Why choose natural antioxidants

Interaction With Other Dietary Antioxidants

The potential for the interaction of carotenoids with other antioxidants is discussed in detail in Chapter 3 and only an outline is given here. Truscott (72) first proposed a plausible mechanism for the interaction of vitamins C and E with b-carotene whereby the carotenoid molecule repairs the vitamin E radical reaction (8) and the resulting carotenoid cation radical is, in turn, repaired by vitamin C reactions (9) and (10) . An additive response has been observed for b-carotene and vitamin E, but a synergistic response was only seen when vitamin C was also present (73). If this model is correct then the reduction in the levels of vitamin C in the plasma of smokers compared with nonsmokers (74) is of significance as the repair of any b-carotene radical cations formed would be impaired. A xanthophyll such as zeaxanthin whose conjugated system spans the membrane (see above) would, in theory, be able to interact much more effectively with both lipid- and water-soluble antioxidants than...

Production by Free Radicals

It has been known for many decades that free radicals generated in a variety of chemical systems lowered the viscosity of HA solutions (65-67). Free radicals are also generated by cellular processes such as defense mechanisms of leukocytes (68). The burst of oxidative metabolism which occurs when polymorphonuclear leukocytes (PMNs) are stimulated generates superoxide, a highly reactive free radical (68-70) and secondarily, singlet oxygen and hydroxyl radical are formed. Peroxynitrite can be formed under physiological conditions from nitric oxide, which is synthesized by both neutrophils (71) and macrophages (72), and superoxide (73). Cleavage of HA is also brought about by the OCl generated by the myeloperoxidase system (74). McNeil et al. (63) showed that in three systems autooxidation of ferrous ions, the action of xanthine oxidase on hypoxanthine and stimulated PMNs the products generated were polydisperse. The major fraction was reduced to a size of 104 Da and was not reduced...

Antioxidant Response Element

Induction of phase II enzymes, which conjugate reactive electrophiles and act as indirect antioxidants, appears to be an effective means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part, through ARE found in the regulatory regions of their genes. The transcription factor Nrf2, which binds to ARE, appears to be essential for the induction of phase II enzymes, such as glutathione S-transferases (GSTs), NAD(P)H quinone oxidoreductase (NQO1) (154), as well as the thiol-containing reducing factor, thioredoxin (155). Constitutive hepatic and gastric activities of GST and NQO1 were decreased by 50-80 in Nrf2-deficient mice compared with wild-type mice (154). Several studies have shown that antioxidants present in the diet, such as terpenoids, phenolic flavonoids (e.g., green tea polyphenols and epigalloca-techin-3-gallate), and isothiocyanates may work as anticancer agents...

Free Radicals and Antioxidants

Over the past two decades, a persuasive theory of why cells gradually lose function has evolved - the free radical theory of aging. A free radical is a highly reactive molecule whose structure contains an unpaired, unstable electron. Free radicals in the body react with and oxidize nearby molecules and damage cell membranes, fatty acids, proteins, and DNA. Many free radicals are toxic derivatives of oxygen, produced by cell metabolism (as byproducts of energy-producing reactions) or environmental toxins (chemicals, radiation). To help protect themselves against free radicals, our cells evolved a complex array of free-radical defenses, or antioxidants. These antioxidants can neutralize free radicals and protect the cell. (For a detailed discussion of free radicals and antioxidants, see pp. 115). What is particularly intriguing about the free radical theory is that it suggests a practical means of modifying the effects of aging. Boosting levels of natural antioxidant compounds in cells...

Do Carotenoids Act As Antioxidants In Vivo

Much of the fundamental information regarding the antioxidant potential of carotenoids with a range of oxidizing species (especially radicals) has been gathered in vitro by challenging individual carotenoids (often simply in organic solvents, simple micelles, or liposomes) with individual RoS or, more rarely, RNS. While these may provide important intrinsic information on the interactions between a carotenoid and an RoS and serve as a guide to potential antioxidant activity, they do not represent the complex in vivo situation. In vivo, the carotenoid content and composition of the vast majority (if not all) tissues are heterogeneous. Physiologically, carotenoids are present in lower concentrations than typically used in vitro (35), and rather than being free in solution they are generally associated with some form of lipoprotein complex or incorporated into biological membranes. All too often, great claims are made with regard to the antioxidant activity of one carotenoid being x...

Impact of Antioxidant Therapy

Because lipoprotein oxidation is thought to play a major role in atherogenesis, it could be expected that intervention with antioxidants would be protective against atherosclerotic disease. Although antioxidant studies in four different animal models of atherosclerosis (rabbit, mouse, hamster, and monkey) mainly showed positive results (67,82), several large-scale, double-blind, placebo-controlled trials evaluating the effects of different antioxidant compounds on cardiovascular outcome were inconsistent. For instance, two large primary prevention studies, the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study) (83) and the PPP (Collaborative Group ofthe Primary Prevention Project) (84), reported that vitamin E treatment had no apparent effect on MI, CVD, or stroke. The Cambridge Heart Antioxidant Study trial, which included 2002 patients with angiographically confirmed CAD, showed a significant reduction in composite end point (i.e., cardiovascular death and nonfatal...

Oxidative Stress and Antioxidant Response

There is substantial evidence that oxidative damage that occurs in the aging brain of the normal individual is enhanced in AD brains. Recently, defects of mitochon-drial electron transport chain enzymes were found repeatedly in various cells and tissues of patients with neurodegenerative diseases. Indeed, Kim et al. 46 observed reduced levels of complex III core protein 1 in AD (temporal cortex) and of complex V -chain in Down's syndrome (DS) (frontal cortex). A consequence of defective mitochondrial energy production is the increased generation of free radicals (such as superoxide and hydroxyl radicals), which are normally produced as by-products of oxidative metabolism. Mitochondria are in turn damaged by reactive oxygen species. Krapfenbauer et al. 51 investigated the expression of peroxiredoxins (Prxs), a family of six highly conserved antioxidant enzymes expressed in the frontal cortex and cerebellum of patients with AD, PD, and DS. Their results show that Prx II is significantly...

Synthetic Antioxidants And Oxidative Stress

As there is a credible and substantial body of evidence implicating oxidative stress as a major factor in aging, are there therapeutic approaches that can be used to modulate endogenous oxidative stresses and thereby further test the free radical theory as well as point toward potential treatments in humans A variety of studies have been carried out with regard to ameliorating or attenuating aging or the progression of disease by chronic or acute antioxidant treatments (78-86). Such studies have yielded, at best, equivocal or mildly beneficial results with regard to slowing disease progression or improving the mean or maximal life span (85). Chronic dietary supplementation of antioxidants has either failed or met with very limited success in extending the life span or attenuating the rate of physiological decline in organisms from C. elegans to humans (80,82-86). The antioxidants used in previous studies (such as vitamin E) are not particularly effective antioxidants compared with...

Changes in Cell Antioxidant Status

Carotenoids have been reported to affect cell antioxidant status by altering hydrophilic and lipophilic antioxidant absorption and content and by modulating activity and or gene expression of antioxidant enzymes. Therefore, the measurement of cell antioxidant status may be a necessary and helpful tool in order to reveal pro-oxidant effects by carotenoid molecules in biological systems. 1. Nonenzymatic Antioxidants effects of -carotene on 1O2_ initiated photo-oxidation of methyl linoleate (45). In addition, y-tocopherol prevents the pro-oxidant effects of -carotene in purified triacylglycerol fraction of rapeseed oil exposed to light (46) and the pro-oxidant effects of lutein and lycopene in autoxidized triglycerides (47). Carotenoids have also been reported to increase the loss of -tocopherol induced by different sources of free radicals in lipid homogeneous solution (48), in isolated membranes (33,49), and in intact cells (50). These studies suggest that tocopherols may be consumed...


Our bodies have evolved several lines of antioxidant defense against free radicals. Antioxidants are able to interact with and reduce free radicals. By donating electrons, antioxidants convert the radicals to stable, nontoxic metabolites.3 Both individual antioxidants and antioxidant enzyme systems are important in free-radical scavenging. Four of the major antioxidants are essential micronutrients (vitamins C, E, beta-carotene, cysteine), while two can be synthesized in limited amounts by the body (glutathione and coenzyme Q10). Riboflavin and the trace elements selenium, copper, zinc, manganese, and iron are essential components of the major antioxidant enzymes. The major antioxidants The major antioxidants Major antioxidant enzymes and their vitamin and trace-element components Major antioxidant enzymes and their vitamin and trace-element components Antioxidant enzymes Most antioxidants scavenge free radicals by donating an electron. In the process the antioxidant is oxidized. For...

Vegetables and Fruits

Vegetables and fruits are the cornerstones of a healthy diet. They are rich sources of vitamins, minerals, complex carbohydrates, and fiber. Some, such as peas and corn, are also good sources of protein. Moreover, vegetables and fruits are generally inexpensive, contain no cholesterol, have little or no fat, and are low in calories. A high intake of vegetables, particularly of the Brassica family (broccoli, cabbage, cauliflower, and Brussels sprouts) can sharply reduce the risk of cancer.10 These vegetables contain compounds that can help the body detoxify and clear potential carcinogens. In addition, fruits and vegetables are rich sources of antioxidant nutrients, such as beta carotene and vitamin C, that may also protect against cancer and heart disease.2122

Basic Methods of the Aging Process

These methods incorporate microarray analyses that allow determination of alterations in mRNA expression associated with these diets in the aging flies. Chapter 11 is a review of the use of caloric mimetics as applied to aging research. Because caloric restriction of 30-40 in food intake, the level often showing effectiveness in retarding age-related effects in animal models, is not practical for most humans, alternative approaches are needed. Calorie-restriction mimetics target alterations in pathways involved in energy production to mimic the benefits of caloric restriction without the need to significantly reduce food intake. The utility of glycolytic inhibitors, antioxidants, and specific gene-modulators as caloric restriction mimetics are analyzed.

