Free Radicals

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...

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...

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...

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...

Do antioxidants have any activity in COPD

Since oxidant damage may be critical in the pathophysiology of COPD, antioxidant therapy is a logical approach 12 . Reactive oxygen species may be inhaled in cigarette smoke or generated by activated inflammatory cells within the lung, leading to reduced activity of antiproteases, increased production of inflammatory cytokines and direct inflammatory effects (Fig. 11.2). N-acetylcysteine was originally developed as a mucolytic, but has well documented antioxidant effects. Controlled trials have demonstrated that it reduces the frequency and severity of acute exacerbations of COPD 13 , and in an open study it significantly reduced the rate of decline in lung function 14 . It may therefore be useful in long-term management of COPD, but is not No studies with other antioxidants, such as vitamins C and E, have been reported in COPD. More effective antioxidants are now in development and should undergo clinical trials in COPD. It is likely that antioxidants may reduce the inflammation and...

Definition of Types of Antioxidants and Their Doses

It is important to distinguish between dietary (such as vitamin A, vitamin C, vitamin E, and caro-tenoids) and endogenous antioxidants (such as SH compounds, like glutathione and antioxidant enzymes), because they modify the effects of irradiation or chemotherapeutic agents on normal and cancer cells differently. It is equally important to define doses of these antioxidants, because their effects differ depending upon the dose. Antioxidant doses are often referred to as low, high, and toxic without specific reference to any biological criteria. For this review, low doses are referred to those that do not affect the growth of normal or cancer cells. In humans, antioxidant micronutrient supplements at about RDA doses can be defined as low dose. In tissue culture, vitamin C doses of up to 50pg mL, vitamin E (a-tocopherol) doses of up to 5 g mL, D-a-tocopherol succinate (aTS) doses of up to 2pg mL, retinoid doses of up to 5pg mL, and p-carotene doses of up to 1 pg mL can be defined as low...

Types of Antioxidants

Our hypothesis is based on the effect of dietary antioxidants in modifying damage due to irradiation or chemotherapeutic agents on normal and cancer cells. The other hypothesis does not distinguish between dietary and endogenously made antioxidants in modifying injuries produced by cancer therapeutic agents. Thus, if the conceptual framework and its respective experimental designs of one hypothesis are not extrapolated to the other, the current debates regarding the use of antioxidants during radiation therapy or chemotherapy can easily be reconciled without questioning the validity of the conceptual framework of each hypothesis. the effects of individual dietary and endogenously made antioxidants and their mechanisms of action are briefly described. All studies described below have been performed with high doses of dietary antioxidants and under experimental conditions in which the agents are present before and after the treatment with cancer therapeutic agents for the entire...

Effect of High Doses of Individual Dietary Antioxidants

Several studies have now established that high doses of individual antioxidant micronutrients such as vitamin A (including retinoids) (16-19), vitamin C (16, 17, 20), vitamin E (21-26), and carote-noids including p-carotene (27-30) inhibit growth and cause differentiation and apoptosis in cancer cells in culture. They also reduce the growth of tumors in animal models (27, 31-34) and certain human tumors (35-41) without affecting the growth of normal cells. More recently, we have shown that D-a-tocopheryl succinate (a-TS) inhibits the growth and reduces the levels of mitotic accumulation in human cervical cancer cells and human ovarian carcinoma cells, but it has no such effect on three lines of human normal fibroblasts (42). a-Tocopheryl succinate also increases the level of chromosomal damage in cancer cells without producing such effects on normal cells (43). The growth-inhibitory doses of these antioxidant micronutrients vary from one species to another for the same tumor type....

High Doses of Dietary Antioxidants Enhance the Effect of Chemotherapeutic Agents on Cancer Cells

The direct interaction between antioxidants and cancer therapeutic agents can initially best be tested on cancer cells in culture. Several cell culture studies have revealed that vitamin C, a-TS, a-TA, vitamin A (retinoids), and polar carotenoids including p-carotene enhance the growth inhibitory effect of most of the chemotherapeutic agents on some cancer cells in culture (8-10). Chemotherapeutic agents used in these studies include 5-fluor-ouracil (5-FU), vincristine, adriamycin, bleomycin, dacarbazine, cisplatin, tamoxifen, cyclophospha-mide, mutamycin, chlorozotocin, and carmustine. The extent of this enhancement depends on the dose and form of the antioxidants, the dose and type of chemotherapeutic agent, and the type of tumor cell. Some examples of antioxidant-induced enhancement of the effect of chemotherapeutic agents are described below. An aqueous form of vitamin E (a-TA) enhances the effect of vincristine on neuroblastoma cells in culture (10) (Fig. 11.5). Vitamin C...

Efficacy of Individual Antioxidants in Combination with Hyperthermia

Table 11.7 Enhancement of the effect of certain chemotherapeutic agents by a mixture of four antioxidants on human melanoma cells in culture Antioxidant mixture Cisplatin + antioxidant mixture Tamoxifen + antioxidant mixture DTIC + antioxidant mixture Interferon-a2b + antioxidant mixture The antioxidant mixture consisted of vitamin C, 50 g mL polar carotenoids, 10 g mL a-tocopheryl succinate, 10 g mL, and 13-cis-retinoic acid, 7.5 g mL, added at the time of plating. Data were summarized from a previous publication (20). a, standard error of the mean polar carotenoids were originally referred to as p-carotene (40). control have been observed. The temperatures used range from 43-45 C. Hyperthermia, for the most part, has not proved to be of any significant value in improving the cure rate or survival time of any type of human cancer, but has proved to be of some value in improving quality of life for a variable period of time. Therefore, the current treatment approaches must be altered...

