Antioxidants: Role on Health and Prevention

T Srdic´-Rajic´, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
A Konic´ Ristic´, Institute for Medical Research University of Belgrade, Belgrade, Serbia
ã 2016 Elsevier Ltd. All rights reserved.

Oxygen is essential element for life. Human cells, as well as
those of other aerobic organisms, use oxygen to break down
nutrients and provide energy. In the mitochondrial energygenerating system, oxygen is reduced to water, and energy is
stored inside ATP molecules. However, this process is a natural
phenomenon, as it is essential for life and can be harmful to
our body at the same time. Different chemical entities that
contain partially reduced oxygen are called reactive oxygen
species (ROS). They are continuously produced in the mitochondrial respiratory chain and some other biochemical reactions and have very important signaling role in various cellular
processes. Most of them are very reactive, with great affinity to
vital molecules of human cells – proteins, lipids, and deoxyribonucleic acids (DNA). Oxidative damage of macromolecules
can lead to the disturbance of their function and the development of various diseases. However, in normal conditions, the
levels of ROS are low, and human cells protect themselves from
their action with efficient antioxidant machinery. Surprisingly,
the human body can even use the deleterious action of ROS to
help the immune system, destroy foreign substances, and combat infectious diseases. Undoubtedly, the delicate balance
between physiological effects of ROS, as signaling molecules
and efficient component of immune cells, and their pathological effects is under the control of complex system of antioxidant defense and represents a key aspect of life. However, in
pathological states, production of ROS can overcome the capacity of antioxidants. This state is called oxidative stress. The
precise definition given by Sies in the early 1990s describes
oxidative stress as an “imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage.”
So, it is not just about the increase in ROS (if it induces more
efficient antioxidant defense) or about the decrease in antioxidants (if the level of ROS are low); it is a disturbance in their
balance that could end with the damage of our body.
ROS is a term that encompasses all highly reactive, oxygencontaining molecules, including free radicals. ROS includes
superoxide (O2• ), hydroxyl (•OH), peroxyl (ROO•),
lipid peroxyl (LOO•), alkoxyl (RO•) radicals. Reactive nitrogen species (RNS) include nitric oxide (NO•) and nitrogen
dioxide (NO2•). Oxygen and nitrogen free radicals can be
readily converted to other nonradical reactive species that are
also dangerous for health. Hydrogen peroxide (H2O2), ozone
(O3), singlet oxygen (1O2), hypochlorous acid (HOCl), nitrous
acid (HNO2), peroxynitrite (ONOO ), dinitrogen trioxide
(N2O3), and lipid peroxides (LOOH) are not free radicals but
generally named oxidants and can easily lead to free radical
reactions in living organisms.
All ROS and RNS are capable of reacting with membrane
lipids, nucleic acids, proteins and enzymes, and various small
molecules, resulting in cellular damage.

Encyclopedia of Food and Health

Mechanisms of ROS Generation
ROS can be produced from both endogenous and exogenous
sources. Production of ROS in the body is continuous and a
normal part of our physiology.
Endogenous sources of ROS include the following:
Mitochondrial respiratory chain (MRC). It is the main source
of ROS, particularly O
2 , the most crucial one as it can induce
formation of several other reactive oxygen intermediates. O
2 is
formed by reduction of molecular oxygen with electron
‘leaked’ from the MRC.
Respiratory burst and NADPH oxidase. Respiratory burst is the
process by which phagocytic cells consume large amounts of
oxygen during phagocytosis, mainly via activation of NADPH
oxidase and O
2 release into the extracellular space or phagosomes. NADPH oxidase is an enzyme present in the plasma
membrane and phagosomes of phagocytes such as monocytes,
macrophages, neutrophils, and eosinophils. Relocation of the
cytosolic components of NADPH oxidase to the cell membrane
induces its activation. Enzyme is normally latent in phagocytes
but is activated in the membrane before respiratory burst.
There are six homologues of NADPH oxidase, collectively
called the NOX family of NADPH oxidases.
Xanthine oxidase (XO). It is found on the outer surface of the
plasma membrane and in the cytoplasm. It catalyzes oxidation
of hypoxanthine to xanthine and, further, to uric acid as part of 

purine catabolism. Both reactions generate O
2 . However, O2
has a short half-life and is readily reduced to H2O2, so is not
considered as highly reactive. Additionally, due to charged
moiety of O
2 , it cannot pass through lipid membranes. The
production of xanthine and XO is greatly enhanced during
ischemia, accompanied with the loss of antioxidant enzymes.
