INTRODUCTION
Herbs and spices are traditionally defined as any part of a plant that is used in the diet for their aromatic properties with no or low nutritional value (Davidson 1999; Hacskaylo 1996; Smith and Winder 1996). However, more recently, herbs and spices have been identified as sources of various phytochemicals, many of which possess powerful antioxidant activity (Larson 1988; Velioglu et al. 1998; Kähkönen et al. 1999; Dragland et al. 2003). Thus, herbs and spices may have a role in antioxidant defense and redox signaling. In the scientific and public literature, antioxidants and oxidative stress are very often presented in a far too simple manner. First, reactive oxygen species (ROS) are lumped together as one functional entity. However, there are many different ROS that have separate and essential roles in normal physiology and are required for a variety of normal processes. These physiological functions are not overlapping, and the different ROS that exist cannot, in general, replace each other. Different ROS are also strongly implicated in the etiology of diseases such as cancers, atherosclerosis,neurodegenerative diseases, infections, chronic inflammatory diseases, diabetes, and autoimmune diseases (Gutteridge and Halliwell 2000; McCord 2000). Second, the various antioxidants that exist are often viewed as a single functional entity. However, the different endogenous antioxidants that are produced by the body (e.g., glutathione, thioredoxins, glutaredoxin, and different antioxidant enzymes) cannot, in general, replace each other. They have specific chemical and physiological characteristics that ensure all parts of the cells and the organs or tissues are protected against oxidative damage. Dietary antioxidants also exist in various forms, with polyphenols and carotenoids being the largest groups of compounds. These have different functions and are produced by plants to protect plant cells against oxidative damage (Halliwell 1996; Lindsay and Astley 2002). Based on the complex nature of antioxidants and ROS, it would thus be extremely unlikely that a magic bullet with a high dose of one or a few particular antioxidants such as vitamin C, vitamin E, or β-carotene would protect all parts of the cells, organs, and tissues against oxidative damage and oxidative stress, at the same time without destroying any of the numerous normal and beneficial functions of ROS. Indeed, supplementation with antioxidants has often resulted in no effect or even adverse disease outcomes. Recently, several reviews and meta-analyses have concluded that there is now a strong body of evidence indicating that there is no beneficial effect for supplemental vitamin C, vitamin E, or β-carotene (Vivekananthan et al. 2003; Eidelman et al. 2004; Bjelakovic et al. 2007; Bjelakovic et al. 2008). An alternative and much more likely antioxidant strategy to test protection against oxidative stress and related diseases would be to test the potential beneficial effects of antioxidant-rich foods, since such foods typically contain a large combination of different antioxidants that are selected, through plant evolution, to protect every part of the plant cells against oxidative damage. This is especially relevant for herbs and spices. The aim of this chapter is to discuss the potential role of antioxidants in herbs and spices in normal physiology, oxidative stress, and related diseases. We begin with a brief introduction of ROS and their role in normal physiology and oxidative stress, and then present data that demonstrate herbs and spices are the most antioxidantdense dietary source of antioxidants that has been described. We end the chapter with a discussion on the potential role of herb and spice antioxidants in oxidative stress.
REACTIVE OXYGEN SPECIES: COMPLEX ROLES IN NORMAL PHYSIOLOGY
ROS molecules are simply oxygen-containing molecules that are reactive. They can be divided into free-radical ROS and nonradical ROS. Free-radical ROS have unpaired electrons in their outer orbits; examples of such molecules are superoxide and hydroxyl radical. Nonradical ROS do not have unpaired electrons; however, these are chemically reactive and can be converted into free-radical ROS. One example of a nonradical ROS is hydrogen peroxide.
Role of Reactive Oxygen Species in Cell Signaling
To survive, cells must sense their immediate surroundings and change their activity according to their microenvironment. This is accomplished through cell signaling. A basic signaling pathway relays a signal through the cell by modulating the activities of proteins along the pathway. A “mediator” or “second messenger” is a molecule that promotes (or inhibits) a step in a signaling pathway. Functions of ROS have been described at different locations of signaling pathways. The ROS molecules have been described as the very first stimulus that starts the cascade of a signaling pathway, the “initiator,” and also as the last step of a signaling pathway, the so-called effector. Furthermore, ROS can also be involved somewhere between the start and the end of the signaling pathway, either as the molecule that relays the signal itself or by promoting a step in the signaling pathway. In both cases, ROS can be seen as the mediator in the particular pathway (for review, see the work by Hancock [2009]). However, for ROS to function as signaling mediators, they should be produced where and when they are needed, sensed by some mechanism, and should be rapidly removed to stop the signal from being sustained.
