Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

Recent large epidemiological studies show that a higher intake of fruits and vegetables is associated with a lower risk of cardiovascular disease (102–104) and all-cause mortality (102–105). A dietary pattern characterized by increased consumption of fruits and vegetables is associated with reduced markers of inflammation and endothelial dysfunction (106). Diets high in fruits and vegetables lower blood pressure (107–109) and reduce markers of oxidative stress induced by acute hyperlipidemia (110). Adherence to the Mediterranean diet, which is characterized by a high intake of fruits, vegetables, and whole grains, and lower consumption of red meat and saturated fats is associated with lower circulating levels of C-reactive protein, IL-6, and fibrinogen (111), and a recent trial showed the Mediterannean diet reduced C-reactive protein and IL-6 in adults (112).

5.3. Vitamin E

Vitamin E acts as a chain-breaking antioxidant that prevents the propagation of lipid peroxidation. The biochemistry, metabolism, and role of vitamin E as an antioxidant is presented in detail in Chapter 3 (Subheading 5.4.).

5.4. Selenium

Selenium is an essential trace element for humans and plays an important role in normal cellular growth and function. Selenium is active as a component of selenoenzymes that include antioxidant enzymes such as glutathione peroxidase, selenoprotein-P, gastrointestinal glutathione peroxidase, and thioredoxin reductase (113). Selenium is widely distributed in human tissues and is found mainly as selenomethionine and selenocysteine. The selenium content in foods can vary widely, depending on the selenium content of soils where foods of plant origin are grown and the selenium content of foods used as animal feed. Clinically apparent selenium deficiency is generally rare and is characterized by an endemic cardiomyopathy known as Keshan disease in China (114). In the United States, over 95% of adults >70 yr of age in the National Health and Nutrition Examination Survey (NHANES) III, 1988–1994, had serum selenium concentrations greater than 100 μg/L (115) that are considered consistent with adequate selenium status (116). Selenium plays a role in redox regulation through selenoenzymes such as glutathione peroxidase and thioredoxin reductase (97). Low selenium intake is associated with low serum selenium and lower activity of selenoenzymes (101).

5.5. Ascorbate

Vitamin C, or ascorbate, is a water-soluble vitamin that is essential for the biosynthesis of collagen, carnitine, and catecholamines. It serves as a strong antioxidant and protects proteins, lipids, and DNA from oxidative damage. Ascorbate acts as an antioxidant via its ability to donate electrons (117). The biochemistry, metabolism, and role of ascorbate as an antioxidant are presented in detail in Chapter 9.

5.6. Plant Polyphenols

Plant polyphenols, found in foods such as fruits, vegetables, wine, tea, and chocolate, are reducing agents that decrease oxidative stress. Polyphenols are the most abundant group of dietary antioxidants, and flavonoids account for about two-thirds of the dietary polyphenols (118). The relationship between polyphenols and risk of cardiovascular disease, cancer, and other chronic diseases is emerging as a fairly recent area of investigation (119,

Table 1

Proposed Mechanisms by Which Polyphenols May Reduce Risk for Cardiovascular Diseases

Oxidative stress

Scavenge reactive oxygen and nitrogen species Chelate redox-active transition metal ions Spare and interact with other antioxidants

Inhibition of the reduction oxidization-sensitive transcription factors Inhibition of pro-oxidant enzymes

Inhibition of antioxidant enzymes Growth of atherosclerotic plaque

Reduce adhesion molecule expression Anti-inflammatory

Reduce the capacity of macrophages to oxidatively modify low-density lipoprotein Platelet function and haemostasis

Inhibit platelet aggregation

Blood pressure and vascular reactivity

Promote nitric oxide-induced endothelial relaxation Plasma lipids and lipoproteins

Reduce plasma cholesterol and triglycerides

Reprinted from ref. 119, with permission of Lippincott Williams & Wilkins.

120). Polyphenols may reduce the risk for cardiovascular disease through several possible mechanisms, as shown in Table 1 (119). Flavonoids are among the better known polyphenols, and there are over 8000 individual compounds known (121). The basic structure of flavonoids is a flavan nucleus, consisting of 15 carbon atoms arranged in three rings (C6- C3-C6), A, B, and C. The flavonoids are classified into flavones, flavanones, flavonols, flavanolols, isoflavones, and other groups based on level of oxidation and patterns of substitution of the C ring (121). Flavonoids act as antioxidants by inhibiting enzymes that generate superoxide anion and by reducing superoxide, peroxyl, alkoxyl, and hydroxyl radicals (121). Dietary polyphenols have moderate antiangiogenic functions (Fig. 5) (122) and have also been shown to be vasoprotective (123). Some of the more well-characterized flavonoids are summarized in Table 2 (121,124). Plant polyphenols can be measured in serum or plasma, but owing to the relatively short half-life, it is not optimal to utilize fasting blood samples. Perhaps this has been one barrier to the study of serum polyphenols in epidemiologic studies, as most study protocols involve the collection of fasting blood samples.