O2 is an electron acceptor and cofactor for XO, thus generating
O
2 and H2O2, a major ROS in ischemia, causing damage to
ischemic cells and tissues of different origins.
Lipoxygenases (LOX). They are nonheme iron enzymes that
catalyze dioxygenation of polyunsaturated fatty acids and
formation of hydroperoxyl derivatives that can be subjected
to reduction and give corresponding hydroxyl derivatives,
including leukotrienes and lipoxins. In humans, oxidation of
arachidonic acid by LOX generates ROS. Five LOX enzymes
identified in humans, named based on position of oxygenated
residues, catalyze four different reactions that produce fatty
acid hydroperoxides. LOX are deeply involved in the process
of atherogenesis.
Myeloperoxidase (MPO). It is a heme enzyme localized in
lysosomes of neutrophils, macrophages, and monocytes. It
catalyzes the reaction of H2O2 to highly reactive HOCl and
an oxidation of thiocyanate (SCN) to hypothiocyanite
(OSCN).

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227

trans fatty acid. endothelial NOS (eNOS or NOS III). or enhance capacity of endogenous antioxidants act as exogenous antioxidants. a nitration product of DNA and RNA. anesthetics. This reaction is coupled to the reaction catalyzed with glutathione reductase (GSSG-R). minerals. and acrylamide). glue. are the most important exogenous antioxidants. COX releases arachidonic acid (AA) from membrane phospholipids and catalyzes further conversion of AA to prostanoids. GPX has very important role in protecting cells from the harmful effects of peroxide decomposition. and catalase. It is a significant contributor to oxidative stress as source of a large number of free radicals and other oxidative and aromatic agents acting as direct or indirect ROS generators. and water pollutants (chloroform and other trihalomethanes) are potent generator of free radicals. Cancer chemotherapy induces generation of ROS and decrease in vitamin E and beta-carotene levels that often cause toxic side effects. It can trigger the production of free radicals as toxic by-product of intensive metabolism. Food can contain different ROS or compounds that can generate ROS within a human body (iron. NOS can also generate H2O2 within a  reaction with O 2 at low L-arginine levels. including vitamins. Antioxidant Defense System Nature has endowed each cell of our body with adequate antioxidant mechanisms for protection against any harmful effects of ROS generated within the body or those that entered our body from the environment. Cyclooxygenase (COX). This is also an important feature of a great number of anticancer agents. electron donors. and pesticides). which often act as therapeutic through generation of ROS. and most of them have selenocysteine residues at their active site. Transition metals. singlet oxygen quenchers. Mn-SOD is essential for life. In addition. It is a heme-containing monooxygenase that generates NO. Dietary compounds. or metal-chelating agents. There are two isoforms of COX. Three different isozymes of NOS have been identified: constitutively expressed neuronal NOS (nNOS or NOS I). manganese-containing mitochondrial SOD (Mn-SOD). formaldehyde. followed by generation of L-citrulline and NO. It is a bifunctional enzyme with both COX and peroxidase activities. crucial for their action. which can further generate O 2 . glutathione reductase. RNA.and zinc-containing SOD (EC-SOD). gastrointestinal (GI). and form reactive intermediates: NO2. chemical solvents (cleaning products.or cytotoxin-inducible NOS (iNOS or NOS II). and lipids and disrupt their function. hydrogen donors. Many drugs (glucocorticoids. polyphenols. susceptible systems are the cerebrovascular. prostacyclins. and orally bioavailable resulted in their most often use as antioxidant supplements in the prevention or therapy of stress-related diseases. Air pollutants (asbestos. different substances or agents that can scavenge reactive oxygen metabolites. perfumes. Formed H2O2 is reduced by GPX present in the mitochondrial matrix. Pollutants. and toluene). Increase in oxidative stress has been observed in postprandial states after high-fat and/or high-sugar meals. The generation of HO  through this pathway accelerates lipid peroxidation. synergists. Glutathione peroxidase (GPX) converts glutathione into oxidized glutathione (glutathione disulfide. COX catalyzes oxidation of AA to unstable cyclic hydroperoxide (PGG2) and further its reduction of PGG2 endoperoxide due to its peroxidase activity (PGH2).228 Antioxidants: Role on Health and Prevention Nitric oxide synthase (NOS). is a potent prooxidant and mutagen. Antioxidants act as radical scavengers. 