Production of Reactive Oxygen Species
ROS molecules are created during the reduction of oxygen to water. The addition of one electron to oxygen creates superoxide, whereas further reduction gives hydrogen peroxide. Production of ROS can also be a consequence of endogenous or exogenous stimuli, including ultraviolet (UV) radiation, chemotherapy, environmental toxins, and exercise (Blomhoff 2005). Deliberate production of ROS occurs in different cellular compartments from enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH), oxidases (NOX and dual oxidase [DUOX]), nitric oxide (NO) synthase (NOS), xanthine oxidase, and from the electron transport chain of the mitochondria. There are seven NADPH oxidases (i.e., NOX1 to NOX5 and DUOX1 and DUOX2). These are transmembrane proteins that produce superoxide or hydrogen peroxide. The oxidases NOX1 through 5 produce superoxide by the transfer of an electron through the membrane from NADPH to oxygen. The enzymes DUOX1–2 are calcium-dependent enzymes and produce hydrogen peroxide directly by virtue of a peroxide-like subunit located on the outer side of the membrane in addition to the transfer of an electron from NADPH. The enzymes further differ in their cellular compartmentalization, their upstream activators, and the associated subunits. Known inducers of NOX are growth factors, cytokines, and vitamin D (Brown and Griendling 2009; Chen et al. 2009; Leto et al. 2009). Mitochondria have traditionally been thought to produce ROS only as an unwanted by-product of energy production in the electron transfer chain. However, deliberate ROS production also occurs from the mitochondria. This occurs at least partially by the inhibition of cytochrome c oxidase by NO leading to increased superoxide production without affecting energy production. Mitochondrial superoxide dismutase converts superoxide to hydrogen peroxide, which can cross the membrane and take part in cytosolic signaling (Brookes et al. 2002).
How Are Reactive Oxygen Species Perceived?
ROS can alter the production, stability, or function of proteins. The redox status may alter the activity of transcription factors in the nucleus. In general, the reduced transcription factor binds to deoxyribonucleic acid (DNA) and promotes transcription, whereas an oxidized transcription factor will not be able to bind to DNA and thus will not promote transcription. Furthermore, the stability of proteins can be affected by the oxidation of proteasomes. Oxidation of proteasomes may render them inactive and unable to degrade proteins, thus maintaining or increasing the level of proteins. Finally, the function of proteins and molecules can be modified through oxidation by the following three different strategies: (1) Proteins, such as thioredoxin, can be oxidized, resulting in alteration of the activity of the protein directly. (2) The oxidation targets a chaperone protein that usually inhibits protein activity; on oxidation, the protein can dissociate from its inhibitor and thus become active. (3) Phosphatases and kinases can be targets for oxidation, and subsequently alter the activity of proteins through posttranslational modifications. Protein tyrosine phosphatases are often inactivated by oxidation, whereas the different kinases are generally activated. The most common targets of oxidation are cysteine residues, but other amino acids like tyrosine and methionine can also be targets. Further oxidation of target molecules may lead to irreversible oxidative damage. Oxidized cysteine residues can be protected from further oxidation by the formation of thiol bridges. In phagocytosis, ROS is an effector that is produced by NOX2 inside the phagosome to kill phagocytozed microbes. Targets of ROS in signaling pathways include transcription factors, redox sensors, and phosphatases/kinases. Transcription factors include Nrf2, NF-kB, p53, AP-1, cyclic adenosine monophosphate response element binding (CREB), HomeoboxB5, and nuclear receptors such as the estrogen receptor. Redox sensors include thioredoxin, glutharedoxins, peroxiredoxins, glutathione, and redox effector factor-1 (Ref-1), whereas phosphatases/kinases include PTP, Akt, JNK, ERK, Src, and CDK (Brown and Gutteridge 2007; Halliwell and Gutteridge 2007; Kamata et al. 2005; Kiley and Storz 2004; Trachootham et al. 2008). To counteract the possible toxic effects of ROS and enable ROS to act in signaling pathways, intricate systems of antioxidants have evolved. This system is highly specialized in terms of both removal of specific ROS and compartmentalization of the different antioxidants. For a discussion of various antioxidant systems, please see the excellent book by Halliwell and Gutteridge (2007).