Modification of Radiation Damage by Endogenous Antioxidants

Extensive studies have been published to show that endogenous antioxidants such as SH compounds and their derivatives (cysteamine, glutathione, and others) protecte normal and cancer cells in vitro and in vivo when given before roentgen ray irradiation at doses which do not cause toxicity (1, 2). In fact, differential radiosensitivity, which is commonly observed during various phases of the cell cycle, is related to different levels of SH compounds. It has been shown that mitotic cells, which are most radiosensitive, have the lowest levels of SH compounds, and that S-phase cells, which are most radioresistant, have the highest levels of these compounds (80). Antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase play an important role in protecting normal cells against damage produced by reactive oxygen species. Therefore, one would predict that they play a similar role in cancer cells. Indeed, overexpression of antioxidant enzymes increased the...

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...

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 www.ms-cam.org). 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....

Mechanisms of Action of Dietary Antioxidant Induced Enhancement of Radiotherapy and Chemotherapy

The exact reasons for the dietary antioxidant mi-cronutrient-induced enhancement of damage produced by standard therapeutic agents on cancer cells are unknown. We propose the following Free radicals produced by cancer treatment become irrelevant to antioxidant-affected cancer cells however, other mechanisms of damage continue to exert their influence. Micronutri-ents such as retinoic acid inhibit the repair of radiation damage in cancer cells more than in normal cells (60). In contrast to cancer cells, normal cells are not harmed by these dietary antioxidants. When treated with radiation or chemotherapeutic agents, antioxidants protect them at least from damage by free radicals.

Dietary AntioxidantInduced Alterations in Gene Expression in Cancer Cells

Formation, and apoptosis have been carried out only in cancer cells. These studies reveal that retinoids, vitamin E, and p-carotene attenuate the levels of those cell-signaling systems and gene expressions that can lead to decreased cell proliferation rate, increased differentiation, and or ap-optosis. They include expression of c-myc, H-ras (50, 51), N-myc (51), mutated p53 (27), protein kinase C (52, 53), caspase (54), tumor necrosis factor (55), transcriptional factor E2F (25), and Fas (24). Retinoids, vitamin E, and p-carotene enhance the levels of those cell signaling pathways and gene expression that can lead to reduced growth rate, increased differentiation, and or apoptosis, and they include the expression of wild-type p53 (27) and p21 (32), transforming growth factor p (TGF-p) (22), and the connexin gene (28). The above changes (Table 11.2) in gene expression may be one of the major factors that account for the growth-inhibitory effects of these dietary antioxidant...

Clinical Studies with Multiple Dietary Antioxidant Micronutrients in Combination with Standard Therapy

A randomized placebo-controlled trial on the use of antioxidants during radiation therapy has not been performed as yet. Dr. Jae Ho Kim of the Henry Ford Hospital in Detroit, Michigan, has completed a randomized pilot trial with high-dose multiple micronutrients including dietary antioxidants (vitamin C and vitamin E, and natural p-carotene) in cancer patients receiving chemotherapy and radiation therapy. Results showed that all patients tolerated high-dose micronutrients well and that quality of life was improved during radiation therapy with no adverse effect on the efficacy of standard therapy (personal communication). A few oncologists have used high dose multiple antioxi-dants in combination with standard cancer therapy, and improved outcomes have been reported (39, 40). A preliminary randomized trial with high dose antioxidants in combination with chemo-therapeutic agents (cisplatin and paclitaxel combination) in patients with advanced non-small cell lung carcinoma reported...

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...

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 bis-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,...

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...

Effect of Multiple Dietary Antioxidants

A mixture of dietary antioxidants is more effective in reducing the growth of cancer cells than the individual antioxidants. A mixture of retinoic acid, a-TS, vitamin C, and polar carotenoids produced approximately 50 growth inhibition in human melanoma cells in culture at doses which produced no significant effect on growth when used individually (Table 11.3). Doubling the dose of vitamin C in the mixture caused a dramatic enhancement of growth inhibition. Similar observations were made on human parotid carcinoma cells in culture (16). A reduction of 50 in the dose of each micronutrient in a mixture did not affect the growth of human melanoma cells in culture. Each of the dietary antioxidants has different modes of Table 11.3 Effect of a mixture of four antioxidant micronutrients on growth of human melanoma cells in culture action and therefore, it is essential that multiple dietary antioxidants are used in combination with radiation therapy.

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

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...

Effect of Low Doses of Individual Dietary Antioxidants

In contrast to the effect of high doses of dietary antioxidant micronutrients, low doses of these mi-cronutrients can have no effect on the growth of cancer cells and normal cells, or they can stimulate the growth of some cancer cells without affecting the growth of normal cells. For example, vitamin C at a low dose stimulated the growth of human parotid carcinoma cells in culture (16) and human leukemic cells in culture (15), but had no effect on the growth of human melanoma cells in culture (16) or murine neuroblastoma cells (20). Polar car-otenoids at low doses can stimulate the growth of human melanoma cells in culture (17). In addition, certain amounts of antioxidants are needed for the growth of normal and cancer cells. Therefore, we do not recommend low doses of individual or multiple antioxidants during radiation therapy.

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...