Vitamin A All transRetinol

Vitamin A is a fat soluble vitamin derived from fi-carotene. The alcohol form of vitamin A, retinol, is the storage form in the body. The aldehyde form, retinal, has a role in vision. The acid form, retinoic acid, functions in embryonic development. Vitamin A acts to some extent in the body as an antioxidant, protecting against oxidative damage. See also Antioxidants, Reactive Oxygen, Oxygen Metabolism and Human Disease, ff-Carotene, G Proteins in Vision, Lipid-Soluble Vitamins, Vitamins

Preferred Form and Dosage Schedule

Vitamin E may increase resistance to viral and bacterial infections. It enhances antibody production by white blood cells and increases their ability to phagocytize (engulf and destroy) bacteria.16 Also, by means of its antioxidant actions, vitamin E protects white blood cells from oxidant damage during their response to an infection.16

Overview of Carotenoid Function in the

The physiological role of the macular carotenoids has been the subject of considerable research interest. They are efficient antioxidants in a tissue composed of polyunsaturated lipids subject to significant oxidative stress from intense light and high oxygen levels (16,17). They absorb light with high efficiency in the 400-to 500-nm range, the region of the visible spectrum considered to be most phototoxic to the retina. Recent animal studies have indicated that lutein and or zeaxanthin supplementation may provide protection in experimental models of retinal light damage (18). It is also possible that the macular carotenoids may help improve visual function by ameliorating chromatic aberration and haze caused by short-wavelength visible light (19). The Eye Disease Case-Control (EDCC) study was the first large-scale study to provide epidemiological evidence that lutein and zeaxanthin may protect against age-related macular degeneration (ARMD), the leading cause of blindness among the...

Use in Prevention and Therapy

Riboflavin functions as an antioxidant throughout the body and may be especially important in the lens of the eye. Ample intake of riboflavin can reduce the risk of developing cataract. As a cofactor of glutathione reductase, riboflavin helps maintain the body's supply of reduced glutathione, an important antioxidant.1

Oxidative And Nitrosative Stress And Parp Activation In Myocardial Ischemia And Reperfusion

The concept that myocardial ischemia and reperfusion injury are the result of deleterious actions of reactive oxygen- and nitrogen-derived species has been widely accepted. The production of oxyradicals starts early in the ischemic period in mitochondria with altered redox balance and is further enhanced during reperfusion by a massive activation of xanthine oxidase in endothelial cells, and NADPH oxidase in infiltrated neutrophils.26 A plethora of nitrogen derivatives, highly reactive and capable of oxidation, are also formed during the early phase of reperfusion and may contribute to tissue injury. A characteristic marker of the occurring nitrosative stress is represented by the chemical alteration of the myocardial protein structure due to nitration of tyrosine residues.19,27,28 A number of chemical reactions with NO derivatives can yield nitrotyrosine formation. Nitrotyrosine can be formed from the reaction of peroxynitrite, the reaction of nitrite with hypochlorous acid, or the...

Protein Threedimensional Hydroarrays

To immobilize protein on a solid support in a way that preserves their folded configuration, Arenkov P. et al. 13 arrayed functionally active proteins within microfabricated polyacrylamide pads and microelectrophoresed proteins to accelerate diffusion. However, the polymerization of acrylamide requires free radicals, which may damage proteins as well as produce an unstable morpholino derivative that can negatively affect the stability and shelf life of the chip itself. initiated by water. This bypasses the need to use free radicals or organic solvents, creating a microenvironment into which proteins can be directly encapsulated during polymerization. In addition, (1) the initiation of polymerization, (2) the binding of proteins to the hydrogel backbone, and (3) the binding of the hydrogel microdroplets to the glass slide are mediated by the same isocyanate reactive groups in conditions that can be meticulously controlled. Consequently, the molar concentration of proteins immobilized...

Vladimir V Shuvaev Thomas Dziubla Rainer Wiewrodt and Vladimir R Muzykantov

The streptavidin-biotin system may be used to synthesize immunoconjugates for targeted delivery of drugs, including therapeutic enzymes. The size of antibody-enzyme conjugates, which is controlled by the extent of biotinylation and molar ratio between the conjugate components, represents an important parameter that in some cases dictates subcellular addressing of drugs. This chapter describes the methodology of formation and characterization of polymeric immunoconjugates in the nanoscale range. A theoretical model of streptavidin conjugation based on general principles of polymer chemistry is considered. Factors that influence size and functional characterization of resulting polymer conjugates, as well as advantages and limitations of this approach, are described in detail. The protocols describe the formation of immunoconjugates possessing an antioxidant enzyme, catalase, directed to endothelial cells by anti-platelet endothelial cell adhesion molecule antibodies. However because of...

Analysis of the Mechanism of Action

Carotenoids are well known as natural antioxi-dants and have potent activity to scavenge free radicals. Since inflammation is accompanied with excess production of free radicals, the scavenging activity of carotenoids against free radicals seems to play an important role in prevention of hepatitis virus infection-related liver carcinogenesis. In addition to the free radical scavenging activity, carotenoid-induced modulation of the expression of various genes also seems to be important. For example, lycopene has been found to increase the promoter activity of anti-oncogenes, such as the RB gene and the Wafl gene (Table 2).

Physiologically Active Substances A

Among the commonly used antibiotics, the tetracyclines have shown the most favorable effects on survival rates of mice (222) this is believed to be the result of an increase in metabolic activity. A gallate-tannin complex (223) was active probably because of its antioxidant effect. 5,7-Dihydroxyisoflavones are effective when administered to mice per-cutaneously but not intraperitoneal (224), presumably because of protection of the capillaries. O-jS-Hydroxyethylrutoside is also protective in mice, possibly by strengthening vascular walls and reducing bacterial invasion of the bloodstream (225). The radioprotective effect of rutin and other fla-vonoids has been controversial.

Protection by Anoxia or Hypoxia

1.5.2 Inhibition of Free-Radical Processes. Mechanisms of protection involving free-radical scavenging are based on the assumption that the free radicals resulting from radiolysis of water are the main cause of radiation damage to the cells. Radioprotectors then would react with these radicals, such as H', HO , and and prevent them from damaging biologically important molecules. This concept received support when a correlation was found between the protective action of about 100 substances in two systems an aerated aqueous solution of polymethacrylate and the mouse (125). It is probable that radical scavenging is the primary event in the prevention of radiolytic fragmentation of the polymer Reaction of sulfhydryl compounds with free radicals formed on macromolecules is considered more likely than reaction with HO', to account for radioprotection in mammalian cells. Reaction rates with such radicals were measured for several radiation protectors MEA, AET, APT, thiourea, cysteine,...

Reactions And Reactivity Of Carotenoids A General Properties

Oxidative stress and free radical attack on biological structures are believed to be major factors in the initiation and propagation of the development of many degenerative diseases. Biomembranes rich in polyunsaturated fatty acids are particularly susceptible to the degradative process of lipid peroxidation (mediated by free radicals in particular). Carotenoids may function as chain-breaking antioxidants reducing lipid peroxidation of such vulnerable membranes. The ability of molecules such as carotenoids to act as antioxidants depends on a number of factors, including its structure and resulting chemical properties but also in relation to its location and form in biological tissues (see below). The antioxidant properties of carotenoids are primarily associated with their ability to quench singlet oxygen (19,20) and scavenge free radicals (21-24). In carote-noids the conjugated carbon double-bond system is considered to be the single most important factor in energy transfer...

The quest for a biochemical marker of myocardial ischemia

Ischemia can result in tissue damage through the formation of a number of injurious compounds. A significant body of research over the past 15-20 yr has focused on the role of reactive oxygen species (ROS), including oxygen free radicals, singlet oxygen, and peroxides. The tissue damage induced by such compounds is well described and appears to be an ubiquitous biological phenomenon (Fig. 4). The alterations that occur to proteins, lipids, nucleic acids, membranes, and so forth are relatively independent of the tissue involved. However, the propensity to generate any specific ROS may differ among tissues and even between species for the same tissue. Furthermore, natural protective measures, such as catalase and superoxide dismutase, also vary in their distribution among tissues and show significant interspecies variations. Both the inherent propensity to generate a specific profile of ROS under given pathophysiological conditions and the intrinsic protective pathways will ultimately...

Partial Pressure of Oxygen

The antioxidant behavior of b-carotene is, in part, dependent on the partial pressure of oxygen (po2). Burton and Ingold (21) showed that at low po2, b-carotene acted as a chain-breaking antioxidant consuming peroxyl radicals Eq. (2) , while at higher po2 the carotenoid lost its antioxidant ability and actually exhibited prooxidant behavior due to autoxidation. This was demonstrated in solution using the trichloromethylperoxyl radical and b-carotene. At low po2, the b-carotene radical cation was readily formed, whereas in air and oxygen-saturated solutions a carotene radical adduct was also formed (22,43). This second species decayed to the relatively unreactive carotene radical cation. At low po2 this process consumes peroxyl radicals and the carotenoid acts as a chain-breaking antioxidant. At high po2 the carotenoid radical reacts with oxygen to produce a carotenoid peroxyl radical autoxidation reaction (5) , which is capable of acting as a prooxidant. Peroxidation is promoted in...