EXAMPLES OF THE DUAL ROLES OF REACTIVE OXYGEN SPECIES IN PATHOLOGIES
Increased levels of ROS have been implicated in numerous chronic degenerative diseases such as cardiovascular diseases, cancers, type 2 diabetes, neurodegenerative diseases, obesity, and hypertension. However, ROS may have dual roles in many pathologies.
Reactive Oxygen Species in Rheumatoid Arthritis
Dual roles of ROS have been found in many types of autoimmune diseases. Most often, the focus was on lowering the levels of ROS as a treatment in diseases such as rheumatoid arthritis (Hultqvist et al. 2009). As NOX2 has been found to produce ROS in rheumatoid arthritis, it would, therefore, be a natural target for therapy. In a murine model of rheumatoid arthritis, mice with dysfunctional NOX2 were found to have decreased ROS production; however, these mice had increased rather than decreased symptoms of rheumatoid arthritis. These mice had more active T cells, and that this increased T-cell activity was due to the dysfunction of NOX2 in macrophages, which rendered the macrophages unable to downregulate T-cell activity. By restoring ROS signaling in the macrophages, the altered T-cell activation was reversed and the increased rheumatoid arthritis symptoms were decreased (Hultqvist et al. 2004; Gelderman et al. 2007).
Exploitation of Reactive Oxygen Species Signaling by Cancer Cells to Survive and Grow
Normal cells have a low level of ROS. Increased ROS, for example, due to inflammation or environmental factors, are generally thought to increase mutations in DNA and thereby risk of cancer. However, the increased level of ROS in cancer cells is balanced by an increased defense against ROS so that the cell does not exceed the ROS threshold for cell death. The increase in ROS leads to activation of signaling pathways that favor cell growth, migration, and proliferation. Furthermore, many cancer therapies (e.g., radiation, chemotherapy) induce massive amounts of ROS that exceed the ROS threshold and induce cancer cell death (reviewed by Trachootham, Alexandre, and Huang 2009). Thus, although antioxidants may theoretically prevent transformation of normal cells to cancerous cells, they may theoretically also lower the efficacy of cancer treatment.
Positive Role of Reactive Oxygen Species in Exercise
During exercise, several adaptive responses occur that are related to the increased level of ROS production via mitochondria. These adaptations include increased antioxidant defense, increased insulin sensitivity in muscle, and biogenesis of mitochondria. Thus, physical activity and exercise decreases the risk of several diseases, although exercise is known to induce the production of ROS. A study by Ristow and collaborators (2009) shed new light on the effect of exercise on ROS production. In their clinical trial, subjects were divided into previously trained or untrained individuals, and these two groups were randomized to consume either high doses of vitamin C and E supplements or placebo during an exercise regimen. Exercise was found to increase ROS, induce ROS defense, and insulin sensitivity. However, these changes were not found in those subjects who had consumed vitamin C and E supplements. Furthermore, these differences were most evident in the previously untrained subjects (Ristow et al. 2009.) Thus, these data suggest that adaptive responses to ROS are an important mechanism that mediates the beneficial effects of exercise.
IS THERE A ROLE OF DIETARY ANTIOXIDANTSIN OXIDATIVE STRESS?