High Doses of Dietary Antioxidants Enhance the Effect of Irradiation on Cancer Cells

Dietary antioxidants enhance the effect of irradiation selectively on cancer cells while protecting normal cells against some of the injuries. To observe this effect, antioxidants must be given before and after irradiation at high doses, and they must be present throughout the experimental period. The extent of enhancement of radiation damage by dietary antioxidant micronutrients depends upon the dose of radiation, dose and types of antioxi-dants, treatment period, and type of tumor cells. against chromosomal damage (43). In another study, we have reported that an aqueous form of a-tocopheryl and a-TS enhanced the level of radiation-induced growth inhibition in neuroblastoma (NB) cells (Fig. 11.4) (43, 61). Vitamin C enhanced the effect of irradiation on neuroblastoma (NB) cells, but not on glioma cells in culture (20). Dehy-droascorbic acid (DHA), the major metabolite of ascorbic acid, acts as a radiosensitizer for hypoxic tumor cells (62). These studies show that certain antioxidant...

Mechanisms of Action of High Doses of Dietary Antioxidants on Tumor Cells

To study the mechanisms of differential effects of antioxidant nutrients in cancer cells, it is important to establish whether the greater sensitivity of cancer cells to dietary antioxidant micronutrients (vitamin A, vitamin C, vitamin E, and carotenoids) is due to increased accumulation of antioxidants in these cells in comparison to that found in normal cells or whether cancer cells and normal cells accumulate the same levels of these antioxidant mi-cronutrients, with cancer cells being more sensitive to these micronutrients than normal cells.

Accumulation of Dietary Antioxidants in Normal and Cancer Cells

The administration of radioactively labeled vitamin C into animals carrying transplanted tumor (44). A similar observation was made earlier in patients with leukemia (37). Thus, increased accumulation of vitamin C by tumor cells following high-dose supplementation may be responsible for its anticancer activity. Our results show that human cervical cancer cells (HeLa cells) and normal human fibroblasts in culture accumulate similar levels of a-TS within 24 hours of treatment (Table 11.1). This suggests that tumor cells acquired increased sensitivity to a-TS for growth-inhibition, differentiation, and or apoptosis during transformation. The relative uptake of other antioxidant micronutrients such as retinoids and carotenoids by normal and cancer cells in culture has not been studied. The analysis of the basal levels of antioxidant micronutrients in human tumors and their adja cent normal tissues shows that the levels of individual antioxidant micronutrients in tumor tissue may be...

Antioxidants

Antioxidants protect DNA and cell membranes from damage caused by oxidation and thus contribute to protecting the organism from mutations and maintaining the cell's integrity. This protective effect is based on the ability of antioxidants to prevent the formation of free radicals by capturing reactive oxygen compounds, or to make an electron available to existing radicals without becoming a reactive radical itself. The so-called exogenous or nonenzymatic antioxidants (vitamins C and E, p-carotene, and some other caroten-oids) together with the endogenous or enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, catalase, and others) form an effective The balance between free radicals and antioxi-dants can be disturbed by a number of exogenous and endogenous processes as a result, the protective antioxidant potential may soon become exhausted. Exogenous tumor initiators include smoke, ionizing radiation, ultraviolet light, ozone, as well as dietary factors and deficits....

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...

To Radiotherapy Chemotherapy and Experimental Cancer Therapies 151

_ Antioxidants 152 Definition of Types of Antioxidants _ Experimental Basis of Our Hypothesis .157 High Doses of Dietary Antioxidants Enhance the Effect of Irradiation High Doses of Dietary Antioxidants Enhance the Effect of Chemotherapeutic Efficacy of Individual Antioxidants Effect of Individual Antioxidant Vitamins in Combination with Certain Biological Antioxidants Selectively Protect Normal Cells against Damage Produced by Radiation and Chemotherapeutic by Endogenous Antioxidants 165

Use in Prevention and Therapy

Vitamin A is one of nature's primary anticancer substances, particularly in the skin and mucous membranes. Ample intakes of vitamin A have been shown to protect against cancers of the lung, bladder, prostate, larynx, esophagus, stomach, and colon. Vitamin A can prevent precancerous lesions, such as oral leukoplakia (white patches on the lips and mouth often found in smokers) and cervical dysplasia, from developing and may produce regression and disappearance of these disorders.15 As a cancer treatment, large doses of retinoic acid may reduce growth and recurrence of certain forms of skin cancer.16 As an antioxidant, beta-carotene helps provide protection against damage from many xenobiotics (such as polychlorinated biphenyls PCBs ). It may also reduce the risk of skin cancer associated with exposure to sunlight6 and radiation.2

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...

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...

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

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...

C Formulation of Hypothesis Does Carbon Monoxide Have a Physiological Function

It has been proposed16,17 that CO endogenously produced by lipid peroxidation18 modulated blood vessel tone. Since CO shares the ability of NO to activate sGC,19,20 it has been proposed that the modulation of blood vessel tone by CO occurs by activation of sGC.16,17 Since lipid peroxidation is only a minor source of endogenous CO, we drew attention to the fact that the major source of endogenous CO was heme which would be metabolized by the HO enzyme to biliverdin, iron, and CO20a (Figure 1.1). CO is formed at the rate of 16.4 pmol h in the human body. It has been customary to think of HO as the source of biliverdin and bilirubin (Figure 1.1) and as an enzyme whose activity results in the important clinical problem of hyperbilirubinemia. A paradigm shift occurred with regard to thinking about this enzyme when both biliverdin and bilirubin were shown to function as antioxidants and data supported the idea of a beneficial role for bilirubin as a physiological, chain-breaking...