6. ANTIOXIDANT SUPPLEMENTS VS A HEALTHY DIET

The recent investigations of the relationship between inflammation, hypertension, cardiovascular disease, and healthy diets that are rich in fruits, vegetables, and whole grains (102–108) contrast sharply with early research from the 1980–1990s that focused on megadose supplementation with single nutrients such as β-carotene and vitamin E for the prevention of cardiovascular disease and/or cancer, with negative and even harmful results (125,126). Many of the large clinical trials utilized nonphysiological megadoses of β-caro- tene that increased serum β-carotene levels 10to 12-fold above the normal range, and

402 Handbook of Nutrition and Ophthalmology

Table 2

Some Common Flavonoids and Their Sources in Food

Based on refs. 121,124.

teins (134). NF-κB is maintained in the cytoplasm where it is bound to IκB. ROS enhance the signal transduction pathways for NF-κB activation in the cytoplasm through serine or tyrosine phosphorylation of IκB (134), and disruption of the IκB:NF-κB interaction is followed by translocation of NF-κB from the cytoplasm to the nucleus, where NF-κB regulates the transcription of IL-1β (5), IL-6 (16), and IL-18 (22). AP-1 is a nuclear transcription factor that is regulated through synthesis of Jun and Fos proteins and their phosphorylation (135,136). Two signaling cascades, c-Jun N-terminal kinases (JNK) and p38 mitogenactivated protein kinase (MAPK), lead to the induction of jun and fos genes (135). ROS play an important role in the activation of both JNK and MAPK pathways (134,135,137). Selenium is involved in signal transduction of AP-1 (97). Selenomethionine and selenocysteine can attenuate the peroxynitrite-mediated activation of AP-1 and NF-κB (138). The redox regulation of NF-κB and AP-1 are involved in the expression of many cytokines that are elevated in the proinflammatory state, such as TNF-α, IL-1β, IL-6, and IL-18. These cytokines, in turn, are involved in a complex cascade that involves the upregulation of C-reactive protein (35) and feedback loops involving IL-10 and other inflammatory mediators (67).

7.2. Oxidative Damage to DNA, Protein, and Lipids by Reactive Oxygen Species

As noted previously, ROS can be involved in the pathogenesis of disease through two major mechanisms, the first by upregulation of inflammatory cytokines, and the second through direct damage to biomolecules. Most ROS have extremely short half-lives in vivo and are difficult to measure directly in humans. Thus, in human studies, oxidative stress is usually assessed by measuring oxidative damage to biomolecules due to ROS (139).

7.2.1. OXIDATIVE DAMAGE TO DNA

One of the most important targets of oxidative damage in cells is DNA, as damage to DNA can readily accumulate in many types of cells (140). ROS-mediated DNA damage occurs in the mitochondria, where most of the ROS are generated, and in the nucleus, both from ROS generated in and outside of mitochrondria. DNA damage is thought to generally increase with age (141). DNA damage can consist of singleand double-strand breaks, interstrand/intrastrand and DNA–protein cross-links, and other oxidation and fragmentation products (142). In animal models, aging is associated with increased nuclear DNA damage in the brain, liver, heart, kidney, and skeletal muscle. In human studies, oxidative damage to DNA is often assessed using urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a measure of the specific oxidation of the C-8 of guanidine (139,143), or single cell gel electrophoresis using peripheral blood mononuclear cells (PBMCs) (144). An international expert panel on genotoxicity concluded that single cell gel electrophoresis, or the comet assay, using PBMCs is the assay of choice for assessing cellular DNA damage in humans (145).

Elevated urine 8-OHdG occurs in diabetes and cancer patients (146,147), among smokers (148), and among men with low serum β-carotene levels (149). The multicenter Project Generale recently demonstrated that urine 8-OHdG is a strong independent predictor of atherosclerosis (H. Poulsen, personal communication). PBMCs accumulate DNA damage and mutation with increasing age (150–153), and oxidative stress-related factors are associated with DNA damage (141,154–158), including exposure to carcinogens (153,159, 160), ionizing radiation (159,161), chemotherapy (162), hypoxia (163), toxic substances (164–166), and cigarette smoking (153,164,167,168). Increased DNA damage in PBMCs has been described in inflammation-related conditions such as coronary artery disease (169,170), diabetes mellitus (171), Alzheimer disease (172,173), and cancer (174,175). The capacity to repair induced DNA damage in lymphocytes may decrease with age (176), but studies to date have been limited. In humans, DNA damage in PBMCs is increased by hyperbaric oxygen treatment (177) and mutagens (178), and decreased by antioxidant supplementation (179), vitamin E supplementation (180), and consumption of antioxi- dant-rich fruit (181) and carotenoids (182,183). DNA damage in PBMCs decreased after treatment with atorvastatin (184), which has antioxidant properties (185). Although oxidative DNA damage has been studied in many disease states and conditions and oxidative stress within the eye is implicated in ocular disease, the relationships between systemic markers of oxidative DNA damage and eye diseases such as age-related macular degeneration, diabetic retinopathy, and cataract have not been characterized.