8-Nitroguanine. benzene. enzyme inhibitors. and NO. They are capable to nitrate and nitrosate important biological macromolecules such as DNA. and alcohol. SOD and catalase provide major antioxidant defenses against ROS. but in reaction with O2 generates OONO. respectively. and volcanic activities also can generate free radicals. Thermally treated lipids and alcohol can be significant contributors to oxidative stress. Superoxide dismutases (SOD) are enzymes that catalyze dismutation of O 2 into O2 and H2O2. Burning of organic matter during cooking. which accumulate in cells. O 2 formed in the mitochondria is converted to H2O2 by the action of Cu-Zn-SOD of the mitochondrial intermembranous space and Mn-SOD of the mitochondrial matrix. forest fires. and nonsteroidal anti-inflammatory agents) and xenobiotics generate free radicals. Neurons are characterized by very low levels of GSH and thus are particularly vulnerable to free radical damage. food. the enzyme responsible for maintaining optimal reduced glutathione (GSH) levels. proteins. hormones that mediate stress reaction in the body (cortisol and catecholamine) decompose into destructive free radicals. All types of NOS catalyze the oxidation of L-arginine to an intermediate. GSSG) and simultaneously reduces H2O2 to H2O and lipid hydroperoxides (ROOH) to corresponding stable alcohols. and they are oxidized to Fe3þ and Cu2þ. Endogenous antioxidant defense system (ADS) comprises enzymatic and nonenzymatic antioxidants. glutathione peroxidase. paint thinners. enzyme inducers. The peroxidase activity of COX generates NAD and NADP radicals. paints. Mental stress. Cigarette smoke. block their generation. N2O3. NO is a weak oxi dant. chlorine. and thromboxane A2. Oxidative stress can also be triggered by external factors acting as direct or indirect sources of ROS: Radiation and chemotherapy. and hematopoietic systems. and carotenoids. Besides endogenous antioxidants. peroxide decomposers. and endotoxin. Transition metal ions such as iron (Fe2þ) and copper (Cu) are involved in the Fenton reaction that generates HO and OH from H2O2. COX-1 and COX-2. NO and OONO can further form very stable nitrite (NO 2 ) and nitrate (NO 3 ) ions. Particularly. The fact that they are safe. cheap. There are eight isotypes of GPX in humans. copper.and zinc-containing SOD (Cu-Zn-SOD). and extracellular copper. There are three isoforms of SOD in humans: cytosolic copper. PGH2 is converted to stable prostanoids such as PGE2. Uncharged H2O2 passes the mitochondrial membranes and . isothiocyanates. carbon monoxide. Xenobiotics including drugs. Endogenous Enzymatic Antioxidants The major antioxidant enzymes in human cells are superoxide dismutases. Ionizing radiation can produce HO by radiolysis of water or other ROS via secondary reactions. N-hydroxy-L-arginine. ozone.

Minerals (zinc (Zn). LOX. via its products. and the decrease in GSH levels is a signaling factor for GST induction. GSH is an important antioxidant. Less lipophilic isothiocyanates enter the cell in a time-dependant manner and react with GSH. glucosinolates. semidehydroascorbic acid E. it is an important protector of the liver from oxidative stress induced by alcohol consumption. and selenium (Se)) are antioxidant micronutrients as they are cofactors of important antioxidant enzymes. Thioredoxin system is composed of thioredoxin (Trx) and thioredoxin reductases (TrxR). It converts H2O2 to H2O and O2. Levels of Antioxidant Action An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it. As an essential nutrient. Polyphenols are shown to be potent inhibitors of XO. microsomal monooxygenases. biliverdin. and glycine. Isothiocyanates are bioactives of cruciferous vegetables. manganese (Mn). O3. mainly fresh fruits and vegetables. Endogenous Nonenzymatic Antioxidants Glutathione (GSH). which bioactivity still needs to be confirmed. It neutralizes HO and peroxyl radicals. GST. Se is a major antioxidant as it is a component of selenoproteins. but are potent inducers of antioxidant enzymes. their direct antioxidant potential is compromised by their low bioavailability and extensive metabolism. It is mainly present in its reduced form. Catalase is a heme enzyme located mainly in peroxisomes. but they can act as either prooxidant or oxidant depending on the level of O2 and carotenoids. it scavenges ROS and recovers from the formed oxidized Trx state (Trx-S-S) via reduction catalyzed by a flavoenzyme TrxR and NADPH. it can protect cells against oxidative stress. GI tract. Glutathione reductase (GR or GSR) is a homodimeric flavoprotein disulfide oxidoreductase. The resulting ascorbate free radicals reduce to a neutral ascorbate molecule. is found in all eukaryotic cells and represents one of the key nonenzymatic antioxidants in the body. A large number of antioxidants. which results in the formation of an intermediate free radical. In its dithiol form. The first line of defense comprises preventive antioxidants. and thus. However. iron (Fe). Plant polyphenols are important dietary antioxidants. and dietary intake of these compounds can be up to 1200 mg day1. and induce increase in cellular glutathione levels. It exists in two isoforms. 