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...

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...

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...

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...

Modeling And Identification Of The Dynamics Of The Mfinfluenced Freeradical Transformations In Lipidmodeling Substances

Recently a number of experimental studies on the influence of the magnetic field on the chemical reactions of free radicals and on processes involving triplet excited molecules in solutions has been carried out 14, 17 , and physically justified models of these phenomena have been proposed 25 . However, the relation between the magnetic field strength and the reaction rate (including qualitative change in terms of rate increase or decrease) has not been established for many such reactions in the ranges of field strength frequently encountered by humans, and the review of reported results reveals a significant knowledge gap in this area. There are also only a few well-documented examples involving biological systems. McLaucham and Steiner 13 , Harkins and Grissom 11 , and Grissom 8 show that an applied external magnetic field can alter the rate of T-S interconversion in radicals, and potentially affect enzyme activity. Chignel and Sik, 3 showed The mathematical modeling of MF-sensitive...

Endogenous Carcinogenesis

The rate of damage to DNA produced by oxygen radicals, which are continuously generated in cells by normal metabolism, isn't clear, but it could be as high or higher than depuri-nation. Measurements in human urine of 8-hydroxydeoxyguanosine and thymine glycol, which are oxidative breakdown products of DNA, suggest that 10,000 oxygen radical-induced alterations in DNA could occur per cell per day.49 However, cells have stringent mechanisms to protect themselves against free radicals generated by cellular metabolism. These include superoxide dismutase (SOD), catalase, and glutathione generating systems. Oxygen radical damage, if unrepaired, can produce single-strand and doublestrand breaks in the DNA backbone.

Replicative Senescence And Hiv Disease

Produce soluble antiviral factors, generate sufficient antioxidants, and traffic normally into the tissues will undoubtedly diminish the quality of the protective immune response. Admittedly, it is possible to argue that the above characteristics, rather than being abnormal, reflect the evolution of a mature immune response. Namely that the CD28+CTL precursors first proliferate and secrete antiviral factors, and, as they divide, an increasing proportion of cells lose CD28 expression, have shortened telomeres, and the amount of antiviral factors decreases as the cytotoxicity is enhanced and reaches its peak at the point at which the CD8 T cells can no longer undergo proliferation. This alternative scenario, however, seems less likely, inasmuch as the increase in the proportion of CD28 T cells correlates with disease progression and ultimate loss of control over the infection. More detailed elucidation of what seem to be discrete stages CD8 T-cell effector cell progression in...

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...

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...

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

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(lll)...

Photolithographic Patterning of Hydrogels

The union of hydrogel photopolymerization chemistry with photolithographic techniques from the microprocessor industry has enabled the rapid prototyping of hydrogel structures that are uniform in the z-direction but vary in structure or composition in the x- and y-directions. In one method, a cell suspension is mixed with a hydrogel precursor solution and applied to a flat substrate 28, 83, 84 . Illumination of the solution through a mask permits crosslinking only in defined regions. The opaque regions of this photomask block light and inhibit photopolymerization in these shadowed regions while the transparent regions allow light to pass through and initiate hydrogel crosslinking. Simply rinsing the substrate with water removes the uncros-slinked regions, revealing free-standing hydrogel posts containing living cells (Fig. 4.5). It is important to note that although free radical polymerization is a fast chemical process, it is efficiently quenched by atmospheric oxygen and other free...

Regulatory framework for food contact materials in the United States

To understand FDA's current approach to toxicology review and risk assessment for components of food contact materials, it is critical to be aware of FDA's longstanding distinction between food additives and constituents of food additives. Generally, substances added to or present in a food contact material to accomplish a technical effect are considered food additives if they migrate to or are reasonably expected to migrate to food. Examples include polymers, colorants, antioxidants, clarifying agents, and biocides. The additives that are intentionally used, however, are generally not a single chemical but a commercial product that contains several constituents in varying concentrations. Substances that may migrate, or that are reasonably expected to migrate to food may be minor constituents. Examples include monomers, oligomers, catalysts and polymer processing aids whose presence in the final material is not intentional. Many food contact materials are deemed to be food additives...

Inducers Of Apoptosis Exist In The Ad Brain

Apoptosis can be induced in most neurons by a variety of stimuli, a number of which appear to accumulate in the aging and AD brain. In the aging and AD brain, the P-amyloid protein (AP), a 40-42 amino acid peptide, accumulates in the extracellular space as small deposits and senile plaques. Based on the observation that neurites surrounding AP deposits show both sprouting and degenerative responses, we proposed that this peptide is not metabolically inert, but rather possesses biological activity. Our findings established two key principles that AP induces neurotoxicity in a conformation-specific manner and that apoptotic mechanisms underlie this toxic-ity (1,2) these observations have since been confirmed by many others. Interestingly, prior to causing cell death, AP also induces the formation of dystrophic-like neurite morphology in cultured neurons (3,4). Oxidative insult readily initiates apoptosis (5), which is known to occur in the aging and AD brain (6). Similarly, reductions...

