance in alcoholic liver disease, to the extent that some authors regard ethanol itself as nonhepatotoxic, and that the liver disease associated with chronic ethanol intake is caused purely by inadequate nutrition, in both animal models and human disease.20,21 Most authors now, however, regard ethanol as hepatotoxic and that the degree of hepatotoxicity is modified by nutritional factors.4,22 Not surprisingly for a disease associated with free-radical production, dietary antioxidant intake is of great importance in alcoholic liver disease. Particular interest has been shown in a possible relationship between vitamin E status and alcoholic liver disease. However a-tocopherol status of alcoholics has been variably reported as increased, decreased, or unchanged compared to controls (e.g., 23-25 , 26-28 ). These differences may be due to the degree of liver damage in the studied groups and or whether a-tocopherol levels are normalized to plasma lipid levels....

Prevention of dementia I

Age and the role of antioxidants One particular strategy involving the ingestion of antioxidants may already be informally in place. Antioxidants potentially have a role in preventing dementia. As the brain ages, its capacity to remove certain harmful small molecules known as 'free radicals' is reduced, resulting in cell death and increased susceptibility of nerve cells to other factors that cause damage. The brain cells' natural defences against this damage include manufacturing antioxidants that mop up free radicals, but with age some of these protective mechanisms decline. Curcumin (from the herb turmeric), alpha-lipoic acid, flavonoids, vitamin B6, vitamin C, vitamin E and vitamin A are just a few of the many antioxidants available on the shelves in health food stores. A number of these substances have been examined for There is modest evidence that vitamins C and E may have a protective role against dementia. The Honolulu-Asia Aging Study found that older men who took supplements...

Carbonyl and quinone reductases

Two forms of cystosolic quinone oxidoreductase have been described. NQO1 (also known as DT-diaphorase) and NQO2 are FAD-containing enzymes that utilize NAD(P)H and dihydronicotinamide riboside, respectively, as electron donors.79 From a functional standpoint, NQO1 has been more extensively studied, and is known to act as a chemoprotective enzyme cellular defenses against the electrophilic and oxidizing metabolites of a wide variety of xenobiotic quinones.80 Obligatory two-electron reduction by the enzyme bypasses the formation of semiquinone radicals, which is important because the semiquinone radical can be reoxidized by molecular oxygen 'futile cycling' with concomitant production of ROS that can lead to cellular damage. NQO1 also participates in reduction of endogenous quinones, such as vitamin E quinone and ubiquinone, generating antioxidant forms of these molecules. Because NQO1 is overexpressed in some tumour types, its enzyme activity has been exploited in the design of...

Conclusions And Future Prospects

Should the reader feel that the above discussion has led to few definite conclusions regarding whether there is a role for CoQ in alcoholic liver disease, our objective has been achieved. As alcoholic-liver disease involves, at least in part, free radicals in its pathogenesis, and CoQ can be consumed in free radical producing systems,77 it is possible that ethanol could cause a decrease in hepatic mitochondrial CoQ levels. This could cause a direct decrease in the rate of mitochondrial -oxidation or have a secondary effect by exacerbating free radical attack in the liver. As there is an interaction between vitamin E and CoQ78,79 as lipophilic antioxidants and CoQ can regenerate or spare vitamin E both in vitro18 and in vivo,13,80 supplementation with CoQ and or vitamin E is of possible interest in the amelioration of alcoholic liver disease.

Mechanisms Of Toxic Injury

This toxic mechanism, which had its most active interest in the late 1970s and early 1980s, occurs when chemicals are metabolized to free radicals or other highly active molecules. These radicals then covalently alkylate nearby mac-romolecules. Such macromolecules can include proteins, cellular membranes (including plasma membranes, nuclear membranes, membranes of organelles, etc.), and genetic components such as DNA and RNA. If metabolically critical areas of these large molecules become covalently bound to a metabolic product, they may become inactivated. Specific toxic effects will depend on which biological macromolecules become inactivated. An example is the case of carbon tetrachloride that becomes oxidized by liver P450 enzymes to the trichloromethane free radical. This active alkylating agent attaches itself to nearby liver parenchyma, resulting in the classic liver toxicity described for carbon tetrachloride. Research interest in covalent binding as a mechanism of toxicity...

Iron Potentiates Ethanolinduced Oxidative Stress

Iron may also act as a cofactor that increases the oxidative liver damage exerted by other hepato-toxins such as alcohol. Ethanol is metabolized by the enzyme cytochrome P4502E1 (CYP2E1). During this metabolism the CYP2E1 generates free radicals,42 and increased oxidative stress was found in livers exposed to ethanol.43 When iron is added to ethanol treatment, liver damage and indices of oxidative stress are greatly enhanced.44,45 We found that the combination of iron and ethanol significantly decreased the hepatic contents of reduced ubiquinone-9 and increased the serum aminotransferase activities, as compared with either substance given alone38 (Figure 23.2). In this respect, the free iron pool may play a major role in catalyzing oxidative damage exerted by ethanol.24 In the Fenton reaction, ferrous iron catalyzes the production of hydroxyl radicals from hydrogen peroxide. Indeed, chelating free iron by desferrioxamine reversed the increased levels of aminotransferases that were...