229 Carotenoids and vitamin A are thought to be antioxidants. it needs to be taken from foods. the GSH system serves as an antioxidative barrier. It is accompanied by three enzymes involved in its homeostasis: GR. Heme oxygenase (HO) catalyzes degradation of heme and formation of CO. GPX. O 2 . Liver and kidney cells. In the gut mucosa. as well as erythrocytes. These antioxidants delay or inhibit cellular damage mainly through their free radicalscavenging property. cysteine. acting this way. such as GST. GR’s main role is to protect red blood cells. and they all posses strong antioxidant potential confirmed in chemically based assays. Vitamin E and a-tocopherol. and cell membranes from oxidative stress. Se deficiency can result in toxicity through increased O 2 . and thus. They do not exert direct antioxidant activity. and uric acid. nitrosating compounds. and Cu are cofactors of superoxide dismutase (Cu/Zn-SOD). Exogenous Antioxidants Vitamin C or ascorbic acid is the primary antioxidant in the plasma and cells. It donates two electrons from C-2 and C-3 double-bond carbons. They can also be cytotoxic depending on their concentration and the side chain. It is a valuable protector of the mitochondria against oxidative stress. GPX. sulfur radicals. Melatonin is a hormone of the pineal gland but can be found also in the retina. are produced in the body during normal metabolism. but they can also act as prooxidants and reduce transition metals. Dietary levels of isothiocyanates cannot exert toxic effects on normal cells. It does not have a direct antioxidant enzymatic function. widely distributed in fruits and vegetables. able to suppress the formation of free radicals. More lipophilic ones enter the cell very fast resulting in immediate deprivation of GSH levels and induction of cytotoxic effects. present in the form of their precursors. resulting in net increase of cellular GSH levels. and glutathione S-transferases (GST). and peroxidase are known to decompose lipid . The mode of action depends on the level of a-tocopherol. It can react with various ROS. repair and de novo synthesis. RNS. but indirectly. are rich in catalase. as it can pass through the mitochondrial membrane. GST. HO-1 expression is induced by heat shock. They form the glutathione system. Trx is disulfide-containing oxidoreductase that modulates activity of redox-sensitive transcription factors. and HOCl. so it is often called a suicidal or terminal antioxidant. protect cell’s lipids from peroxidation by scavenging ROS. lymphocytes. Other antioxidants are obtained from a diet. and lipid peroxidation. a tripeptide consisting of glutamate. NO.Antioxidants: Role on Health and Prevention can be scavenged in the cytosol by cytosolic Cu-Zn-SOD or catalase. The ADS assumes several different acting levels such as prevention. inducible HO-1 and constitutively expressed HO-2. ubiquinol. hemoglobin. and iron. including glutathione. It is a water-soluble vitamin found in all body fluids. and HOCl. radical scavenging. and Fe is a component of catalase. phospholipid hydroperoxide glutathione peroxidase (PHGPX). Bioactive plant polyphenols are secondary plant metabolites. They can also be susceptible to the metabolic transformation by intestinal microbiota resulting in a wide variety of simple compounds. and adaptation as the lines of defense. Mn. The characteristic of this antioxidant is that it is irreversibly oxidized. Zn. thus reducing its capacity to damage. copper (Cu). Antioxidants interact with free radicals and terminate chain reactions by removing free radical intermediates and inhibit other oxidation reactions by being oxidized themselves. GSH. CO 3 . and procyanidins. resulting in very low levels of the parent compounds (in aglycone from) and metabolites. as the most active form of this vitamin. or ischemia/reperfusion injury. COX. UV radiation. Main polyphenol classes are flavonoids. NO2. It reduces oxidized glutathione (GSSG) to GSH. and bone marrow. phenolic acids. and NADH oxidase and are capable to chelate transition metals and indirectly suppress ROS production.