Based on the dual role of ROS described in Section 2.3 and the large variety of ROS and mechanisms involved, it is clear that a beneficial effect of a large intake of one single antioxidant (such as highdose vitamin C, vitamin E, or β-carotene supplement) would not be expected. An alternative and much more likely strategy would be to test the potential beneficial effects of antioxidant-rich foods, since such foods typically contain a large combination of different antioxidants, which are selected through plant evolution to protect every part of the plant cells against oxidative damage. Moreover, this “package” of antioxidants with different functions is also present in much lower doses than those that are typically used in antioxidant supplements. Thus, we suggest that dietary antioxidants taken in their usual form of food may decrease risk of chronic diseases without compromising the normal functions of ROS (Blomhoff 2005). There are numerous antioxidants in dietary plants. Carotenoids are ubiquitous in the plant kingdom, and as many as 1000 naturally occurring variants have been identified. At least 60 carotenoids occur in the fruits and vegetables commonly consumed by humans (Lindsay and Astley 2002). Besides the pro-vitamin A carotenoids, α- and β-carotene, and β-cryptoxanthin, lycopene and the hydroxy carotenoids (xanthophylls) lutein and zeaxanthin are the main carotenoids present in the diet. Their major role in plants is related to light harvesting as auxiliary components and quenching of excited molecules, such as singlet oxygen, that might be formed during photosynthesis. Phenolic compounds are also ubiquitous in dietary plants (Lindsay and Astley 2002). They are synthesized in large varieties, and belong to several molecular families, such as benzoic acid derivatives, flavonoids, proanthocyanidins, stilbenes, coumarins, lignans, and lignins. Over 8000 plant phenols have been isolated. Plant phenols are antioxidants by virtue of the hydrogen-donating properties of the phenolic hydroxyl groups. We hypothesize that antioxidant-rich foods may be beneficial and provide a balanced combination of a variety of antioxidants in appropriate doses that would protect against excessive oxidative stress and oxidative damage without disturbing the normal role of ROS. In order to test this hypothesis, we first need to identify antioxidant-rich foods, that is, foods that contain relatively large amounts of total antioxidants. Therefore, we perform a systematic screening of the total antioxidant content (Benzie and Strain 1996) of more than 3500 foods (Halvorsen et al. 2002; Halvorsen et al. 2006; Carlsen et al. 2010). This novel and unique antioxidant food table enables us to calculate the total antioxidant content of complex diets, identify and rank potentially good sources of antioxidants, and provide the research community with data on the relative antioxidant capacity of a wide range of foods. There is not necessarily a direct relationship between the antioxidant content of a food sample consumed and the subsequent antioxidant activity in the target cell. Factors influencing the bioavailability of phytochemical antioxidants include the food matrix and food preparation methods, as well as absorption, metabolism, and catabolism. With the present study, food samples with high antioxidant content are identified, but further investigation into each individual food is needed to identify those samples that may have biological relevance and the mechanisms involved in antioxidant activity. Such studies, including mechanistic cell-culture and experimental animal research, preclinical studies on bioavailability and bioefficacy, as well as clinical trials, are in progress.
to be continued...
Herbs and spices are traditionally defined as any part of a plant that is used in the diet for their aromatic properties with no or low nutritional value (Davidson 1999; Hacskaylo 1996; Smith and Winder 1996). However, more recently, herbs and spices have been identified as sources of various phytochemicals, many of which possess powerful antioxidant activity (Larson 1988; Velioglu et al. 1998; Kähkönen et al. 1999; Dragland et al. 2003). Thus, herbs and spices may have a role in antioxidant defense and redox signaling. In the scientific and public literature, antioxidants and oxidative stress are very often presented in a far too simple manner. First, reactive oxygen species (ROS) are lumped together as one functional entity. However, there are many different ROS that have separate and essential roles in normal physiology and are required for a variety of normal processes. These physiological functions are not overlapping, and the different ROS that exist cannot, in general, replace each other. Different ROS are also strongly implicated in the etiology of diseases such as cancers, atherosclerosis,neurodegenerative diseases, infections, chronic inflammatory diseases, diabetes, and autoimmune diseases (Gutteridge and Halliwell 2000; McCord 2000). Second, the various antioxidants that exist are often viewed as a single functional entity. However, the different endogenous antioxidants that are produced by the body (e.g., glutathione, thioredoxins, glutaredoxin, and different antioxidant enzymes) cannot, in general, replace each other. They have specific chemical and physiological characteristics that ensure all parts of the cells and the organs or tissues are protected against oxidative damage. Dietary antioxidants also exist in various forms, with polyphenols and carotenoids being the largest groups of compounds. These have different functions and are produced by plants to protect plant cells against oxidative damage (Halliwell 1996; Lindsay and Astley 2002). Based on the complex nature of antioxidants and ROS, it would thus be extremely unlikely that a magic bullet with a high dose of one or a few particular antioxidants such as vitamin C, vitamin E, or β-carotene would protect all parts of the cells, organs, and tissues against oxidative damage and oxidative stress, at the same time without destroying any of the numerous normal and beneficial functions of ROS. Indeed, supplementation with antioxidants has often resulted in no effect or even adverse disease outcomes. Recently, several reviews and meta-analyses have concluded that there is now a strong body of evidence indicating that there is no beneficial effect for supplemental vitamin C, vitamin E, or β-carotene (Vivekananthan et al. 2003; Eidelman et al. 2004; Bjelakovic et al. 2007; Bjelakovic et al. 2008). An alternative and much more likely antioxidant strategy to test protection against oxidative stress and related diseases would be to test the potential beneficial effects of antioxidant-rich foods, since such foods typically contain a large combination of different antioxidants that are selected, through plant evolution, to protect every part of the plant cells against oxidative damage. This is especially relevant for herbs and spices. The aim of this chapter is to discuss the potential role of antioxidants in herbs and spices in normal physiology, oxidative stress, and related diseases. We begin with a brief introduction of ROS and their role in normal physiology and oxidative stress, and then present data that demonstrate herbs and spices are the most antioxidantdense dietary source of antioxidants that has been described. We end the chapter with a discussion on the potential role of herb and spice antioxidants in oxidative stress.