How Does Glutamate Kill Cells

Oxygen species (ROS, oxygen free radicals) and peroxynitrite, a toxic reaction product of NO and superoxide. These reaction cascades culminate in lipid peroxidation, DNA strand breaks, and activation of caspases and poly (ADP-ribose) polymerase (PARP). As a result of these events, the affected cells die, through both apoptosis and necrosis (Fig. 1) (14,15). In the lung, we have shown that acute NMDA exposure increases NO production and activates caspase-3 (15). Furthermore, both NO synthase (NOS) inhibitors and PARP inhibitors block the development of high-permeability pulmonary edema in response to NMDA, and injury is attenuated or delayed in both neuronal NOS- and PARP-knockout mice compared to wild-type (16).

Splanchnic Occlusion Shock

May be related to the interruption of positive-feedback cycles i.e., inhibition of PARP, in an indirect way, influences the amounts of reactive peroxynitrite produced. Although the mechanism of this action clearly requires further work, the following scenario should be considered. Because 3-aminobenzamide reduced neutrophil influx into the reperfused myocardium, it is expected that a subsequent reduced production of neutrophil-derived oxidants (including superoxide and peroxynitrite) occurs. It is well established that myocardial ischemia and reperfusion are associated with neutrophil accumulation with a subsequent burst of oxygen free radical production, activation of inflammation, excessive calcium entry, and, ultimately, cell death. Activation and accumulation of polymorphonuclear cells is one of the initial events of tissue injury, which triggers the release of oxygen free radicals, arachidonic acid metabolites, and lysosomal proteases, with subsequent more-pronounced infiltration...

Consequences of Altered Glucose Metabolism Oxidative Stress

Oxidative stress is defined as an imbalance between oxidants and antioxidants in favour of the oxidants. The oxidants, also termed ROS, are present as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. They are intermediate compounds derived from the univalent reduction of molecular oxygen (by electrons and protons), characterised by a spared electron in the external orbital, which confers them a particular instability (anion superoxide O2- hydroxyl radical OH-) or compounds such as hydrogen peroxide (H2O2), which react with oxidable functional groups. Anion superoxide and hydrogen peroxide are poorly reactive but in the presence of the transitional form of some metals, such as Fe3+, they generate the more reactive hydroxyl radical. These compounds are partially useful but potentially toxic, so the body is provided with several systems to counteract their activity. These systems include antioxidants produced in the body,...

The Role of Acute Phase Response in Cachexia

Tissue damage is a threat to well-being because it is self-promoting that is, hydrolases released from inflammatory or injured cells cause further injury and provide substrate for formation and propagation of free radicals. For this reason, the body must localise and limit the injury and clear tissue debris. To perform these functions, the organism has developed an acute-phase response that includes stereotyped, coordinated adaptations ranging from behavioural to physiological 1 . The acute-phase response includes the hepatic synthesis of large quantities of proteins. The functions of the acute-phase proteins vary widely and include binding proteins (opsonins), protease inhibitors, complement factors, apoproteins, fib-rinogen, and others.

Markers Of The Prooxidant Activity Of Carotenoids

Changes in cell antioxidant status Nonenzymatic antioxidants Tocopherols Ascorbic acid Glutathione Enzymatic antioxidants Superoxide dismutase Catalase production of bioactive free radical species (b) the modulation of cell antioxidant defences (c) the oxidative damage to specific cell targets, such as DNA, lipids, and proteins (d) the changes in the expression of redox-sensitive genes and or genes involved in the maintenance of intracellular redox status and (e) the modulation of redox-sensitive transcription factors.

Increased Production of Bioactive Free Radical Species

In the human body, a range of free radical species are produced, including 1O2, OH', O2 , and H2O2 and many organic products (36). While in the past carotenoids have been exclusively considered for their ability in inhibiting the formation of free radicals (5-7), at the moment they have also been suggested to enhance the formation of these species, under certain conditions. A direct generation of free radical species by -carotene has been reported in several cultured tumor cells (24,25,37). In these studies, reactive oxygen species (ROS) production is measured by different fluorescent probes, such as dichlorofluorescein diacetate (DCF-DA) and or dihydrorhodamine (DHR), able to detect ROS produced in whole cytoplasm or mitochondria, respectively. Interestingly, carotenoids may induce enhanced ROS levels at very different concentrations, depending on cell types. Some human colon adenocarcinoma cells (LS-174) show an increase in ROS production at a b-carotene concentration of 2.5 mM...

Modulation of Redox Sensitive Genes

Increasing evidence shows that b-carotene inhibits tumor cell growth through the involvement of a pro-oxidant mechanism and the modulation of redox-sensitive genes. We recently hypothesized a strict relationship between changes in intracellular redox potential and cell growth by b-carotene in tumor cells (26). The increase in ROS production and or the levels of oxidized glutathione induced by the carotenoid in human colon adenocarcinoma (24) and leukemia (25) cells are highly coincident with its ability to induce apoptosis and to arrest cell cycle progression. Interestingly, in these cells, the carotenoid is also able to decrease the expression of Bcl-2 (25,38), a protein whose antiapoptotic effects has been at least partially explained by its antioxidant properties (80). In addition, in HL-60 cells, the carotenoid also induces an increased expression of p21WAF-1, which is implicated in the arrest of cell cycle progression at the G1 phase (25). A recent finding suggests that this...

Cytoprotective Agents Aminothiols

Organic thiols neutralize free radicals generated in tissues exposed to cytotoxic drugs. Amifostine is a phosphorylated aminothiol initially developed as a radioprotective agent at the Walter Reed Army Institute in the 1970s. Following administration, amifostine is phosphorylated by tissue alkaline phos- phatase, an enzyme with greater activity in normal tissue than in tumor tissue. Active free thiol thus accumulates in the normal tissue, neutralizing the destructive free radicals. Thus, amifostine has been used as a radio- and cytoprotective agent for the treatment of solid tumors. In addition, amifostine protects primitive hematopoietic progenitors from chemotherapy-induced toxicity and stimulates hematopoiesis in preclinical models and in vitro studies.53

Recommended Daily Intakes

E as an antioxidant antioxidant High doses of GLA, EPA, and DHA should always be taken with additional vitamin E. As body stores of these polyunsaturated fats increase, additional vitamin E antioxidant protection is required. When taking omega-3 and omega-6 fatty-acid supplements, additional vitamin E (30-100 mg) and selenium (50100 ug) is recommended.

Other Laboratory Test Results That Correspond With Liver Disorders

Beta Gamma Bridging

Although there are many classic and reference methods for quantification of serum protein, the biuret reaction has become the most commonly used method in the clinical laboratory. The peptide bonds of proteins react with biuret reagent containing Cu2+ ions in an alkaline solution to form a violet color measured at 540 nm. Sodium potassium tartrate is a component of the reagent and functions to maintain copper in the correct valence state and in an alkaline solution, while potassium iodide is present as an antioxidant.

Cysteine and Glutathione

The amino acid cysteine contains a sulfur group that allows it to function as an important antioxidant. Cysteine can function independently as an antioxidant, or it can be combined with glutamic acid and glycine in liver cells to form glutathione. Glutathione is a principal water-soluble antioxidant in cells and the blood.1 The dietary supply of cysteine is a primary determinant of how much gluta-thione is synthesized in the body, and supplements of cysteine can boost tissue levels of glutathione. Antioxidant and detoxification function. Cysteine, alone or as part of glutathione, is a potent antioxidant, protecting against free radical damage.2 Glutathione, working with the enzyme glutathione peroxidase (a selenium-containing enzyme), detoxifies free radicals, drugs, and toxic chemicals. It also recycles oxidized vitamin E and vitamin C, conserving body stores of these antioxidants.3

Epidemiological Evidence And Human Intervention Studies

Carotenoids have been implicated as important dietary phytonutrients having cancer-preventive activity (1). Interest in carotenoids, especially -carotene, arose not only because of their antioxidant activity but also because their metabolites, vitamin A and retinoic acid, may be active via other mechanisms, such as induction of cellular differentiation or cell death. -Carotene has received the most attention because of its provitamin A activity and its prevalence in many foods. However, intervention studies with -carotene yielded disappointing findings (see below), and thus other carotenoids became the subject of more intensive investigation. Two carotenoids with provitamin A activity, -carotene and -cryptoxanthin, are also abundant in foods and contribute substantially to vitamin A intake. Carotenoids without vitamin A activity that are relatively well studied because of their high concentration in serum include lycopene, lutein, and zeaxanthin. Much of the evidence, particularly in...

Gene Therapy for Protection From Ischemia and Reperfusion Injury

The continuum of myocardial injury that is initiated by a coronary ischemic event and perpetuated by reperfusion (I R injury) may be clinically manifested in patients undergoing thrombolytic therapy following an acute coronary episode. The increase in ROS formation during reperfusion of the ischemic myocardium may eventually deplete the buffering capabilities of endogenous antioxidant systems, thereby exacerbating the cytotoxic effects of these reactive species (83). The development of gene therapies for acute myocardial infarction has been difficult because the time required for transcription and translation of therapeutic genes with the current generation of vectors exceeds the time window for successful intervention. An alternative gene therapy for myocardial protection is to prevent I R by the transfer of cytoprotective genes into the myocardium of high-risk patients prior to ischemia using a gene delivery method that could confer long-term therapeutic gene expression. This novel...

Rosmediated Cytotoxicity Of Antitumor Drugs

Involvement of free radicals in the mediation of side effects is well documented in the case of cisplatin and adriamycin and may be implicated in the toxicity of other cytostatics as well. High-dose cisplatin therapy produces untoward side effects of nephrotoxicity, bone marrow toxicity, gastrointestinal toxicity, ototoxicity, and peripheral neuropathy.3132 The mechanism of nephrotoxicity is still not understood completely, but generation of free oxygen radicals by the proximal tubular cells has been proposed as a major pathogenic mechanism.33 Cisplatin treatment resulted in depletion of glutathion (GSH) and protein thiols34 in the kidney. Studies performed on renal cortical slices revealed that depletion of mitochonrial GSH was an early event after cisplatin treatment that was followed by increased lipid peroxidation (measured by the amount of thiobarbituric acid reactive substance) and decreased mitochondrial protein concentration.35 The imbalance of the antioxidant system was...