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

Cytoprotection the second major determinant of toxic potential

The progression to cell damage after the production of primary or secondary cyto-toxic mediators is not inevitable, nor is it irreversible. A battery of chemical and enzymic cytoprotectants prevails within the liver. These cytoprotectants combat the endogenous production of potential cytotoxins (such as reactive oxygen species ROS and cytokines) and reverse their adverse effects (by the repair of oxidized proteins, damaged membranes and methylated DNA). The cytoprotectants include the antioxidant vitamins A, C and D, reduced glutathione (GSH) and numerous chemicals, proteins and enzymes with complementary functions in maintaining redox status with its normal reductive bias. Particularly important are the enzymes detoxifying ROS, e.g. superoxide dismutase, catalase and the glutathione-depen-dent enzymes. The latter include glutathione peroxidase, which reduces hydrogen peroxide in mitochondria where catalase is absent, and the glutathione transferases which catalyse the detoxication of...

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

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.

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...

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.

Magnetic Field Effects

EM interaction mechanisms have been proposed but are not well established. Valberg et al. 22 have reviewed several mechanisms by which electric and magnetic fields at 50 50 Hz might influence biology, e.g., energy transfer, force, resonance, and magnetic moments including signal averaging. Proposed mechanisms include induced electric currents, direct effect on magnetic biological materials, effects on free radicals, and excitation of cell membranes.

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.

Summary of ELF Interaction Mechanisms

It is concluded from the three biophysical mechanisms (induced electric currents, direct effect on magnetic biological materials, and effects on free radicals) that high field strength is needed to produce noticeable biological effects in living systems. These strengths are usually much higher that the typical environmental exposures. However, to understand the bioelectrochemical mechanism, we need to emphasize how ELF fields affect life processes. Most life scientists believe that only the chemical processes is involved in growth and healing in the living system. A clear distinction between this mechanism and the previous three biophysical mechanisms is summarized in Adair's comment 36 , any biological effect of weak ELF fields on the cellular level must be found outside the scope of conventional physics.

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.

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.

Why Do We Need To Detect Ischemia

Ischemia is the link between coronary disease and myocardial dysfunction (Fig. 1). It exists when oxygen supply is inadequate to meet myocardial oxygen demands, and can occur through both supply-side and demand-side etiologies. Events that occur at the level of the artery mirror those of the ventricle injury, dysfunction, activation of autocrine endocrine pathways, and remodeling. When plaque rupture occurs in an ACS, intracoronary thrombus and superimposed vasoconstriction can limit oxygen supply. There can also be increased oxygen demand due to enhanced sympathetic activity from pain or in response to reduced cardiac output. Ischemia can result in myocardial injury from both reperfusion and from failing to reperfuse. In the latter case myocytes die following prolonged hypoxia. In the former, direct myocardial injury results from oxygen free radicals generated during reperfusion. In either case there will be systolic dysfunction in proportion to the extent of ischemia initially, and...

Epidemiology and etiology

However, extranodal MZLs are relatively rare, while H. pylori infection is extremely common, being present in the stomach of one half of the world population.24 Therefore, both bacterial and host factors have to interact to cause lymphoma. Polymorphisms affecting genes involved in inflammatory responses and antiox-idative capacity may be part of the genetic background for the MALT lymphomagenesis in individual H. pylori infected persons.25 The persistent antigenic stimulation may render the clone more susceptible to genetic alterations that can result in neoplastic transformation and tumor progression. Free radicals are likely to play a role in the development of B-cell genomic damage in the chronic gastritis, and their presence is increased in the presence of the CagA-positive strains of H. pylori.26

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...

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.

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...

Hypothesis of Melatonin

One possible interaction hypothesis under investigation is that exposure to EM fields suppresses the production of melatonin, which is a hormone produced by the pineal gland, a small pinecone-shaped gland located deep near the center of the brain. Melatonin is produced mainly at night and released into the blood stream to be dispersed throughout the body. It surges into almost every cell in the human body, destroying free radicals and helping cell division to take place with undamaged DNA. Melatonin also assists in regulating the female menstrual cycle and circa-dian rhythms. Melatonin secretion decreases over a lifetime, peaking in childhood and gradually lessening after puberty. Usually, people over 60 secrete far less than they do when young. Also, melatonin regulates sleep, mood, behavior, and gene expression. It reduces secretion of tumor-promoting hormones. It has the ability to increase cytotoxicity of the immune system's killer lymphocytes therefore, its production is...

Meinhard Wlaschek and Karin Scharffetter Kochanek Introduction

There is a strong association between exposure to ultraviolet irradiation (UV) induced reactive oxygen species (ROS), human skin cancer, and premature aging of the skin.1-3 Reactive oxygen species (ROS) are part of normal regulatory circuits and the redox state is tightly controlled by antioxidants. Cells and tissues are equipped with a complex enzymatic and nonenzymatic antioxidant defense system. UV generation of ROS results in a loss of cellular antioxidant homeostasis, thus tilting the balance towards a prooxidant state. The increase in UV irradiation on earth due to the stratospheric ozone depletion will lead to a substantially higher risk of photooxidative damage to the skin, resulting in a dramatic increase in skin tumor incidence.4 Increased ROS level and loss of cellular redox homeostasis can contribute to photoaging and photocarcinogenesis. ROS and free radicals have the capacity to cause permanent structural damage in different cellular target structures, such as DNA, lipid...