REACTIVE OXYGEN SPECIES: COMPLEX ROLES IN NORMAL PHYSIOLOGY
ROS molecules are simply oxygen-containing molecules that are reactive. They can be divided into free-radical ROS and nonradical ROS. Free-radical ROS have unpaired electrons in their outer orbits; examples of such molecules are superoxide and hydroxyl radical. Nonradical ROS do not have unpaired electrons; however, these are chemically reactive and can be converted into free-radical ROS. One example of a nonradical ROS is hydrogen peroxide.
Role of Reactive Oxygen Species in Cell Signaling
To survive, cells must sense their immediate surroundings and change their activity according to their microenvironment. This is accomplished through cell signaling. A basic signaling pathway relays a signal through the cell by modulating the activities of proteins along the pathway. A “mediator” or “second messenger” is a molecule that promotes (or inhibits) a step in a signaling pathway. Functions of ROS have been described at different locations of signaling pathways. The ROS molecules have been described as the very first stimulus that starts the cascade of a signaling pathway, the “initiator,” and also as the last step of a signaling pathway, the so-called effector. Furthermore, ROS can also be involved somewhere between the start and the end of the signaling pathway, either as the molecule that relays the signal itself or by promoting a step in the signaling pathway. In both cases, ROS can be seen as the mediator in the particular pathway (for review, see the work by Hancock [2009]). However, for ROS to function as signaling mediators, they should be produced where and when they are needed, sensed by some mechanism, and should be rapidly removed to stop the signal from being sustained.
Production of Reactive Oxygen Species
ROS molecules are created during the reduction of oxygen to water. The addition of one electron to oxygen creates superoxide, whereas further reduction gives hydrogen peroxide. Production of ROS can also be a consequence of endogenous or exogenous stimuli, including ultraviolet (UV) radiation, chemotherapy, environmental toxins, and exercise (Blomhoff 2005). Deliberate production of ROS occurs in different cellular compartments from enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH), oxidases (NOX and dual oxidase [DUOX]), nitric oxide (NO) synthase (NOS), xanthine oxidase, and from the electron transport chain of the mitochondria. There are seven NADPH oxidases (i.e., NOX1 to NOX5 and DUOX1 and DUOX2). These are transmembrane proteins that produce superoxide or hydrogen peroxide. The oxidases NOX1 through 5 produce superoxide by the transfer of an electron through the membrane from NADPH to oxygen. The enzymes DUOX1–2 are calcium-dependent enzymes and produce hydrogen peroxide directly by virtue of a peroxide-like subunit located on the outer side of the membrane in addition to the transfer of an electron from NADPH. The enzymes further differ in their cellular compartmentalization, their upstream activators, and the associated subunits. Known inducers of NOX are growth factors, cytokines, and vitamin D (Brown and Griendling 2009; Chen et al. 2009; Leto et al. 2009). Mitochondria have traditionally been thought to produce ROS only as an unwanted by-product of energy production in the electron transfer chain. However, deliberate ROS production also occurs from the mitochondria. This occurs at least partially by the inhibition of cytochrome c oxidase by NO leading to increased superoxide production without affecting energy production. Mitochondrial superoxide dismutase converts superoxide to hydrogen peroxide, which can cross the membrane and take part in cytosolic signaling (Brookes et al. 2002).
How Are Reactive Oxygen Species Perceived?