Nutritional Support

Catecholamines and cytokines, which are elevated in heart failure, are stimuli for free-radical production. Therefore, antioxidants and free radical scavengers, such as vitamins C and E, are therapeutic options in cardiac cachexia. This was proven by a study showing that muscle wasting in mice was prevented by an antioxidant 92 . Additionally, it was shown that antioxidants suppress the production of free radicals in leucocytes 93 . The presence of elevated levels of markers of oxidative stress in heart-failure patients correlates with functional class, reduced exercise tolerance, lower antioxidant levels, and worse prognosis, including cachexia 94, 95 . These patients also tend to have micronutrient deficiency through, e.g. urinary losses or therapy with diuretics. Deficiencies of specific micronutrients, such as selenium, copper, calcium, zinc, or thiamine, can also cause heart failure 96 . Thus, it is important to keep CHF patients on a diet with sufficient calories and with...

Aminoglycoside Toxicity

Pletely satisfactory indeed, multiple mechanisms may be at work. One of the two most complete theories states that redox-active aminoglycoside iron complexes catalyze the formation of free radicals, which are destructive to the hair cells of the inner ear (71). The other theory holds that for at least some individuals aminoglycosides bind to mitochondrial ribosomes and shut down protein synthesis (72). Because of its ribosome involvement only the second theory will be discussed here.

Mw 144 C6h7o2k Mw 150

Various other additives are employed in dilutable soft drinks manufacture including antioxidants, acidity regulators, emulsifiers and stabilisers. Stabilisers are particularly important for ensuring physicochemical stability of the product to avoid unsightly oil ring formation or undue sedimentation of fruit components. Cloudy agents are often used to boost the turbidity of natural fruit components. These ingredients can also be made to incorporate citrus oils and colourings by creating an oil-in-water emulsion using a mixture of permitted emulsifiers and final emulsification of cloud to a low particle size (

Good Dietary Sources

A diet rich in fresh fruits and vegetables, whole grains, nuts, and seeds provides a balanced intake of antioxidants.13 In addition, many foods contain non-nutritive antioxi-dants that may be important in protection from oxidative stress.14,15 However, it is very difficult to obtain the recommended amounts of many of the antioxidants using only food sources. For example, to obtain 200 mg of vitamin E one would need to eat 2 kg of peanuts or 300 g of sunflower seed oil. To obtain 500 mg of vitamin C in a day, one would need to eat more than 0.5 kg of oranges or broccoli. Supplementation with a complete antioxi-dant formula is an efficient way to maintain antioxidant levels in the body. Non-nutritive antioxidants in the diet Non-nutritive antioxidants in the diet Antioxidants Fig. 3.24 Interdependence of the principal antioxidants. Fig. 3.24 Interdependence of the principal antioxidants.

Cellular And Molecular Mechanisms Of Carotenoid Action

As discussed below, carotenoids exert pleiotropic effects on various aspects of cell function that can explain their interference in different stages of cancer development. This chapter focuses on processes that are important for the regulation of cell proliferation, including cell cycle progression, growth factor signaling, and gap junctional intercellular communication. Additional mechanisms have been suggested to underlie the anticancer activity of carotenoids, including antioxidant (this volume, Chapter) and pro-oxidant (this volume, Chapter) effects, antigenotoxic actions (82,83), and immunomodulation (84,85).

Survival And Functional Recovery Of Xenografts In Preclinical Models

Although these data are generally encouraging, xenotransplants are nearly completely killed following transplantation (7). Even with extensive immunosuppression, at least 90-95 of the implanted allo- or xenogeneic cells die because of intrinsic developmental signals, damage incurred during cell preparation, inadequate trophic support, and oxidative stress (1315). Increasing the numbers of cells implanted, or protecting the cells with trophic factors and antioxidants, can partially overcome nonimmunological cell death, but cell- and antibody-mediated rejection processes still actively kill the transplanted cells. This happens, despite that the inflammatory response occurring to CNS grafts is relatively minor, compared to rejection of peripheral tissue grafts. The relatively low immunological reaction in the brain results partly because neurons express virtually no major histocom-patibility complex (MHC)-I, and the blood-brain barrier restricts the entry of complement and immune cells...

Specific Morphological Features Of Neurones

Lysosomes are found in the cell body and seen as 0.25-1 m diameter acid phosphatase-containing vesicles that are strongly osmiophilic in electron micrographs (Fig. 1d, Fig. 4a). They contain many other hydrolytic enzymes and play an important role in the recycling of material from effete organelles and removal of unwanted material in the cell body. Enzymatic deficiencies in lysosomes can result in the lethal accumulation of partially metabolised material in neurones that characterise the lysosomal storage diseases. The capacity of neurones to take up and transport some foreign material from the periphery makes the degradative function of lysosomes important. Retrogradely transported tracers, such as horseradish peroxidase, are destroyed by lysosomes after about 4 days. In contrast, the retrograde tracer Fluorgold remains for many months in neurones although it does induce lysosomal proliferation although. In some cases (e.g. retrogradely transported ricin or diphtheria toxin) the...

Transcription Factor Activation And Gene Regulation By Vasoactive Agents

Effects of MEK inhibitor and antioxidants on 5-HT-induced activation of p42 p44 MAPK. Bovine pulmonary artery smooth muscle cells (SMCs) were pretreated with PD98059 (PD, 10 M), tiron (2 mM), N-acetylcysteine (NAC, 10 mM), or Ginkgo biloba (GK, 200 J,g mL), then incubated with 5-HT. Phosphorylation of p42 p44 MAPK was determined by Western blot analysis using the phospho-specific antibody. The figure was reproduced from Lee et al. (43), with permission. Fig. 6. Effects of MEK inhibitor and antioxidants on 5-HT-induced activation of p42 p44 MAPK. Bovine pulmonary artery smooth muscle cells (SMCs) were pretreated with PD98059 (PD, 10 M), tiron (2 mM), N-acetylcysteine (NAC, 10 mM), or Ginkgo biloba (GK, 200 J,g mL), then incubated with 5-HT. Phosphorylation of p42 p44 MAPK was determined by Western blot analysis using the phospho-specific antibody. The figure was reproduced from Lee et al. (43), with permission.

Micronutrient Metabolism

Deficiencies of water-soluble vitamins, including vitamin C, and the B complex compounds, are particularly common in cirrhotic patients with active alcoholism. Similarly, low plasma concentration of fat-soluble vitamins (A, E, D, and K) may occur in patients with cirrhosis of any aetiology 72 . Abnormalities in vitamin activation, conversion, release, and transport by carrier molecules all result from hepatocellular injury. Low serum levels of some trace elements, such as zinc and selenium, have also been detected in cirrhotic patients 73 . In most patients with liver cirrhosis, while micronutrient deficiencies are clinically silent, the biological antioxidant effects of micronutrients are notably impaired.

Simulated Ischemia In Flowadapted Endothelial Cells In Vitro

Naling molecules required prior flow adaptation of the cells and were inhibited by pretreatment of cells with either of the antioxidants -acetylcysteine or DPI. Thus, generation of ROS by the endothelial cells with ischemia appears to represent a cell signaling mechanism.

ATP depletion cation shifts and oxygenderived free radical injury

Interestingly, the rate and extent of increase in total renal sodium (largely intracellular) in the IPRK was also reduced by pretreatment with dimethylthiourea (DMTU) and dimethylsulfoxide (DMSO), both scavengers of oxygen-derived free radicals (OFR) 94 . These studies supported similar indirect evidence for OFR-induced injury during reperfusion 146, 147 . The

LMF as a Pleiotropic Mediator

An interesting question is whether there is any survival advantage to tumours that produce cata-bolic factors such as LMF. Tumours preferentially use glucose rather than lipids as an energy source due to the low oxygen tension. Since UCP-2 is thought to be involved in counteracting oxidative damage, if LMF induced UCP-2 expression in the tumour, this may be important in detoxifying free radicals, which are produced in excess during cachexia. Many anticancer drugs, such as adri-amycin, bleomycin, and mitomycin C, exert their action through the generation of reactive oxygen radicals, and induction of UCP-2 by LMF may protect tumour cells from their cytotoxic action. This important issue was recently addressed experimentally, and the results showed that LMF antagonises the antiproliferative effect of agents working through a free-radical mechanism, which may partly explain the unresponsiveness to chemotherapy of cachexia-inducing tumours 26 .

Reflectance Measurement of Carotenoids in Skin

300 Chroma Meter

Levels of skin carotenoids as compared to nonsmokers. Furthermore, the study showed that people with habitual high sunlight exposure have significantly lower skin carotenoid levels than people with little sunlight exposure, independent of their carotenoid intake or dietary habits. When analyzed by a chemical assay based on urinary malondialdehyde excretion, an indicator of oxidative lipid damage, people with high oxidative stress had significantly lower skin carotenoid levels than people with low oxidative stress. Again, this relationship was not confounded by dietary carotenoid intakes that were similar in both groups. These observations provide evidence that skin carotenoid resonance Raman readings might be useful as a surrogate marker for general antioxidant status (89). Studies are also underway to determine whether low skin Raman measurements may be associated with increased risk of various skin cancers. Initial studies have demonstrated that lesional and perilesional Raman...