7.2.2. OXIDATIVE DAMAGE TO PROTEINS

Protein oxidation is the covalent modification of a protein that is induced either directly by ROS (186), by-products of lipid and free amino acid oxidation (187), and reactive nitro-

gen species (188,189). Oxidation preferentially affects certain protein side chains, especially Pro, Arg, Lys, and Thr residues, and when oxidized, these produce carbonyl groups (aldehydes, ketones) (190). Protein carbonyls are the most studied marker of protein oxidation (188–192). Protein carbonyls lead to loss of structural integrity, cell function (191, 193), and increased susceptibility to proteolysis (194,195). Protein carbonyls represent several pathways of oxidative protein damage and are useful in epidemiological studies because they are stable and relatively easy to measure (190). A disadvantage is that protein carbonyls do not reflect any one specific pathway (188). More specific protein oxidation products can be examined but may be limited by problems of low concentrations and need for complex laboratory analyses (196). In model systems, induced oxidative stress increases protein carbonyls in serum and tissues and is associated with skeletal muscle atrophy (196–200). Increased protein carbonyls in tissue are associated with reduced life span in animal models (201–203). Protein carbonyls increase in liver, brain, skeletal muscle, and other tissues with age (189). In humans, elevated oxidized protein levels are found in serum of older compared with younger adults (158,189,204) and among people with cystic fibrosis (205,206) and acute renal failure (207). Elevated protein carbonyls have been described in inflammation-related conditions such as Alzheimer disease (208), atherosclerosis (209), chronic renal disease (210), diabetes mellitus (211–213), and peripheral artery disease (214). Protein carbonyls have been used as an outcome measure in an increasing number of clinical trials (215). Protein carbonyls increase with intravenous iron treatment (a known pro-oxidant) (216) and decrease after vitamin C (217) and grape juice flavonoid intake (218). Oxidative damage to proteins, as reflected by circulating protein carbonyls, appears to exquisitely sensitive to antioxidant nutrient status. Although protein carbonyls are an important general marker for oxidative protein damage and have been widely applied in epidemiologic studies, the relationship between markers of systemic oxidative protein damage and eye diseases has not been characterized.

7.2.3. OXIDATIVE DAMAGE TO LIPIDS

Oxidative damage to lipids, or lipid peroxidation, occurs when polyunsaturated fatty acids (PUFA) in cell membranes are exposed to ROS, resulting in altered cell membrane structure, impaired function, and cell loss. The initial products of lipid peroxidation are conjugated dienic lipid hydroperoxides, which decompose into alkanes and various aldehydes. Peroxidation of a specific PUFA, arachidonic acid, results in the generation of F2 isoprostanes (219,220). Isoprostanes generated initially in the cell membrane after reaction with ROS and are chemically stable (221). Isoprostanes are then cleaved, presumably by phospholipases, circulate in the plasma, and are excreted in the urine (221). The most widely used measures of lipid peroxidation are F2 isoprostanes, hydroperoxides, malondialdehyde, and breath hydrocarbons (222,223). Of these, the measurement of F2 isoprostanes using mass spectrometry is currently considered the best available biomarker for lipid peroxidation (224). Increased levels of isoprostanes have been described in many conditions that are characterized by increased inflammation, including coronary heart disease (225–228), diabetes (227,228), congestive heart failure (229), and obesity (230). F2 isoprostanes are also elevated in smokers (231,232). Although lipid peroxidation has been studied in atherosclerosis and cardiovascular disease (224), the relationship between systemic markers of lipid peroxidation and eye diseases has not been well characterized.

8. CONCLUSIONS

Although there is much evidence from animal and cellular studies that redox status is a key factor in the upregulation of proinflammatory cytokines, surprisingly little work has been done to characterize the relationship between oxidative stress, the proinflammatory state, and eye diseases that occur in older adults. An underlying assumption in many of the epidemiologic studies of the relationship between nutritional status and cataract (Chapter 2), age-related macular degeneration (Chapter 3), and diabetic retinopathy (Chapter 5) is that low serum or plasma levels of antioxidant nutrients are consistent with increased oxidative stress. In turn, oxidative stress is a major trigger for the inflammatory state, which is presumably followed by eye disease. Investigations of markers of systemic oxidative damage to DNA, protein, and lipids, and markers of systemic inflammation could add greater insight into the pathogenesis of eye diseases.

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