Selenium is an important component of antioxidant defense. and orange vegetables and fruits from solar radiation damage. and . uric acid. including total reactive antioxidant potential. vitamin C. However. are known. and chocolate. cabbage. very often. or the ferrous oxidationxylenol orange assays. albumin. Oxidative stress has been demonstrated by depressed levels of antioxidant substances (e. Therefore.230 Antioxidants: Role on Health and Prevention hydroperoxides to corresponding alcohols. The fourth line of defense is another adaptation mechanism. celery. they have been shown to affect redox states in the cell by acting as signaling molecules. plums. grapes. influencing different processes of the human body. Plant bioactives. and wine (monomeric flavanols). Berry fruits are also the main dietary source of anthocyanins (subclass of flavonoids) that are also present in substantial quantities in grapes. the Trolox-equivalent antioxidant capacity. Selenium should be taken from foods. watercress. lose the antioxidant potential of the parent compounds. GPX. cantaloupe. squash. green peppers. and seeds. In addition to many vitamins and minerals as nutrients. Rich sources of phenolic acids are berry fruits. eggs) are the preferred sources for maintaining and increasing bodily GSH levels. which repair the damaged DNA. cherry. The third line of defense is the repair and de novo synthesis of antioxidants. Food sources of peroxidase are horseradish root. Glutathione (GSH) protects cells from toxins including free radicals. Still. present in the cytosol and in the mitochondria of mammalian cells. and wine. Depending on the particular class or subclass of polyphenols. kiwi. turnip. synthesized in the liver from methionine. their metabolites. cherries. as the most studied of more than 600 different carotenoids that have been discovered. squash. eggs. corn flour. apricots. Food sources with the highest amounts of naturally occurring GSH include asparagus. a naturally occurring amino acid that is the most important nutritional source of Se. The DNA repair systems also play an important role in the total defense system against oxidative damage. grapefruit. and beans (flavonols). apples. soybean. confirmed in numerous chemically based assays. It is hypothesized that it plays a similar role in the body. carotenoids. and peptidases. cantaloupe. artichoke. parsley. broccoli. and glutamic acid. nuts. peach.’ increased levels of ROS can cause long-term damage that has been implicated in numerous degenerative diseases. The second line of defense comprises antioxidants that scavenge the active radicals to suppress chain initiation and/or break the chain propagation reactions. One of the most investigated activities is their antioxidant potential. and strawberries. shellfish. Important sources include citrus fruits. and horseradish. Cysteine is incorporated in the cellular glutathione. and leukocytes and consisting of a protein complex with hematin groups that catalyzes the oxidation of various substances. Various kinds of enzymes such as glycosylases and nucleases.. The human body produces GSH from the synthesis of three key amino acids: cysteine. Fish. main dietary sources of these bioactive compounds are numerous. and CAT). citrus fruits and juices (flavanones). potatoes. broccoli. spinach. mango fruit. chicory. kale. watermelon. and uric acid). proteases. yellow. cauliflower. zucchini. In pathological conditions. the human body is in a steady state with ROS being continuously generated and quenched. chicken. Excessive intake of cysteine can result in liver damage. raw cabbage. in the state of ‘oxidative stress. vitamin E. kale. and remove oxidatively modified proteins and prevent their accumulation.. Isothiocyanates are the main bioactives of cruciferous vegetables including broccoli. Vitamin E (tocopherols and tocotrienols) is a fat-soluble vitamin that can be stored in the liver and other tissues. The proteolytic enzymes. avocado. Role on Health and Prevention Oxidative Stress and Disease In physiological conditions. meat. degrade. It is often indicated for a range of states. and apricots are particularly rich sources of beta-carotene. green and black tea. the oxygen radical absorbance capacity. green leafy vegetables. apricots. and garlic.g. and capsicum pepper (flavones). kidney stone formation. Beta-carotene. change in overall antioxidant capacity of plasma using different chemically based assays. and foods that yield sulfurcontaining amino acids (e. where the signal for the production and action of reactive species induces formation and transport of the appropriate antioxidant to the right site of action. Carrots. low levels of enzymes that are important parts of the ADS or their activity (SOD. from aging delay to sunburn healing. red meat. and thiols) and lipophilic (vitamin E and ubiquinol). which works along with vitamin E to protect cells against free radical oxidant damage. broccoli. and potatoes. peach. proteinases. green and black tea. aubergine. glycine. protects dark green. tomatoes. and turnip. The examples include both hydrophilic (vitamin C. Animal proteins are better sources of sulfur amino acids compared to proteins from vegetables. berry fruits. ciders and coffee. Cysteine is an important antioxidant in cellular systems. tomato. which are the form of bioactives that can be found in the circulation. PHGPX is unique as it can reduce hydroperoxides of phospholipids integrated into biomembranes. broccoli. potato. garden salad. sweet potatoes. glutathione. grains.g. milk. Cereals contain selenomethionine. peaches. beans. Vegetables can also be a good source if grown in selenium-rich soils. Glutathione peroxidase and catalase reduce hydrogen peroxide to water. kale. plants are rich sources of nonnutritive dietary compounds and plant secondary metabolites – phytochemicals – and many of them are bioactive. collards. soy and soy products (isoflavones). a balanced diet that includes both animal and vegetable proteins (from grains and beans) would provide adequate cysteine intake. apple. as large doses that can be present in supplements can exert toxic effects. Important dietary sources of vitamin E are wheat germ. or even some forms of neurological disturbances. Bioactives of other flavonoid subclasses can be found in onion. Cysteine is a nonessential amino acid. strawberries. bilirubin. the ferric reducing/antioxidant power. Good food sources include fish. Peroxidase is an enzyme occurring especially in plants. recognize. Antioxidants in Human Diet Vitamin C cannot be stored in the body and should be included in regular diet.