Mitochondrial Checkpoints of TCell Activation and Apoptosis

Ppp Ribose Serine

Overview of mitochondrial redox and metabolic checkpoints of T-cell activation and apoptosis signals. Antigen binding-initiated signaling through the T-cell receptor complex CD3 and the CD28 costimulatory molecule activate phosphatidylinositol 3-kinase (PI3K) and protein tyrosine kinases (PTK). Increased cytosolic Ca2+ concentration activates the serine threonine phosphatase calcineurin, which dephosphorylates the nuclear factor for activated T cells (NFAT). Dephospho-rylated NFAT can translocate to the nucleus, where it promotes transcription of IL-2 in concert with AP-1, NF-kB, and Oct-1. Ca2+ flux into mitochondria increases production of ROS and NF-kB activation (88-90). Mitochondrial membrane integrity is maintained by a balance of membrane-stabilizing bcl-2 and bcl-XL and pore-inducing bax and bad (34) as well as the metabolic capacity to synthesize reducing equivalents, NADPH, GSH, and TRX. Controlled increase of ROS levels activates NF-kB and promotes cell growth....

Free Radical Scavenging by Carotenoids

In the human body, a range of ROS are produced, including 1O2, OH , O2-, and H2O2 (1). The mechanisms and rate of scavenging of free radicals by carotenoids in solution is strongly dependent on the nature of the ROS itself (33). Carotenoids such as b-carotene are very reactive to peroxyl radicals but much less so to OH and O2 (21). The structure of the carotenoid molecule is also important, and the nature and position of substituent groups on the carotenoid molecule may directly affect its antioxidant ability. The reactivity of a number of carotenoids with ROS has been examined (34,35) and differences in reactivity between molecules shown to be related to differences in their electron density profiles. For example, the effect of keto groups at C-4 and C-4' in astaxanthin and canthaxanthin (which significantly alters their electron density profiles), or hydroxy groups at C-4 and C-4' in isozeaxanthin is to reduce the reactivity of these molecules by preventing hydrogen abstraction from...

Markers of ischemia

Human serum albumin is a complex protein with an N-terminus capable of binding metals such as cobalt. During ischemic events, free radicals are released, resulting in acetylation of the N-terminus and alteration of the cobalt binding site. Therefore, ischemia-modified albumin (IMA) is unable to bind cobalt, and the free metal can be detected using a specific assay. The higher the amount of free cobalt detected, the greater the degree of ischemia 64 . The advantage of this test is that IMA becomes positive within a few minutes of the ischemic event. A positive test despite negative tro-ponin places the patient at high risk for a cardiac event 65 . It has a sensitivity of 83 , specificity of 69 , negative predictive value (NPV) of 96 , and a positive predictive value (PPV) of 33 . Sensitivity increases to 92 when combined with positive ECG findings, and 95 when combined with positive troponin and ECG. Conversely, a combination of negative IMA, negative troponin, and negative ECG has 99...

Puzzles And Perspectives

Complex, which consists of BRCA-associated proteins that are involved in the recognition and repair of defective DNA (143). Le Page and coworkers (144) have shown that the products of the BRCA1 and BRCA2 genes are required for transcription-coupled repair of oxidative 8-OHdG lesions in human cells, and BRCA1 nullizygous embryonal cells are unable to perform transcription-coupled repair of oxidative DNA lesions (145). These observations would be consistent with the suggestion (from a single laboratory at the time of this writing) that the FANCC protein plays a direct role in the repair of oxidatively damaged DNA (129). The putative FA-BRCA connection should therefore shed new light on the oxidative stress hypothesis in FA and perhaps clarify some of the controversy surrounding the idea that the FA family of proteins represents a new class of proteins with direct or indirect antioxidant functions. It is quite obvious that warm-blooded and long-lived mammals that generate high endogenous...

Case study traceability of plastic materials for food contact

Plastic materials consist at the minimum of polymers (sometimes referred as 'resins') and one or more additives the additives can be added to improve the processability of the polymer (e.g., antioxidants, slipping agents, etc.) or to impart specific physical and technological properties to the finished product

Degradation products and impurities

Dltdp Machanism

Many of the reaction products derived from stabilisers can be predicted because they are added to react with free radicals or chemicals released during processing of the polymer. Many plastics will react with oxygen during processing and if additives are not present to reduce this autoxidation, the polymer will undergo 'ageing' reactions that have detrimental effects on their properties, such as discolouration, surface cracking and poorer physical properties such as impact strength. The most important primary antioxidants used in food contact polymers are usually based on hindered phenols. These react by interfering with the chain propagation reactions, where oxygen reacts with an alkyl free radical in the polymer chain (P ) to form a peroxy radical (PO 2). These propagation reactions tend to occur when the polymer is at high temperature (for example during processing) or under stress and where a certain amount of oxygen is available. A simple primary antioxidant is BHT...

Chemical migration from food packaging adhesives

In most cases an adhesive is not simply composed of the high molecular weight 'gummy' materials discussed in section 14.2 but it also contains additives which provide specific characteristics. A variety of additive types may be used, including carriers (water or organic solvents), plasticisers, tackifiers, thickeners and fillers, surfactants, biocides and fungicides, catalysts, pH adjusters, emulsifiers, waxes and antioxidants. Adhesives by their 'gummy' nature are difficult to clean up. This is in contrast to bulk polymers where unwanted substances can be removed by vacuum stripping. Hence a variety of different materials in adhesives can, in theory at least, migrate into food

Epidemiologic Evidence for Metal Involvement in Melanin Etiology and Pathogenesis

There is a considerable amount of occupational epidemiology that suggests that high exposure to metals or polyphenol chlorinated biphenyls (PCPs) is a risk factor for melanoma (Austin and Reynolds 1986 Loomis et al. 1997). Relative risks for printers, lithographers, electrical utility, and semiconductor workers are consistently elevated (1.5-4.0), and in many studies a dose and time exposure effect are evident (i.e., Loomis et al. 1997). Dietary studies also implicate excessive alcohol ingestion as a risk factor (RR above 2.0) (Millen et al. 2204), probably working through its metabolite acetaldehyde, which results in increased ROS. In contrast, broad dietary studies suggest that dietary antioxidants are protective against melanoma development (RR 0.7).

Neurodegenerative Diseases And Apoptosis

Oxidative Decarboxylierung

ALS is a progressive neurological disorder that is associated with the death of motor neurons in the spinal cord and brain, leading to paralysis. ALS occurs in both sporadic and familial forms, and about 20 of the familial forms are associated with mutations in the gene encoding the cytosolic CulZn superoxide dismutase-1 (SOD 1) (Rosen et al., 1993). Transgenic mice, which express human mutant SOD1, develop a motor neuron degenerative syndrome that closely resembles ALS (Gurney et al., 1994). The mutations do not decrease antioxidant activity of the enzyme, but result in the gain of an adverse pro-apoptotic activity that may involve increased peroxidase activity. Through interactions with hydrogen peroxide or superoxide anion, the mutant enzyme may induce oxidative damage to membranes and disturbances in mitochondrial function that make neurons vulnerable to excito-toxic apoptosis (Kruman et al., 1999).

Redox Status of Melanocytes and Melanoma Cells

Fig. 1 The altered state of melanin during melanomagenesis. Melanin is normally in a reduced antioxidant state. Exposure to ROS leads to an oxidized condition which facilitates binding of transition metals (and other compounds such as polyphenol chlorinated biphenyls). Metal uptake into the cell is closely regulated by a family of metallothioneins. This situation sets up the oxidized melanin as a redox generator, which leads to increasing intracellular oxidative stress, a widespread adaptive response including TF upregulation, cell death, a high rate of cellular turnover and secondary intrinsic drug resistance (see Meyskens et al. 2001) Fig. 1 The altered state of melanin during melanomagenesis. Melanin is normally in a reduced antioxidant state. Exposure to ROS leads to an oxidized condition which facilitates binding of transition metals (and other compounds such as polyphenol chlorinated biphenyls). Metal uptake into the cell is closely regulated by a family of metallothioneins....

Relationship Of Molecular And Cellular Defects To Clinical Features

The neurological abnormalities found in the more severely affected patients with XP are less readily explained. One possibility is that free radicals, which are abundant in neurons, produce lesions in the DNA that are normally repaired by NER. In XP cells, these lesions accumulate, resulting in premature neuronal death (136). Recently, it has been suggested that 8,5'-(S)-cyclo-2'-deoxyadenosine (cy-clo-dA), a free radical-induced bulky lesion that is repaired extremely poorly in

Oxidation Products of Carotenoids

The different mechanisms by which carotenoids scavenge ROS may lead to a variety of carotenoid free radicals and adducts. These in turn determine the nature of the final reaction products. The potential harmful or beneficial effects of carotenoid oxidation products are an important consideration in assessing their biological effects. The structure of carotenoids, with its extensive conjugated double-bond system, means that the number and type of autoxidation products of molecules such as -carotene may be very complex, especially as the sites for attack include the polyene chain as well as the -ionone end groups. Identification of the reaction products resulting from the oxidation of molecules such as -carotene and lycopene can, in theory, provide useful information on the The nature of the oxidizing species itself may have a marked influence on the reaction products found. For example, while Handelman et al. (8) observed a similar set of reaction products under both spontaneous and...

Oxidative And Nitrative Stress In Ad

Damage resulting from excessive production of reactive oxygen species (ROS), a condition known as oxidative stress (10), is evident in the AD brain in the form of oxidized proteins and lipids, and nuclear, and mitochondrial deoxyribonucleic acid (11-21). Such oxidative damage has a regional distribution that parallels the density of senile plaques, being greatest in the parietal lobe and hippocampus and low in the cerebellum (15). In view of the corresponding locations of senile plaques and oxidative damage in the AD brain, it is interesting that AP is not only neurotoxic (22-24), but the underlying mechanism involves increased ROS generation and oxidative stress (25). Furthermore, the neurotoxicity of AP in vitro is blocked by several antioxidants (26), including a-tocopherol (vitamin E ref. 27), curcumin (28), and melatonin (29). It has been sug gested that one way that Ap may mediate increased ROS production is by impairing the glutathione (GSH) antioxidant system (30). However, it...