ROS can alter the production, stability, or function of proteins. The redox status may alter the activity of transcription factors in the nucleus. In general, the reduced transcription factor binds to deoxyribonucleic acid (DNA) and promotes transcription, whereas an oxidized transcription factor will not be able to bind to DNA and thus will not promote transcription. Furthermore, the stability of proteins can be affected by the oxidation of proteasomes. Oxidation of proteasomes may render them inactive and unable to degrade proteins, thus maintaining or increasing the level of proteins. Finally, the function of proteins and molecules can be modified through oxidation by the following three different strategies: (1) Proteins, such as thioredoxin, can be oxidized, resulting in alteration of the activity of the protein directly. (2) The oxidation targets a chaperone protein that usually inhibits protein activity; on oxidation, the protein can dissociate from its inhibitor and thus become active. (3) Phosphatases and kinases can be targets for oxidation, and subsequently alter the activity of proteins through posttranslational modifications. Protein tyrosine phosphatases are often inactivated by oxidation, whereas the different kinases are generally activated. The most common targets of oxidation are cysteine residues, but other amino acids like tyrosine and methionine can also be targets. Further oxidation of target molecules may lead to irreversible oxidative damage. Oxidized cysteine residues can be protected from further oxidation by the formation of thiol bridges. In phagocytosis, ROS is an effector that is produced by NOX2 inside the phagosome to kill phagocytozed microbes. Targets of ROS in signaling pathways include transcription factors, redox sensors, and phosphatases/kinases. Transcription factors include Nrf2, NF-kB, p53, AP-1, cyclic adenosine monophosphate response element binding (CREB), HomeoboxB5, and nuclear receptors such as the estrogen receptor. Redox sensors include thioredoxin, glutharedoxins, peroxiredoxins, glutathione, and redox effector factor-1 (Ref-1), whereas phosphatases/kinases include PTP, Akt, JNK, ERK, Src, and CDK (Brown and Gutteridge 2007; Halliwell and Gutteridge 2007; Kamata et al. 2005; Kiley and Storz 2004; Trachootham et al. 2008). To counteract the possible toxic effects of ROS and enable ROS to act in signaling pathways, intricate systems of antioxidants have evolved. This system is highly specialized in terms of both removal of specific ROS and compartmentalization of the different antioxidants. For a discussion of various antioxidant systems, please see the excellent book by Halliwell and Gutteridge (2007).
EXAMPLES OF THE DUAL ROLES OF REACTIVE OXYGEN SPECIES IN PATHOLOGIES
Increased levels of ROS have been implicated in numerous chronic degenerative diseases such as cardiovascular diseases, cancers, type 2 diabetes, neurodegenerative diseases, obesity, and hypertension. However, ROS may have dual roles in many pathologies.
Reactive Oxygen Species in Rheumatoid Arthritis
Dual roles of ROS have been found in many types of autoimmune diseases. Most often, the focus was on lowering the levels of ROS as a treatment in diseases such as rheumatoid arthritis (Hultqvist et al. 2009). As NOX2 has been found to produce ROS in rheumatoid arthritis, it would, therefore, be a natural target for therapy. In a murine model of rheumatoid arthritis, mice with dysfunctional NOX2 were found to have decreased ROS production; however, these mice had increased rather than decreased symptoms of rheumatoid arthritis. These mice had more active T cells, and that this increased T-cell activity was due to the dysfunction of NOX2 in macrophages, which rendered the macrophages unable to downregulate T-cell activity. By restoring ROS signaling in the macrophages, the altered T-cell activation was reversed and the increased rheumatoid arthritis symptoms were decreased (Hultqvist et al. 2004; Gelderman et al. 2007).
Exploitation of Reactive Oxygen Species Signaling by Cancer Cells to Survive and Grow
Normal cells have a low level of ROS. Increased ROS, for example, due to inflammation or environmental factors, are generally thought to increase mutations in DNA and thereby risk of cancer. However, the increased level of ROS in cancer cells is balanced by an increased defense against ROS so that the cell does not exceed the ROS threshold for cell death. The increase in ROS leads to activation of signaling pathways that favor cell growth, migration, and proliferation. Furthermore, many cancer therapies (e.g., radiation, chemotherapy) induce massive amounts of ROS that exceed the ROS threshold and induce cancer cell death (reviewed by Trachootham, Alexandre, and Huang 2009). Thus, although antioxidants may theoretically prevent transformation of normal cells to cancerous cells, they may theoretically also lower the efficacy of cancer treatment.