Diagnosis And Treatment

Our understanding of the ATM gene and the molecular basis of AT, therapy still focuses on symptomatic relief of neurologic and immunologic problems rather than treatment of underlying deficits (191). Although antioxidants, L-dopa, gene therapy, and neuronal transplants all have been considered as potential therapies, effective treatments have yet to emerge from our new knowledge of AT pathobi-ology. The recent establishment of an Ataxia-Telangiectasia Clinical Center at Johns Hopkins in Baltimore has already led to large-scale studies of the course of the disease and, in the future, may facilitate clinical trials that could lead to the development of new ways to treat this devastating condition (http ww2.med.jhu. edu ataxia clinicar.htm).

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...

Corneal Epithelium Protection for Dry Eye Syndrome and Other Corneal Disorders

Basic studies have been undertaken to try and elucidate the mechanism of hyaluronan for corneal epithelial protection. Hyaluronan facilitates corneal epithelial wound healing in nondiabetic and diabetic rats, although the healing rate in diabetic rats was slower than that in normal control rats (117). Rabbit corneas were used to examine the efficacy of sodium hyaluronate by comparing its effects on the rate of epithelial healing, and sodium hyaluronate concentrations of 0.1 and 0.5 were found to significantly accelerate the recovery time of iodine vapor-induced corneal erosions (118). Topical application of 1 sodium hyaluro-nan enhanced the formation of hemidesmosomes in the basement membrane of rabbit corneas during the early healing phase in n-heptanol-induced corneal wounds (119). Recently, hyaluronan was shown to have antioxidant properties and it tended to reduce the toxic effects of preservatives (120). Therefore, hyalur-onan may be useful not only for dry eye syndrome but also...

The Role of Proinflammatory Cytokines in Cancer Cachexia Personal Studies

In another study 38 , we investigated the presence of a correlation between cytokines (and other biological parameters such as CRP, leptin, and antioxidant enzyme) and the clinically most important indices, such as disease stage and ECOG PS. A direct correlation between stage ECOG PS and serum levels of proinflammatory cytokines, particularly IL-6 and CRP, was observed such that the serum levels of IL-6 and CRP progressively increased from stage II ECOG 0-1 to stage IV ECOG 2-3. Patients at advanced stage and most compromised PS had the highest levels of IL-6 CRP and the lowest levels of leptin, IL-2, and antioxidant enzymes. Thus, it can be hypothesised that in this group of cancer patients the high levels of proinflammatory cytokines severely impaired the energetic and specific metabolic (i.e. glucose, proteic, and lipid) balance 42, 43 , thereby preventing the physiological ability of the organism to maintain body redox equilibrium by synthesising the appropriate amount of...

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 .

Synthesis and Metabolism of Epidermal Hyaluronan

Scavengers of reactive oxygen species like superoxide dismutase, catalase, and desferroxamine slow down hyaluronan disappearance from the epidermis in human skin organ cultures, suggesting that oxygen-free radicals contribute to the degradation (17). However, there was little support for a direct attack of the glycosidic bonds of the polymer, since the molecular mass distribution of hyaluronan was not changed during the treatment (17). The reactive oxygen species may have a more regulatory role, enhancing the cellular uptake of hyaluronan for lysosomal degradation, perhaps by limited cleavages that release the chain free for endocytosis or by inducing cellular signals that stimulate endocytosis.

Genetic Instability And Dna Repair

Pagano and Korkina (126) have reviewed and summarized the numerous efforts to prove the adverse effects of reactive oxygen species on the genome of FA cells. These proponents of the oxidative stress theory in FA believe that in vivo evidence points to the fact that oxidative stress characterizes the metabolic situation of different types of peripheral blood cells from patients with FA (127). By overexpressing thioredoxin, an ubiquitous intracellular antioxidant, in FA fibroblasts, Ruppitsch and colleagues (128) claim to prevent the clastogenic effects of MMC and DEB, which would argue strongly in favor of an oxygen-related path

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...

Degradation Processes In Biodegradable Polymers

The conditions used during the processing and fabrication of polymeric materials may also lead to polymer degradation, consequently influencing their degradation behavior in vivo. Melt-based techniques (injection molding, extrusion, compression molding) are performed at high temperatures and in the first two cases at high shear rates, which may cause some degradation of the material. The production of samples by injection molding leads to a partial material orientation, which is typically higher in the skin than in the core of the molding. The chain orientation across the sample upon processing may be responsible for a faster degradation in the center than in the skin.8 In addition, it is very common to use additives (plasticizers, lubricants, antioxidants, salts, stabilizers) during the processing of polymeric materials, which will leach out after immersion and may enhance or inhibit the degradation process.

Monitoring the effects of therapy

Several drugs are now in development may be useful in COPD. These include LTB4 antagonists and 5-lipoxygenase inhibitors, PDE4 inhibitors, new antioxidants and neutrophil elastase and MMP inhibitors. It will be difficult to demonstrate the efficacy of such treatments as determination of the effect of any drug on the rate of decline in lung function will require large studies over at least 2years. There is an urgent need to develop surrogate markers, such as analysis of sputum parameters (cells, mediators, enzymes), that may predict the clinical usefulness of such drugs.