Modulation By Carotenoids Of Cytochrome P450 Enzyme Activities In Animal Studies

The authors speculated that the lack of phase I induction in conjunction with the enhancement of GST activity indicated promise for RPO as an inhibitor of carcinogenesis. Further work on the modulatory effects of carotenoids on cytochrome P450 phase I and phase II enzyme activities in animal models was conducted by a research group based in Dijon, France and reported in a series of publications in the 1990s (9,11,12,14,19,20,27,28). These workers noted that many prospective epidemio-logical studies have suggested a putative cancer prevention role for carotenoids found in fruit and vegetables. Krinsky (8) has also demonstrated the anti-genotoxic properties of carotenoids in vivo and in vitro. The antioxidant properties of carotenoids have been commonly cited as a potential explanation for their anticarcinogenic and antigenotoxic effects. However, these effects might also be explained, in part, by modulatory effects on phase I and II enzyme systems. In...

Muscle Mass Changes Sarcopenia

A number of mechanisms are thought to cause sarcopenia, including selective decline and changes in motor-unit organisation, contraction-induced injuries, deficient satellite-cell recruitment, increased free radicals and oxidative stress, and age-related accumulation of mitochondrial abnormalities (mitochondrial DNA mutations and electron transport system abnormalities) 55 . More generally, sarcopenia may be considered partly the result of the withdrawal of anabolic stimuli (sex steroids, growth hormones, physical activity, dietary proteins, insulin action), which are prevalent in men, and possibly an increase in cata-bolic stimuli (subclinical inflammation, production of catabolic cytokines such as TNF-a, IL-6, IL-1 3), which are prevalent in women 56 . According to a recent theory on aging, the increase in body fat may have an important role in the increase of pro-inflammatory cytokines. In fact, several studies have demonstrated that adipose tissue secretes IL-6 and TNF-a 26 . The...

Parp Inhibition By Gene Manipulation

Three strains of mice with PARP gene deletion have been independently generated.35-37 They provide an invaluable tool to reassess the biological functions of PARP at the whole-animal level. It is perhaps not entirely surprising that mice without PARP can be produced and reproduced, if one considers that PARP activity is largely dependent on DNA damages. Such DNA damage is often elicited by exogenous chemicals, e.g., monoalkylating agents or ionizing y irradiation, and sometimes due to excessive free radicals produced endogenously in a disease condition. Without exposure to the obnoxious genomic toxins, homozygous PARP knockout (PARP-7) mice are neither embryonic lethal nor grossly abnormal in their life span and in several generations reproduced so far. However, close scrutiny at the cellular level has revealed differences in cell cycle distribution and apoptosis execution between the wild-type and homozygous PARP deletion.

Reactions Of Carotenoids In Biological Systems Interactions With Their Environment

In biological systems carotenoids rarely, if ever, occur as free (monomeric) molecules in solution. Rather they are predominantly found associated (often very tightly) with protein or lipoprotein structures, which may have a profound effect on the properties of the carotenoid molecule, affecting the way that these molecules function and may govern, at least in part, their interaction with ROS, for example. It should be remembered that carotenoids also directly influence their environment so that carotenoids generally bring about a degree of stabilization and are at the same time stabilized. Britton (35) and more recently, Young and Lowe (56) have discussed the role of a number of factors that may influence the antioxidant (or even promote pro-oxidant) activities of carotenoids in biological systems. These are (a) its structure (i.e., size, shape, and the nature, position, and number of substituent groups) and physical form (aggregated or monomeric, cis or trans configuration, etc.)...

Synergistic Inhibition Of Cancer Cell Growth By Combination Of Various Carotenoids And Other Micronutrients

The use of a single plant-derived compound in human prevention studies has not been particularly successful as evidenced from the large intervention studies carried out with -carotene (7-9,11,16). These results seem to indicate that the beneficial effects of diets rich in vegetables and fruit are not related to the action of a single compound but rather to the concerted action of several micronutrients, which when used alone are active only at high (and sometimes toxic) concentrations. To support this hypothesis, it has to be shown that plant-derived constituents, such as carotenoids, have the ability to act synergistically with other compounds in inhibiting cancer cell growth. We have been studying the anticancer activities of combinations of various micronutrients or their metabolites, including carotenoids ( -carotene, lycopene, phytoene, phytofluene, and astaxanthin), polyphenolic antioxidants (e.g., carnosic acid from rosemary), an organosulfur compound (allicin from garlic), the...

Mark A Lane George S Roth and Donald K Ingram Summary

Caloric restriction remains the only nongenetic intervention that has been consistently and reproducibly shown to extend both average and maximal lifespan in a wide variety of species. If shown to be applicable to human aging, it is unlikely that most people would be able to maintain the 30-40 reduction in food intake apparently required for this intervention. Therefore, an alternative approach is needed. We first proposed the concept of caloric restriction (CR) mimetics in 1998. Since its introduction, this research area has witnessed a significant expansion of interest in academic, government, and private sectors. CR mimetics target alteration of pathways of energy metabolism to potentially mimic the beneficial health-promoting and anti-aging effects of CR without the need to reduce food intake significantly. To date, a number of candidate CR mimetics including glycolytic inhibitors, antioxidants and specific gene-modulators have been investigated and appear to validate the...

Pivotal and emerging issues in FDAs approach to safety assessment

Exposure estimates derived from packaging factors are 'averages' across the U.S. population and may be thought of as 'per capita' estimates. FDA believes that this 'per capita' -based approach to estimating exposure to food packaging components is appropriate because consumer selection of food is not generally dependent on the type of packaging rather, it is dependent on the eating habits and spending preferences of the consumer. In fact, one criticism of FDA's approach to consumer exposure for packaging materials is the assumption that a food(s) eaten by a given consumer will have been packaged with the same material 100 of the time. For example, if a notifier proposes use of an antioxidant in high-density polyethylene, the consumer is assumed to ingest the selected food(s) only if it is packaged in the high- density polyethylene with the antioxidant, even though the food(s) may be packaged in other materials as well. With regard to selecting or developing an appropriate CF for a FCS...

Micronutrients Cancer

Supplementation reduces risk of cancer.5,6 An essential component of antioxidant enzyme systems that can protect cells and DNAfrom oxidant damage. Deficiency increases risk of cancer An antioxidant that protects cells and DNAfrom oxidant damage.10 Particularly effective in reducing risk of lung cancer11 and stomach cancerfrom processed meats containing nitrites12 An antioxidant that protects cell membranes and DNAfrom oxidant damage. May reduce risk of cancer6,13-15 Fig. 5.20 Antioxidant vitamins and colonic polyps. Fig. 5.20 Antioxidant vitamins and colonic polyps.

Carotenoids and Radicals Interactions with Other Nutrients

Ascorbic Acid Quench

A nutrient is defined as any substance that has nutritious qualities, i.e., that nourishes or promotes growth, and one that can be metabolized by an organism to give energy and build tissue. In this chapter a nutrient is assumed to be an amino acid, carotenoid, vitamin C, vitamin E, and other antioxidants such as polyphenols (Fig. 1 shows the structures of some important antioxidants discussed in chapter). While carotenoids, vitamin E, and vitamin C are often regarded as our most important dietary antioxidants, little is known of their possible interactions. The aim of this chapter is to discuss such interactions and to suggest how these may explain possible synergistic protective effects as well as how deleterious effects could arise. The carotenoids we consume, from our foods, food colorants, and possibly as dietary supplements, are thought to be antioxidants both by quenching singlet oxygen and by scavenging free radicals. This chapter concerns free radical reactions readers...

Cardioprotective Genes

There are several genes that could be considered for protection of the heart during ischemia. In previous studies, we showed that antisenses to angiotensin II type-1 receptor (23,24), antisense to adrenergic -receptor (25), or antisense to angiotensin-converting enzyme (26) protect rat hearts from ischemia-reperfusion injury. Recent use has shown that heme oxygenase-1 (HO-1) is cardioprotective when delivered in a vigilant vector (27). HO-1 degrades the prooxidant heme and generates carbon monoxide and antioxidant bilirubin (28). Alternatively, superoxide dismutase (SOD) protects the heart against superoxide radicals generated during ischemia-reperfusion (28,29). Thus, these genes are good choices for cardioprotective transgenes in the vector.

Corroborative Results From Genetic And Pharmacological Inactivation Of Parp

The PARP knockout mice also have been used extensively either to confirm or to explore the role of PARP activation in various animal models of human diseases. One of the early implications for its role in pathogenesis came from the finding that PARP activation was the culprit of streptozotocin-induced diabetes, an animal model to study type 1 diabetes.97 In P-islet cells, free radicals derived from streptozotocin catabolism damaged DNA and activated PARP. Consequently, depletion of NAD due to PARP activation prohibited the release of insulin and led to cell death, as PARP inhibitors such as nicotinamide and 3-aminobenzamide prevented stretptozo-tocin toxicity.98 Three groups have now independently replicated the studies in PARP knockout mice, and all demonstrated that PARP gene deletion renders mice resistant to P-islet cell destruction and hyperglycemia after streptozotocin treatment.36,45,46 In the nervous system, PARP activation was found to mediate glutamate excitotoxicity and...