Oxidative stress is involved in the process of the development of cancer and tumors. However. in healthy subjects or participants with the diseases. various respiratory diseases. a great number of intervention trials were conducted in the past aiming to investigate the effects of antioxidants in the prevention (primary. initiated by epidemiological studies. cardiovascular. published a guidance document on the scientific requirements for health claims related to antioxidants. Surprisingly. recent data from the Cancer Prevention Study II Nutrition Cohort indicated an association of flavonoid consumption with lower risk of death from CVD. and eye diseases including cataracts and retinal damage leading to agerelated macular degeneration. polyphenols in general exert pleiotropic effects on cardiovascular health. the putative list of diseases and pathological conditions considered to be associated with oxidative stress should include atherosclerosis. This was confirmed in large number of intervention trials. transcription factors. and increased risk of infectious disease. and neurodegenerative diseases. As shown in numerous intervention studies. coronary heart disease. suggesting relatively new area of isothiocyanate research. Most of previous research was targeted to the elucidation of its role on the pathogenesis of cardiovascular diseases. the European Prospective Investigation into Cancer and Nutrition (EPIC). Still. in numerous clinical trials. Based on their expertise and experience drawn from up-to-date evaluations. Antioxidants and Cardiovascular Disease Animal and human data implicate increased levels of ROS associated with oxidative stress in the pathogenesis of cardiovascular disease. or tertiary) or therapy of chronic diseases. there are many gaps that still need to be filled before the final conclusion about the relevance of antioxidant activity (both direct and indirect) as a mechanism of action of dietary compounds in the prevention and therapy of various diseases. vegetables. European Food Safety Authority’s (EFSA’s) Panel on Dietetic Products. responsible for verifying the scientific substantiation of the health claims. in which cells lose their natural function and spread throughout the blood in the entire body. Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality. diabetes (both noninsulin-dependent and insulin-dependent diabetes). associations were strongest with intermediate intakes. where the disturbance has been shown and correlates 231 with the pathogenesis. and gene tumor suppressors. supplementation with antioxidants could compromise the final outcome of the therapy. causing side effects. Results from intervention trials were promising as well. some antioxidant supplements seem to increase overall mortality in general population and cancer patients. Health Professionals Follow-Up Study (HPFS). which can affect the activities of signal transduction. and even disappointing. their specificity (Comet assay and plasma markers of protein oxidation). Accordingly. Regarding the effects of antioxidants. And the results of recent meta-analyses vary between supportive.Antioxidants: Role on Health and Prevention increased levels of oxidation products (e. Another prospective study showed inverse association between anthocyanin intake and myocardial infarction risk. and cardiovascular health. due to the damage of the macromolecules by generated ROS. secondary.g. there is no scientific evidence for the effects of antioxidant supplementation in the prevention of GI cancers. . an impaired immune system. inconclusive. Some authors share opinion that disappointing results obtained with exogenous antioxidants are not a proof of their inefficiency but rather indicate a misleading approach with the whole body antioxidant defense as a target instead of focusing on disease relevant sites. or skin cancer. at least with small-sized antioxidants. a strategy that will include an approach similar to that in pharmaceutical research could lead to a discovery of new. and protein carbonyls) or markers of macromolecular damage (comet assay for DNA degradation and skin markers for protein degradation). autoimmune conditions including rheumatoid arthritis. malondialdehyde. Antioxidants and Cancer Cancer is uncontrolled cell growth. Nutrition and Allergies (NDA).). has been implicated as underlying cause of various diseases.. producing a state of severe oxidative stress. advanced. and allcause mortality were unsupportive or at least inconclusive. lung cancer. and more efficient antioxidant nutraceuticals. showing beneficial effects of polyphenols intake on variety of CVD risk factors and biomarkers. suggesting that even relatively small amounts of flavonoid-rich foods may be beneficial. On the contrary. Oxidative stress. etc. Based on Cochrane reviews. oxidative damage. cancer. depending on the type of antioxidant and the targeted population. It is still questionable if these effects were a result of direct or indirect antioxidant effects or more specific interactions with relevant molecular and cellular targets. as a result of either excessive generation of reactive species or disturbed antioxidant defense. On the contrary. suggesting an inverse association between diet rich in fruits. numerous studies using valid biomarkers show promising results. However. However. 