Yachie A Kawashima K Ohta Y Saikawa and S Koizumi

Heme oxygenases (HOs) are known to play critical roles in physiological iron homeostasis, antioxidant defense mechanisms, and carbon monoxide (CO) production.1-6 In addition to classical biochemical studies, recent observations in HO-targeted mice have further confirmed the important physiological functions of HOs.7-12 Our laboratory recently reported the first case of human HO-1 deficiency.13-15 The important role of HO-1 in the human body was highlighted at the First International Symposium on Heme Oxygenase (HO CO) held in New York in July of 2000.16 HOs function as the initial and rate-limiting step in heme degradation.1-6 HOs catalyze the conversion of heme into biliverdin, which is subsequently reduced to bilirubin by biliverdin reductase, free iron, and one molecule of CO. Biliverdin is an antioxidant capable of scavenging peroxy radicals. Ferritin is an intracellular repository for iron, and safely sequesters the unbound iron liberated during degradation of heme. Finally, CO,...

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...

Experimental Basis of the Other Hypothesis

Dietary antioxidants such as vitamin E (a-tocophe-rol) when given in a single low dose shortly before irradiation reduced the effectiveness of roentgen ray irradiation in an animal tumor model (14). Similarly, when vitamin C, vitamin E, or N-acetyl cysteine, a glutathione-elevating agent, were added to tumor cell culture in a single low dose that does not affect the growth of cancer cells, shortly before irradiation, they protected cancer cells against radiation damage (11, 13, 14). These data have been used to suggest that antioxidants should not be used during radiation therapy or chemotherapy.

Comments on Current Controversies

The data presented in support of each the proposed hypotheses suggest that the current debates regarding the use of antioxidants during radiotherapy or chemotherapy primarily rest on an extrapolation of one conceptual framework based on specific experimental designs as compared to another one based on experimental conditions that are entirely different with respect to dose, treatment time, and type of antioxidants. Data show that high doses of dietary antioxidants that inhibit the growth of cancer cells but not of normal cells, when given before and after irradiation or chemo-therapeutic agents for the entire observation period, may improve the efficacy of the therapy. However, results also show that low doses of dietary or endogenous antioxidants, when given in a single low dose that does not affect the growth of cancer cells shortly before irradiation, may protect cancer cells against radiation or chemotherapy damage. Some oncologists recommend a multiple vitamin preparation...

Proposed Doses of Micronutrients To Be Used as an Adjunct to Radiation Therapy andor Chemotherapy

The scientific rationale for the proposed micronu-trient protocol has been discussed in detail in recent publications (8, 10). The micronutrient supplement protocol is divided into two categories active treatment phase and maintenance phase. - During the active treatment phase, daily mi-cronutrients are given orally at least 48 hours before radiation therapy or chemotherapy, and continued for the entire treatment period. After the completion of treatment, doses of supplementary antioxidant micronutrients are reduced to half over a four-week period, which is maintained during the maintenance phase (lifetime). The rational for giving micronutri-ents at least 48 hours before standard cancer therapy is that antioxidant-induced damage is initiated in cancer cells but not in normal cells prior to initiation of cancer treatment with standard therapeutic agents. - appropriate minerals but not iron, copper, and manganese, because these three trace minerals interact with vitamin C to produce...

Mechanisms Of Diabetic Peripheral Neuropathy

The theoretical constructs include metabolic, vascular, altered neurotrophic support, autoimmune, and free radicals associated with oxidative stress. Oxygen-free radicals may induce nerve damage directly or by inhibiting nitric oxide production, and thus causing a reduced nerve blood flow. Free radical generation is increased in diabetics by the processes of nonenzymatic glycation and polyol pathway. At the same time, the ability to neutralize free radicals is decreased because NADPH, which deals with cell oxidation reduction status, is diminished as it is consumed by increased activity of aldose reductase (24,69).

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.

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.

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

Emerging Approaches to Treat Renal Dysfunction

6.25.7.1 Antioxidants Antioxidants act by reducing the superoxide that is elevated in hypertension and obesity. The reduction in superoxide levels may enhance NO bioavailability. For example, long-term treatment with the SOD mimetic tempol lowers arterial Antioxidants OH Antioxidants OH

Omega3 Fatty Acids and Oral Nutritional Support

Have suggested that, when given at doses 20-40 times the normal Western dietary intake, n-3 fatty acids are well tolerated 63 and can stabilise patients' weight 64 . On the basis that successful cachexia therapy has to address both metabolic changes and reduced food intake, the combination of a conventional oral nutritional supplement with n-3 fatty acids and antioxidants was developed. The recommended daily intake of two cans provides 620 kcal, 32 g protein and 2.2 g eicosapen-taenoic acid (EPA).

Oxidative Stress Hypothesis And Aging In Ds

Essentially, free radicals (reactive oxygen species ROS ) are produced as a by-product of metabolism of ATP to ADP in the mitochondria. If not tidied up by biological housekeepers, these rogue chemicals can act as destructive agents in the cell, because they are highly effective at reducing chemicals that can induce damage to other larger molecules within the cell. The main ROS are superoxide anion O 2 and hydrogen peroxide H2O2. In the presence of iron, additional substances such as OH and nitric oxide (NO) are also formed. A biological model of the importance of these antioxidants occurs naturally in a rare and occasionally inherited disorder, familial amyotrophic lateral sclerosis (ALS), where a small proportion of families carry inactive copies of their SOD1 gene. The chronic oxidative damage to motor neurons leads to the onset of progressive paralysis and a shortened life span. It appears to preferentially affect specific motor neurons in the anterior horn. Individuals with DS...