Inhibitory Effect Of Shosaikoto On Hepatic Fibrosis

In investigating the mechanism by which Sho-saiko-to inactivates HSCs, Kakumu et al. (1991) showed that Sho-saiko-to enhanced the in vitro production of interferon (IFN)-y and antibodies to the hepatitis B core and e antigens, produced by peripheral blood mononuclear cells from patients with chronic hepatitis (Kakumu et al., 1991). IFN-y is a potent cytokine with immunomodulatory and anti-proliferative properties, which inhibits HSC activation and ECM production in in vivo models of hepatic schistosomiasis and carbon tetrachloride-, DMN-, and PS-induced hepatic fibrosis (Czaja et al., 1989 Rockey et al., 1992 Rockey and Chung, 1994 Baroni et al., 1996 Sakaida et al., 1998b). Oxidative stress, including the generation of ROS, has also been implicated as a cause of hepatic fibrosis. There is evidence to show that the products of lipid peroxidation modulate collagen gene expression (Houglum et al., 1991 Iredale et al., 1992), suggesting that lipid peroxidation is a link between liver...

Results And Discussion

Antioxidant Agents Help Cell Viability and Dye Loading Figure 1. Effects of antioxidant agents in loading of cells from acute brain slices with Ca2+ fluorescent dyes. (A) Indo-1 loaded cells from the CA1 hippocampal region of a young rat at postnatal day 10 following slicing and incubation procedures in the presence of antioxidant agents. Most of the neuronal dendrites resulted well loaded. The time series of pseudocolor images illustrates the Ca2+ i changes occurring in these neurons following perfusion of the slice with 60 mM KCl. The sequence shows the Ca2+ increase in pyramidal neurons occurring several seconds before that in astrocytes (open arrows). The R405 485 is displayed as a pseudocolor scale. Sampling rate 2 seconds. The stimulation with high K+ extracellular solution was obtained by iso-osmotic replacement of Na+ with K+. (B) Kinetics of the Ca2+ j changes in the neurons (continuous lines) and astrocytes (dotted lines), indicated by arrows in panel A, following KCl...

Possible Metabolic Targets for CR Mimetics

CR mimetics have been proposed that target a number of pathways related to energy metabolism such as glycolysis inhibitors, antioxidants, sirtuin regulators, and insulin sensitizers. As summarized previously, inhibition of glycolysis remains a promising target despite our disappointing results with 2DG. Given the popularity and general acceptance of the Free Radical Theory of Aging, antioxidants have been the focus of many studies in biogerontology (15). Treatment with antioxidants has occasionally been shown to lead to an increase in average lifespan however, reproducible increases in both average and maximal lifespan in mammals have not been observed.

Endothelial control of coronary vascular tone

Muscle Endothelium Adenosine

Nitric oxide travels from the endothelium to the vascular smooth muscle where it stimulates guanylate cyclase to produce vasodilatory cGMP. NO has a very short half life (in the order of seconds or smaller), and thus just acts at the site where it is formed. Physiological stimuli that cause release of NO include acetylcholine, increased flow (via shear force), bradykinin,15 hypoxia, and (somewhat surprisingly) endothelin.16 Damage to the endothelium (for example, mechanical insult, formation of free radicals, early atheroma) results in inhibition of NO release. In addition, in the presence of a non-intact endothelium, acetylcholine causes vasoconstriction (by a direct effect on vascular smooth muscle), and angiotensin II, platelet-derived growth factor, free radicals, and thrombin stimulate the release of vasoconstrictory endothelin. ischaemia, O2-derived free radicals, and shear stress.29

Molecular Mechanisms in Angioprevention

Our approach to analysis of the effects of an-gioprevention compounds on endothelial cells has been through employment of microarray analyses (Pfeffer et al. 2005). These studies have demonstrated that the flavonoids and antioxidant compounds all specifically target the NF-kB pathway in endothelial cells (Pfeffer et al. 2005). This can be expanded to include the vast majority of the numerous potential cancer chemopre-vention agents that have been studied by different laboratories these have been shown interfere with pathways leading to NF-kB activation, and to repress AKT activation (Aggarwal and Shisho-dia 2004 Dorai and Aggarwal 2004 Pfeffer et al. 2005 Tosetti et al. 2002). The exceptions to this are the compounds devoid of antioxidant activity, such as the retinoid 4HPR (Ferrari et al. 2005) and possibly the steroid analogs. We have shown that repression of the NF-kB and Akt pathways produces downregulation of downstream elements such as p21, p53, and survivin (Dell'Eva et al.,...

Short Life Is Associated With Increased Sensitivity To Stress

Isolated on the basis of its hypersensitivity to a number of volatile anesthetics (38). As indicated above, both genes have been cloned and the specific mutations identified (39,40). The mutations confer a considerable overlap in phenotypes (P.S.H., N.I., and P.G. Morgan, unpublished data). Most notably, hypersensitivity to free radicals was increased in both as measured during development. In addition, whereas hyperoxia had minimal effects on the life span of wild-type animals, the same treatment dramatically shortened the life spans of both gas-1 and mev-1 mutants. However, the gas-1 and mev-1 mutations differentially affected mutability and anesthetic sensitivity. Specifically, gas-1 but not mev-1 animals were hypersensitive to volatile anesthetics. In addition, whereas the gas-1 mutation had little, if any, effect on spontaneous mutation frequency, mev-1 animals had significantly elevated mutation frequencies at all oxygen concentrations tested, including at atmospheric.

Antioxidative Protective Strategies

The first is direct modification(s) of the hemoglobin molecule including chemical and or genetic engineering of the protein crosslinking of red blood cell antioxidant enzymes, nitroxides, trolox (vitamin E analog), adenosine and reduced glu-tathione to the hemoglobin molecule or even the use of SFH that contains red blood cell antioxidant enzymes (for review, see Alayash, 2004). The second is the indirect use of reducing agents or antioxidants. We have in recent years investigated the role of reducing agents in controlling or suppressing hemoglobin oxidative reactions in vitro and in vivo.Two biologically compatible reducing agents, selenium and ascorbic acid, were investigated in order to determine their reducing action on hemoglobin oxidation reactions in vitro and in vivo. Based on their one-electron reduction potentials in the well-established thermodynamic pecking orders of free radicals and antioxidants (Buettner, 1993), Selenium...

A link between proximal and distal tubular injury and recovery

The studies in the IPRK and in vivo outlined in the previous section highlighted that both proximal straight tubules (S3) and MTAL were potential targets for hypoxic injury. The anatomical proximity of these tubular segments emphasizes the location of both segments in a region under constant threat of hypoxia. Outer medullary hyperaemia is a consistent phenomenon following renal artery clamping to induce acute renal failure first described by Mason and others 158, 159 . It was hypothesized that erythrocyte aggregation and stasis in the outer stripe was produced by oxygen-derived free radicals causing extravasation of plasma and local hemoconcentration, however free radical scavengers were of no benefit, whereas hemodilution and raised intraarterial pressure each reduced both medullary hyperaemia and tubular necrosis 158 . The phenomenon of medullary hyperaemia has not been as well described in the IPRK, probably because eryth-rocytes are usually not added to the perfusate and ischemia...

Heme moiety of hemoglobin

Hemoglobin is a tetrameric protein composed of two alpha (a) and two beta (p) chains. Each globin chain contains an iron-bearing heme prosthetic group. The porphyrin ring structure of heme contains four pyrrole rings. Iron is bound to the four nitrogen atoms of the ring and to the imidazole nitrogen of the proximal histidine at positions 87 and 92 in the alpha and beta chains, respectively. Heme containing iron in the ferrous (Fe2+) state is capable of sharing an electron to allow the reversible binding of oxygen. However, the higher oxidation states of heme iron, such as the ferric (Fe3+) or ferryl (Fe4+) forms, cannot reversibly bind molecular oxygen. Inside the red blood cell, a number of different factors contribute to the maintenance of the functional ferrous heme form. The positioning of heme in a region surrounded by non-polar residues excludes water molecules, thus protecting ferrous iron from oxidation. In addition, the tetrameric conformation of hemoglobin also assists in...

Adaphostin Tyrosine Kinase Inhibitor Or Nontyrosine Kinase Inhibitor

Several groups have reported that in vitro treatment of cells with adaphostin results in a rapid (within eight hours) down regulation of p210Bcr-Abl protein (1013). In addition, adaphostin treatment leads to a rapid rise in intracellular reactive oxygen species (ROS) in both Bcr-Abl expressing and nonexpressing cells (11,13). Pretreatment of cells with antioxidants diminishes the cytoxicity of adaphostin but has no effect upon the down regulation of Bcr-Abl protein indicating that this phenomenon precedes or parallels the generation of ROS (11,13). The down regulation of Bcr-Abl protein by adaphostin was similarly unaffected by proteasome inhibitors and an inhibitor of protein translation, cycloheximide (11). Decreased levels of p210Bcr-Abl protein have also been reported for cells treated with AG957 (10,14) and this has been attributed to the drug, causing covalent crosslinks between Bcr-Abl and its substrate proteins, Grb2 and Shc (14). It has been suggested that the p210Bcr-Abl...

Oxidative Stress And Aging

The free radical theory of aging has consistently lacked direct, definitive support. This primarily has been due to the failures of many intervention studies. The theory lost considerable standing among researchers during the early 1990s, particularly in the light of the then growing evidence that specific genetic loci can influence the rate of aging in model organisms such as Caenorhabditis elegans. In fact, by the mid-1990s, prominent researchers in the molecular gerontological community voiced the opinion that specific genetic regulatory mechanisms, and not oxidative mechanisms, were the likely place to look for the control of aging, and that antioxidant interventions would never forestall aging. The model that then gained adherents postulated specific regulatory mechanisms rather than entropic processes. More recently still, a synthesis of the two views has emerged, as some of the C. elegans genes implicated in the aging process (sometimes called geronto-genes ) have revealed...