8-hydroxy-2-deoxy-guanosin. and whole grains and the incidence of major chronic diseases. Beyond direct effect on DNA. Oxidative damage or genetic defects in enzymes that repair mutations favor age-dependent cancer. major concerns were related to the causal correlation between certain biomarkers and health benefit (biomarkers of plasma antioxidant status). However. supplementation failed to reduce cardiovascular morbidity or mortality. oxi-LDL. including cancer and cardiovascular diseases. However. it was shown that if generation of ROS is deeply involved in the mechanism of action of anticancer agents. Even the results from German EPIC study on the associations between vitamin/ mineral supplementation and cancer. metaanalyses of studies on markers of diseases instead on markers of disease risks were less supportive. ROS-induced oxidation products of lipids (malondialdehyde) can cause mutations or breaks in the DNA double chain or modifications in guanine and thymine bases and sister chromatid exchanges. and applied methodology (ELISA). The effects of antioxidants on the prevention of these pathologies were supported by the results of large prospective studies (Nurses’ Health Study (NHS). Importantly. However. Evaluation of obtained data by focusing on particular class of antioxidants or particular disease or risk factors provides more precise information. some chemotherapeutics or radiation therapy increases ROS and decreases antioxidant content.

the evidence for polyphenol intake associations with cancer incidence is mostly limited to the cancers of gastrointestinal tract. based on the systematic review of the literature. melatonin. produced in retina during light absorption. Additionally. prostate. but not cognitive decline and dementia in general. colon (but not rectal). Liu L. Dinkova-Kostova AT and Kostov RV (2012) Glucosinolates and isothiocyanates in health and disease. curcumin. They provide support to the protective function of epithelial barrier against deleterious effects of prooxidants and proinflammatory agents in the gut lumen through their prebiotic properties on GI microbiota. the major cause of blindness in elderly people. The suggestion that they are triggered. Ginkgo biloba extract. have been shown to exert beneficial effects on oxidative stress in GI tract. vitamins. In substantial number of prospective studies. beta-carotene. at least in part. Antioxidants and Gastrointestinal Diseases The GI tract is an important source of ROS. despite long history of use.’ However. Physiological Reviews 82: 47–95. were shown to have a promising future as antioxidants and anticarcinogenesis agents. The results of both the Rotterdam Study and the Cache County Study supported the hypothesis that high dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer’s disease. However. Antioxidants and Immune Function The protective function against external pathogens carried out by the immune system is by itself a source of ROS. prevent wrinkles. are deeply involved in the progression of the disease. There are also some evidences of benefits from vegetables and fruits rich in lutein and zeaxanthin as antioxidants. and minerals) compared to the effects of isolated compounds. and vitamin C) in the prevention and progression delay. showing no effects of antioxidants (beta-carotene. malignancies. Drake VJ. and null for vitamins and minerals in general.1080/10408398.org/10. Critical Reviews in Food Science and Nutrition. Egg yolk is also a good source of these compounds. A recent and extensive review reports no benefits of vitamin E.MAX) on cognitive performance. Some (but not all) studies initially suggested that specific antioxidant supplements help in the protection against further degeneration. Day BJ (2014) Antioxidant therapeutics: Pandora’s box. the Kame project confirmed a hypothesis that polyphenol-rich fruit and vegetable juice intake may exert beneficial effects in delaying the onset of Alzheimer’s disease. Further Reading Angelo G. Antioxidants and Aging For many people. Trends in Molecular Medicine 18: 337–347. The proposed mechanism is based on the fact that ROS. the discrepancies between epidemiological data and clinical trials with supplements (mainly vitamins and minerals) might be due to the synergistic effects of various bioactives in the whole food (antioxidants. several studies postulated an effect on other diseases of GI tract.VI. mainly polyphenols. vitamin E. since activated neutrophils produce free radicals to a significant extent. as supportive therapy in pneumonia or asthma. Generally. particularly among susceptible individuals. the greatest interest is in antioxidants’ antiaging potential. few doubt the potential value of dietary