Positive Role of Reactive Oxygen Species in Exercise
During exercise, several adaptive responses occur that are related to the increased level of ROS production via mitochondria. These adaptations include increased antioxidant defense, increased insulin sensitivity in muscle, and biogenesis of mitochondria. Thus, physical activity and exercise decreases the risk of several diseases, although exercise is known to induce the production of ROS. A study by Ristow and collaborators (2009) shed new light on the effect of exercise on ROS production. In their clinical trial, subjects were divided into previously trained or untrained individuals, and these two groups were randomized to consume either high doses of vitamin C and E supplements or placebo during an exercise regimen. Exercise was found to increase ROS, induce ROS defense, and insulin sensitivity. However, these changes were not found in those subjects who had consumed vitamin C and E supplements. Furthermore, these differences were most evident in the previously untrained subjects (Ristow et al. 2009.) Thus, these data suggest that adaptive responses to ROS are an important mechanism that mediates the beneficial effects of exercise.
IS THERE A ROLE OF DIETARY ANTIOXIDANTSIN OXIDATIVE STRESS?
Based on the dual role of ROS described in Section 2.3 and the large variety of ROS and mechanisms involved, it is clear that a beneficial effect of a large intake of one single antioxidant (such as highdose vitamin C, vitamin E, or β-carotene supplement) would not be expected. An alternative and much more likely strategy would be to test the potential beneficial effects of antioxidant-rich foods, since such foods typically contain a large combination of different antioxidants, which are selected through plant evolution to protect every part of the plant cells against oxidative damage. Moreover, this “package” of antioxidants with different functions is also present in much lower doses than those that are typically used in antioxidant supplements. Thus, we suggest that dietary antioxidants taken in their usual form of food may decrease risk of chronic diseases without compromising the normal functions of ROS (Blomhoff 2005). There are numerous antioxidants in dietary plants. Carotenoids are ubiquitous in the plant kingdom, and as many as 1000 naturally occurring variants have been identified. At least 60 carotenoids occur in the fruits and vegetables commonly consumed by humans (Lindsay and Astley 2002). Besides the pro-vitamin A carotenoids, α- and β-carotene, and β-cryptoxanthin, lycopene and the hydroxy carotenoids (xanthophylls) lutein and zeaxanthin are the main carotenoids present in the diet. Their major role in plants is related to light harvesting as auxiliary components and quenching of excited molecules, such as singlet oxygen, that might be formed during photosynthesis. Phenolic compounds are also ubiquitous in dietary plants (Lindsay and Astley 2002). They are synthesized in large varieties, and belong to several molecular families, such as benzoic acid derivatives, flavonoids, proanthocyanidins, stilbenes, coumarins, lignans, and lignins. Over 8000 plant phenols have been isolated. Plant phenols are antioxidants by virtue of the hydrogen-donating properties of the phenolic hydroxyl groups. We hypothesize that antioxidant-rich foods may be beneficial and provide a balanced combination of a variety of antioxidants in appropriate doses that would protect against excessive oxidative stress and oxidative damage without disturbing the normal role of ROS. In order to test this hypothesis, we first need to identify antioxidant-rich foods, that is, foods that contain relatively large amounts of total antioxidants. Therefore, we perform a systematic screening of the total antioxidant content (Benzie and Strain 1996) of more than 3500 foods (Halvorsen et al. 2002; Halvorsen et al. 2006; Carlsen et al. 2010). This novel and unique antioxidant food table enables us to calculate the total antioxidant content of complex diets, identify and rank potentially good sources of antioxidants, and provide the research community with data on the relative antioxidant capacity of a wide range of foods. There is not necessarily a direct relationship between the antioxidant content of a food sample consumed and the subsequent antioxidant activity in the target cell. Factors influencing the bioavailability of phytochemical antioxidants include the food matrix and food preparation methods, as well as absorption, metabolism, and catabolism. With the present study, food samples with high antioxidant content are identified, but further investigation into each individual food is needed to identify those samples that may have biological relevance and the mechanisms involved in antioxidant activity. Such studies, including mechanistic cell-culture and experimental animal research, preclinical studies on bioavailability and bioefficacy, as well as clinical trials, are in progress.
to be continued...
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