Loosing Control Inflammatory Escalation during Multiple Sclerosis

During multiple sclerosis (MS), circulating myelin-specific T cells from the lymphatic tissue cross the blood-brain barrier and enter the brain parenchyma, where they engage in close contact with microglial cells, the antigen-presenting immunoeffector cell of the CNS. As a consequence of this contact, microglial cells become activated, stimulate B cells to produce myelin-specific antibodies, and release oxygen and nitrogen free radicals and toxic cytokins, which then attack neurons and the myelin sheath. Together with inflammation, neuronal pathology involving axonal transection plays a pivotal role in MS, and the corresponding animal model disease EAE, even during the early phase of inflammation (Ferguson et al. 1997, Meyer et al. 2001, Trapp et al. 1998, Diestel et al. 2003, Aktas et al. 2005). It has become evident that long-term disability in MS correlates better with ax-onal damage than with the degree of demyelination (Bjartmar et al. 2003). Moreover, cortical thinning has been...

Simultaneous Cross Linking Polymerization

Simultaneous cross-linking polymerization allows one to prepare gel network in a single step in which polymerization as well as cross-linking processes occur simultaneously 144-148 . In these polymerizations, apart from monomer, a cross-linking agent (functionality 3) is used to allow three-dimensional network formation. In such polymerization process, the free radicals formed in the initiation step of the reaction tend to react with monomer and cross-linker molecules to obtain polymeric chains along with some cross-linking points. Intermolecular cross-linking leads to the formation of branched and highly network structure that ultimately is responsible for macroscopic gel product. The intramolecular cross-linking process is responsible for the formation internally cross-linked polymeric chain networks. Figure 6.12 illustrates the difference between inter- and intra-cross-linking behaviors in the simultaneous cross-linking polymerization process. Emulsion Polymerization....

Vitamins and Minerals

Strenuous exercise produces free radicals in muscle, and oxidative damage (see pp.115) may contribute to slow recovery after exercise and early fatigue.13 Foods rich in antioxidants such as the carotenoids, vitamins E and C, and selenium should be consumed daily. In addition, supplemental vitamin E, at doses above those found in usual diets, may help protect exercising muscle from free-radical dam-age.14

Guide To Further Reading

New England Journal of Medicine 338 736-746. Fraser D R 1995 Vitamin D. Lancet 345 104-107 Greenberg E R, Sporn M B 1996 Antioxidant vitamins, cancer and cardiovascular disease. New England Journal of Medicine 334 1198-1190 Humphrey J H, Rice A L 2000 Vitamin A supplementation in young infants. Lancet 356 422-424

Tissue Response To Hemoglobin Metabolites And Possible Neuroprotection

Iron plays a role in neural injury as a potent pro-oxidant, whether it be in ICH, SAH, traumatic brain injury or ischemia. Acutely, iron can participate in chemistry that results in lipid, protein or nucleic acid oxidation, all of which may contribute to aging and neurodegenerative disorders (Zecca et al., 2004). This is confirmed by studies using antioxidants, which can scavenge ROS generated by iron, and others using the high-affinity iron chelator, desferoxamine (DFO), which binds iron and prevent its participation in chemical reactions that generate ROS. For example, potent antioxidants of the 21-aminosteroid class (U74500A) protected against hemoglobin-dependent neurotoxicity in cultured neurons, and the neuroprotection was effective even when the compound was added 8 hours following the beginning of hemoglobin exposure (Regan and Rogers, 2003). A second compound of this class, U74006F, was demonstrated to minimize vasospasm in a preclinical model of SAH in rabbits (Vollmer et...

See also Reactive Oxygen Oxygen Metabolism and Human Disease Superoxide Dismutase Catalase Glutathione Peroxidase

Large scale production of reactive oxygen species has the potential to inflict considerable damage on the tissues in which they are produced, a situation called oxidative stress. Antioxidant compounds, such as glutathione, vitamin C and vitamin E, and uric acid provide non-enzymatic protection against oxidative stress because they can scavenge ROS before the ROS can cause damage. Alternatively, antioxidant compounds can prevent oxidative damage from spreading, such as the chain reaction of lipid peroxidation. Vitamin E is the principal lipid-soluble antioxidant compound and plays an important role in preventing membrane damage. .' -Carotene and other carotenoid compounds related to vitamin A are lipid-soluble antioxidants that also play roles in free radical trapping. Glutathione plays an important role in cellular antioxidant protection. Vitamin C (ascorbic acid) is present in far higher amounts in cellular fluids and probably plays the predominant role in extracellular antioxidant...

Reactive oxygen species

Redox status, patients who are sick and have a poor antioxidant supply may be at higher risk. Oxidative damage is particularly dangerous in the microcirculation because gaps form between the endothelial cells resulting in excess leakage of plasma components into the interstitium. Such leakage disturbs the fluid balance between blood and tissue and alters the kinetics of delivery of intravascularly injected drugs and endogenous enzymes and hormones to various tissues. Thus it is important to remember that blood substitutes should not just be considered as oxygen carriers it is essential that their antioxidant capacity is adequate, because reperfusion of the circulation after loss of blood triggers production of ROS.

Microvessels And Intestinal Mucosa

It is well known that excess ROS oxidize lipids of the cell membranes. Lipid peroxidation damage of membrane components is thought to play an important role in increasing capillary permeability (Granger et al., 1981). Since H2O2 can easily diffuse across cell membranes (Henderson and Chappell, 1993), and O2 can traverse membranes via the chloride anion channel (Terada, 1996), it is likely that these reactive oxygen species will leave the microvasculature and gain access to other cells in the tissue. This action can have deleterious effects. For example, if the ROS reach mast cells in the interstitium they will cause the mast cells to degranulate (Kubes et al., 1993) and release a selection of inflammatory mediators, including histamine. Many studies show that histamine increases microvascular permeability (Fox et al., 1980 Horan et al., 1986 Wu and Baldwin, 1992 Baldwin and Thurston, 1995 Thurston et al., 1995). In addition, degranulating mast cells release eosinophil and neutrophil...

Caloric Restriction

The available evidence suggests that the capacity of an organism to maintain steady state is a prime determinant of longevity. Senescence-related loss of function is due to impairment of a homeostatic state and CR enhances longevity by increasing metabolic stability 161 . Evidence suggests that metabolic stability is a better predictor of longevity than metabolic rate, and an organism's ability to maintain stable levels of free radicals may be more important than how fast it produces them 162, 163 . CR delays deleterious consequences of aging by inducing a stable state of biological parameters that normally demonstrate aging-related declines 164, 165 . Moreover, in the presence of continued CR, a stable state in those parameters is maintained across the lifespan 161, 164 . Thus, it may be that changes in critical biological parameters result in functional decline in the aging brain, and CR may eliminate such changes by inducing a stable state in those parameters.

Cellular Response to Injury

CNS injury results in a rapid glial response around the injury site, leading to gliosis and formation of aglial scar. Although the functional role of glial scarring is not completely understood, it has been suggested that it protects neuronal function following injury. 9 Astrogliosis may for instance contribute to the clearance of glutamate, restoration and maintainance of ion concentrations, and provide anti-inflammatory cytokines as well as neurotrophic support.50 52 However, glial scarring can also be detrimental since it may impede axonal regeneration and thus interfere with neuronal repair. Reactive gliosis involves astrocytes, oligodendrocyte precursor cells, microglia macrophages, leptomeningeal fibroblasts, and eventually forms a scar that is a major impediment to axonal growth. Reactive astrocytes are characterized by a number of cellular changes, including hypertrophy, generation of long and tighdy packed cytoplasmic processes, increased production of the intermediate...

Group of Molecular Chaperones

HSP70 and HSP27, besides their putative role in thermo-tolerance, are of special clinical interest because they are thought to be involved in the MDR phenotype. HSP27 is a major target of phosphorylation upon cell stimulation and has been suggested to have a phosphorylation-regulated function 46 . HSP70 has long been recognized as one of the primary heat shock proteins in mammalian cells, and its structure is highly conserved during evolution. Both proteins have been repeatedly demonstrated to inhibit apoptosis induced by different chemotherapeutics, especially drugs that target topoisomerase II enzymes, such as anthracyclins and etoposide. Studies have shown that the production of reactive oxygen species (ROS) by these drugs has a major role in their apoptosis induction, while treatment with antioxidants increases cellular resistance to these agents 47 . Details about potential mechanisms for inhibition of apoptosis by HSPs can be found elsewhere 48, 49 .

Impaired Insulin Secretion

Once established, hyperglycemia exerts a deleterious effect on insulin secretion. Many studies have provided evidence that an acquired defect in insulin secretion is related to glucose toxicity. It is hypothesized that chronic oxidative stress is an important mechanism for glucose toxicity 32 . The increased expression of antiox-idant and antiapoptotic genes in islets may contribute to beta-cell survival during chronic hyperglycemia 33 . In addition, antioxidant treatment protected beta-cell mass in diabetic mice 34 . It has been shown that chronic exposure to a high level of glucose impaired potassium-channel function 35 , reduced glucose transporter (GLUT-2) expression 36 or led to loss of part of the beta-cell's differentiated phenotype 37 . However, glucose stimulates growth of the islet beta-cell mass and glucose protects against apoptosis 38 . This implies that glucose not only regulates the phenotype of existing beta-cells, but also regulates cell number. One can conclude that...

Biology And The Relationship Between Cancer And Aging

Although several hypotheses have been postulated, the cellular and molecular mechanisms regulating the physiological process of ageing and senescence have not been fully elucidated. Ageing cannot be considered to be directly responsible for the carcinogenic process but the susceptibility of older cells to environmental carcinogens may facilitate some molecular changes involved in carcinogenesis. Some of the mechanism of both geriatric and oncologic interest are the production of reactive oxygen species and free radicals, telomere length, control of tumor suppressor genes No clinically usable test is presently available along those lines.