The Role Of The Immune System In Promoting Tumor Growth

Angiogenesis, and matrix metalloproteinases, which modify the extracellular tissue. Therefore, chronic activation of some innate immune cells is characterized by angiogenesis and tissue remodeling, which favor tumor formation and spread. Innate immune cells may also contribute to malignant transformation of cells by generating free radicals that cause DNA damage and lead to mutations in tumor suppressor genes and oncogenes. Some data suggest that cells of the innate immune system, including mast cells, neutrophils, and macrophages, secrete soluble factors that promote cell cycle progression and survival of tumor cells. The transcription factor NF-kB, which is a key mediator of innate immune responses, may play an important role in inflammation-associated cancer progression. The adaptive immune system can promote chronic activation of innate immune cells in several ways, including T cell-mediated activation of macrophages in the setting of persistent intracellular microbial infections...

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.

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...

Possible Functional Implications of Clusterin Expression Following Acute Insults of the Nervous System

The puzzling role of clusterin in CNS insults is highlighted in ischemia. This condition is associated with a marked astrocytic upregulation of clusterin expression, which is therefore regarded as associated with ischemic neurodegeneration.14 While substantial and general neuroprotection can be obtained by treatment of experimental cerebral ischemia with antioxidants, clusterin upregulation is counteracted only in selected brain regions.15 This discrepancy is additionally intriguing in the light of the downregulation of GFAP expres sion brought about by antioxidant treatment in all brain areas affected by neuronal degeneration.

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...

Biomedical Applications of Fullerenes

Fullerenes have been used as actual therapeutic macromolecules. They are strong antioxidants, capable of scavenging a variety of free radicals associated with medical conditions such as neurodegenerative diseases. Oxygen free radicals use their unpaired electrons to break chemical bonds in critical molecules such as nucleic acids, thereby triggering cell damage and possible apoptosis 306 . Fullerenes are believed to interrupt this process essentially by absorbing the potentially damaging electrons. Fullerenes have been modified with malonic acid moieties, creating a compound, that showed strong activity in animal models of neurodegenerative diseases 306 . In an investigation by Dugan et al. 307 , water-soluble carboxylic acid functionalized fullerene derivatives, containing three malonic acid groups per molecule, were synthesized and found to be efficient free radical scavengers. These data suggest that polar carboxylic acid fullerene derivatives may have attractive therapeutic...

Micronutrients Cervical Dysplasia

Antioxidant formula 3000 ig for women who have an abnormal Pap smear showing cervical dysplasia 800 ig for prevention 5 mg for women who have an abnormal Pap smear 0.4 mg for prevention Should contain ample beta-carotene, vitamin E, and vitamin C, as well as selenium (see pp. 118 for recommended levels of antioxidants) May help reverse dysplasia.27,28 High doses of vitamin A should only be taken with the advice of a physician May reverse dysplasia.29-31 Should be taken as part of a vitamin B complex May help reverse cervical dysplasia. Low intake of antioxidants increases risk28,32,33

BAdrenoceptor Antagonists bBlockers

The first -adrenoceptor antagonist, dichloroisoproterenol, was described by I. Slater in 1957. The first clinically useful b-adrenoceptor antagonists, pronethalol and propranolol (Table 2), were discovered and developed by the British pharmacologist Sir James Black. Their usefulness in the treatment of hypertension was first demonstrated in patients by Prichard. Pronethalol was found to be carcinogenic in mice,25 while propranolol was marketed and is still used in the clinic. The discovery of subtypes of b-adrenoceptors, b1 and b2, facilitated the development of additional antagonists with various affinities for the two receptor subtypes. Propranolol is nonselective it has similar affinity for br and b2-adrenoceptors. Blockade of b2-adrenoceptors is likely to cause bronchial constriction, so that propranolol should not be used in patients with bronchial asthma. Propranolol enters the central nervous system and can produce vivid dreams as one of its side effects. Another nonselective...

Interaction of Flavonoids with Model Phospholipid Membranes

Flavonoids constitute a large and divergent group of plant-derived compounds characterized by a very wide spectrum of biological activities (for chemical structures see Fig. 2 and Table 1). Flavonoids have been commonly reported to protect cells (e.g., cardio- or hepatoprotection) against injuries caused by external factors. Antioxidant activity is often claimed to be the cause of such cell-protective properties of flavonoids. As membrane lipids are cell components that tend to be the most vulnerable to being oxidized by free radicals, the antioxidant activity of flavonoids has been proposed, and subsequently demonstrated, to be correlated with the ability of these compounds to change the biophysical properties of model and biological membranes 84-86 . The antioxidant properties of flavonoids have been recently reviewed by Heim et al. 87 . Different model systems and different methods are used to evaluate the antioxidant properties of flavonoids. The stable free radical...

Interaction of Flavonoids with Erythrocyte Membranes

The literature reports dealing with the effect of flavonoids (Fig. 2 and Table 1) on red blood cells and their membranes are rather scarce. Chen et al. 91 concentrated on antioxidant properties of flavonoids. Flavonoids were found to effectively protect erythrocytes against free radical-induced lysis. When the flavonoids were used at 0.25 mM concentration, quercetin (29) turned out to be the most potent protective agent, followed by myricetin (31), morin (30), kaempferol (28), and apigenin (23). Quercetin was also an active antihe-molytic agent at a concentration two times lower. Since the activity order of the flavonoids recorded in erythrocytes was slightly different than in canola oil, the authors noticed that the antioxidant activity of the flavonoids was governed not only by their chemical structure but also was determined by their interactions with phospholipids, hemoglobin, iron, and other components of red blood cells. The ability of flavonoids to protect erythrocytes against...