Hepatitis Induces Oxidative Dna Damage Of Importance For Hepatocarcinogenesis

The necroinflammatory reaction seen in livers with viral hepatitis is the result of a host immune response to viral antigens.14 Recruited leukocytes and macrophages release reactive oxygen species in areas of infection, which create necrosis of target hepatocytes. The enhanced oxidative stress overwhelms antioxidant defense mechanisms and leads to damage of crucial macromolecules, including DNA. 8-oxo-2'-deoxyguanosine (8-oxo-dG) is continuously produced in liver tissue but in the case of a normal liver, is quickly removed by DNA repair enzymes. However, in chronic hepatitis, oxidative stress is enhanced and cell proliferation increased, which enables DNA replication to occur before the repair of genetic lesions is complete, resulting in mutations. This concept has been tested in the hepatitis B-virus (HBV) transgenic mouse animal model. These mice overexpress the HBV large envelope protein, leading to necrosis, inflammation, and subsequent development of HCC.12 A significant...

Introduction A Background

Classic physical adsorption of macromolecules as an immobilization procedure has some important advantages it is easy to carry out, very reproducible, and suited to the production of large quantities of reagent. Immobilization occurs by the hydrophobic effect upon simple mixing of the latex with a solution of the macromolecule, under the right conditions of pH and ionic strength. This procedure has the additional advantage that a single type of solid phase particle can be used to immobilize a wide range of macromolecules, especially proteins. The most popular polymeric latexes, such as polystyrene, have highly hydrophobic surfaces and charged groups (-OSO3-) which stabilize the colloidal suspension. These groups are derived from the reagents used during synthesis (emulsion polymerization, where persulfate ions are used as a source of free radicals to initiate polymerization). Carboxyl groups may also appear by degradation of the sulfate ions (Kolthoff's reaction) 12 . In summary, a...

Types of Radiation Exposure

Directly, radiation impacts the target molecule and causes damage. In DNA, mutations may arise, resulting in neoplasm or cell death. Indirectly, radiation impacts a molecule and creates a reactive species (free radicals) that may chemically react with organic molecules in cells, altering their structure or function. Usually, time and oxygen allow the organism to repair radiation damage molecular scavengers such as glutathione help protect against free radicals. When these systems are overwhelmed by large doses of radiation, permanent damage may occur.

Mechanisms of Renal Dysfunction

Oxidative stress is defined as an imbalance between prooxidants and antioxidants. Reactive oxygen species (ROS) are intermediary metabolites that are normally produced in the course of oxygen metabolism. There are many reactive oxygen species that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Oxidative stress increases during hypertension due to increased production of ROS such as superoxide, hydroxy radical, and hydrogen peroxide and or decreased superoxide dismutase (SOD), which scavenges ROS. Most recent attention has been given to the role of superoxide. There are many enzymatic sources of superoxide including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. ROS can react with and denature proteins, lipids, nucleic acids, carbohydrates, and other molecules leading to inflammation, apoptosis, fibrosis, and cell proliferation. However,...

Management of Renal Dysfunction

Aside from the classic treatment of hypertension, an emerging approach to renal dysfunction is the treatment of the components that trigger endothelial dysfunction, e.g., NO bioavailability and oxidative stress. For example, oral treatment with L-arginine, the precursor of NO, reduces blood pressure and improves endothelial dysfunction in hypertensive patients.60 Statins and lipid-lowering drugs improve endothelial dysfunction in hypertensive animal models by enhancing NO levels.61 Antioxidants also can improve endothelial dysfunction in hypertensive animal models. For example, the SOD mimetic tempol decreases hypertension and oxidation stress and improves endothelium-dependent relaxation and kidney damage in hypertensive animal models such as AT-II-infused mice and Dahl salt-sensitive rats.62

Oxidative Stress During Initiation And Promotion

The animal model described above has been widely used as an in vivo assay to study the effects of various actions or xenobiotics on liver carcinogenesis.58 Using this model, the number of foci was shown to correspond to the initiating potency, whereas their relative volume was related to the strength of the promoter. Dietary carbonyl iron, known to induce the formation of reactive oxygen species25,35 and decrease hepatic levels of antioxidants,37,39 did not act as initiator or as promoter in this model.34 Carbonyl iron causes decreased weight gain of animals and has mitostimulatory properties on surrounding, noninitiated hepatocytes, both of which decrease the formation of preneoplastic nodules.34 Promotive effects of oxidative stress were seen in experiments in which

Roles Of Oxidative Stress And Ubiquinone During Tumor Progression

The impact of oxidative stress during progression of preneoplastic foci into HCCs has been studied during hepatocarcinogenesis.60,61 We evaluated the effects of long-term exposure to dietary iron during the progression step, and measured tumor contents of antioxidants.61 Although HCCs were histologically iron-deficient, exposure to dietary iron depleted their contents of reduced ubiquinone-9. This finding is in line with results showing an increased uptake of free iron in neoplastic liver cells as compared with nonneoplastic hepatocytes.62 The demonstration of decreased levels of antioxi-dants and increased contents of iron and ferritin in cultured hepatoma cells supports this hypoth-esis.63 In spite of the reduced levels of ubiquinone-9 in HCCs, the number and size of carcinomas were similar between groups, and concentrations of a-tocopherol in tumors were not altered by iron. On the contrary, tumors from iron-treated rats had a higher differentiation as compared with those from...

Endothelium Dependent Vasodilation in Animal Models

This is an increase in oxygen-derived free radicals (57), either because of an increase in free radical production or because of a decrease in the free radical scavenger system. Furthermore, free radical scavengers have been shown to improve the abnormal endot-helium-dependent vasodilation (58,59), implying that such free radicals may contribute to the abnormal endothelium-dependent relaxations.