sources. Eliassen AH. and Rimm EB (2013) High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women. Recent studies support the use of antioxidants specifically targeted to the mitochondria as promising therapy of Parkinson’s disease. Generally. In general. resveratrol. . intake of cruciferous vegetables was positively associated with lower risk of breast. other antioxidants that could be effective in the prevention of Alzheimer’s disease include garlic extract. Free Radical Biology & Medicine 66: 58–64. and lung cancers. Chandel NS and Tuveson DA (2014) The promise and perils of antioxidants for cancer patients. In addition to the beneficial effect of plant bioactives on the prevention of GI cancers. there is no evidence that supplementation with antioxidants will stop hair graying. promising results were obtained in a study investigating the effects supplementation with vitamins and mineral antioxidants (SU. Frequent claims suggest that antioxidants benefit the immune system. Antioxidants and Macular Degeneration Some positive messages were expected from studies of particular antioxidants in macular degeneration.912199. Dro¨ge W (2002) Free radicals in the physiological control of cell function. and direct interaction with their lipid bilayer. The results for age-related cataract were negative. Franz M. considering the rise in the percentage of aged population in developed countries. New England Journal of Medicine 371: 177–178. and Frei B (2014) Efficacy of multivitamin/mineral supplementation to reduce chronic disease risk: a critical review of the evidence from observational studies and randomized controlled trials. or any antioxidant supplements for preventing age-related macular degeneration.232 Antioxidants: Role on Health and Prevention Natural compounds such as polyphenols. Dietary antioxidants. but recent meta-analyses indicated that the results are uncertain even for vitamin C and its beneficial effects on common cold. in particular ()epigallocatechin gallate and resveratrol. The final conclusion drawn in the most recent Cochrane review was supporting. Circulation 127: 188–196. and green tea. However. cognitive function is considered as a very promising target for the action of polyphenols and is relevant. by oxidative and nitrosative stress and sustained by inflammatory cytokine production rationalizes the protection of the central nervous system against these damaging mechanisms with antioxidants as a useful prophylactic and therapeutic approach. A direct correlation was also shown for cognitive performance and total flavonoid intake in a prospective Nurses’ Health Study. and inflammatory bowel disease. anti-inflammatory effects on GI epithelial cells.doi. or provide a ‘fountain of youth. Since the body’s production of its own antioxidants decreases with age. Mukamal KJ. Antioxidants and Neurodegenerative Diseases Oxidative processes have been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Cassidy A. with the limitation that most of the data were taken from one randomize trial. at this moment. This is a putative mechanism of various GI diseases including ulcers.2014. http://dx.

Critical Reviews in Food Science and Nutrition 51: 524–546. Murphy MP (2014) Antioxidants as therapies: can we improve on nature? Free Radical Biology & Medicine 66: 20–23. Journal of the American Medical Association 287: 3223–3229. Guerriero E.Antioxidants: Role on Health and Prevention Engelhart MJ.europa. et al. Kroon PA. American Journal of Clinical Nutrition 95: 454–464. Fezeu L.eurofir. Biochimica et Biophysica Acta 1842: 1282–1294. Anantharam V.com/ – Cochrane. 233 McCullough ML. http://ebasis. Capone F.eu/ – European Food Safety Authority.cochranelibrary. Geerlings MI. Patel R. Shah R.MAX) trial. Peterson JJ. Kalyanaraman B. Castello G. MiniReviews in Medicinal Chemistry 14: 444–452. Colonna G. Hooper L. The American Journal of Clinical Nutrition 88: 38–50. Landete JM (2013) Dietary intake of natural antioxidants: vitamins and polyphenols. Kanthasamy A. Visioli F and Davalos A (2011) Polyphenols and human health: a prospectus. flavonoid-rich foods. Ghosh A. Jeandel C. . Sorice A. and Dwyer JT (2012) Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. et al. (2008) Flavonoids.efsa. Kesse-Guyot E.VI. Jacques PF. and Costantini S (2014) Ascorbic acid: its role in immune system and chronic inflammation diseases. Relevant Websites http://www. Rimm EB. and cardiovascular risk: a meta-analysis of randomized controlled trials. (2002) Dietary intake of antioxidants and risk of Alzheimer disease. (2011) French adults’ cognitive performance after daily supplementation with antioxidant vitamins and minerals at nutritional doses: a post hoc analysis of the supplementation in vitamins and mineral antioxidants (SU. http://www. Ruitenberg A. Critical Reviews in Food Science and Nutrition 53: 706–721. et al. Jin H.org/ – EuroFIR AISB. and Kanthasamy AG (2014) Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. The American Journal of Clinical Nutrition 94: 892–899.