*2.1.7. Carotenoids*

of reduced quantities of cytokines (e.g., tumour necrosis factor-α, interleukin-1β) that are involved in the amplification of the inflammatory response [117,118]. Therefore, at a cellular level, (n-3) PUFAs from fish oils can directly or indirectly modulate a number of cellular

Polyphenols constitute one of the most numerous and ubiquitously distributed groups of plant secondary metabolites, with more than 8000 phenolic structures currently known. Natural polyphenols can range from simple molecules (phenolic acids, phenylpropanoids, and flavonoids) to highly polymerised compounds (lignins, melanins, tannins), with flavonoids representing the most common and widely distributed sub-group [119]. These secondary plant metabolites are known to have potential antioxidant activity and radical scavenging capacity [120-124]. Polyphenols are gaining increased importance due to their beneficial effects on health. Flavonoids are the most abundant polyphenols in our diets. They can be divided into several classes according to the degree of oxidation of the oxygen heterocycle: flavones, flavonols, isoflavones, anthocyanins, flavanols, proanthocyanidins and flavanones [125]. A complication of the epidemiological observations regarding members of the flavonoid family is that subtle differences in their chemical structures can translate into marked differences in their absorption, metabolism and bioactivities [126]. South African herbal teas, rooibos (*Aspalathus linearis*) and honeybush (*Cyclopia ssp*.) are currently gaining popularity worldwide [127, 128], owing to their anti-oxidant, anti-cancer and anti-mutagenic properties [129-131]. Rooibos is a herbal tea made from the leaves and stems of the indigenous South African plant, *Aspalathus linearis* (*Brum.f*) *Dahlg.* (*family Fabaceae; tribe Crotalarieae*) [132,133]. Research has demonstrated that this herbal tea is rich in flavonoids [127, 134]. Animal studies that have investigated the cardioprotective effects of natural or synthetic flavonoids have focused mainly on the acute pharmacological activity of these compounds. For example, *in vivo* studies using animal models have reported acute cardioprotection obtained from intravenous injections of

Natural vitamin E is composed of eight chemical compounds: α-, β-, γ- and δ-tocopherols and their corresponding tocotrienols. α-Tocopherol is the most active form of vitamin E *in vitro*. The tocopherols are saturated forms of vitamin E, whereas the tocotrienols are unsaturated and have an isoprenoid side chain. Tocopherols possess a chromanol ring and a 15-carbon tail. The presence of three *trans* double bonds in the tail distinguishes tocopherols from tocotrienols [137-139]. This may account for the differences in their efficacy and potency *in vitro* and *in*

Red palm oil (RPO) is a rich source of vitamin E. It contains 560–1000 parts per million of vitamin E, of which approximately 18–22% are tocopherols and 78–82% tocotrienols [142-144]. RPO has been shown to offer protection against I/R injury [42, 43, 47, 48] leading to a reduction in oxidative stress [145]. It has also been suggested that palm oil may have some anti-arrhyth‐

mogenic effects, which may reduce sudden death after ischaemic incidents [146].

activities associated with inflammation.

216 Antioxidant-Antidiabetic Agents and Human Health

natural or synthetic flavonoids [135,136].

*2.1.6. Vitamin E*

*vivo* [140,141].

*2.1.5. Polyphenols*

Carotenoids are nature's most widespread pigments, well known for their orange-red to yellow colours, which they impart to many fruits and vegetables. These fat-soluble phyto‐ chemicals have also received substantial attention because of their provitamin A and antioxi‐ dant roles [159]. Carotenoids are polyenoic terpenoids with conjugated trans double bonds. They include carotenes (*β*-carotene and lycopene), which are polyene hydrocarbons and xanthophylls (lutein, zeaxanthin, capsanthin, canthaxanthin, astaxanthin and violaxanthin) that have oxygen in the form of hydroxy, oxo, or epoxy groups [160]. The majority of the 600 carotenoids found in nature are 40 carbons in length and may be pure hydrocarbons, called carotenes, or possess oxygenated functional groups, in which case they are called xanthophylls [161]. The long-chain conjugated polyene structure accounts for the ability of these compounds to absorb visible light, but also makes them quite susceptible to oxidation. This latter property is closely related to their ability to act as antioxidants [162].

The properties and therefore functions of a carotenoid molecule are primarily dependent upon its structure and hence its chemistry [163]. In particular, the conjugated C = C double bond system is associated with energy transfer reactions, such as those found in photosynthesis [164]. In human plasma and tissues, several carotenoids have been well characterized includ‐ ing cyclic (such as β-carotene and α-carotene) and acyclic carotenes (such as lycopene and phytoene), together with a number of xanthophylls (such as zeaxanthin, lutein and betacryptoxanthin), all of which can be directly derived from dietary sources [165]. Carotenoids have generated considerable interest as several studies have suggested an inverse association between the dietary intake of carotenoids and the risk for CVD [166, 167]. Conversely proox‐ idant roles of these phytochemicals have also been reported [168-170].

#### *2.1.8. Possible mechanism(s) of action*

As mentioned earlier, RPO supplementation does offer protection against myocardial I/R injury via several suggested mechanisms. Amongst the proposed mechanisms are the NO– cyclic GMP pathway, phosphorylation of mitogen-activated protein kinases and scavenging of deleterious reactive oxygen species by RPO [42, 43, 47, 48].

Investigations concerning (n-3) PUFAs show that these forms of essential fatty acids reduce the risk of sudden cardiac death as well as fatal and nonfatal myocardial infarction [171-173]. A number of mechanisms have been implicated in the protective effects of (n-3) PUFAs [174, 175]. The (n-3) PUFAs have been demonstrated as altering the transcription of specific genes. These effects are mediated by a variety of mechanisms that involve indirect (i.e., by eicosa‐ noids, hormones) and direct nuclear effects on genes. The PUFAs (i.e., both (n-3) and (n-6) PUFAs) modulate the expression of genes involved in lipogenesis, glycolysis, production of glucose transporters, inflammatory mediators, early response genes and genes for cell adhesion molecules [176, 177].

The primary source of MUFA that lowers cholesterol levels is olive oil [178, 179]. It is evident that olive oil, due to its micronutrient content and fatty acid composition, can play a vital role in maintaining beneficial serum lipid profiles. Together with its ability to reduce systemic oxidative stress, blood pressure and inflammation, it has become an appropriate dietary supplement for lowering the risk of CHD.

Studies had shown that whole, unprocessed and unpeeled nuts have a unique composition that consists of important macro- and micronutrients, which give nuts their multiple beneficial effects on cardiovascular outcomes [189-192]. Most nut constituents have shown beneficial effects when clinically tested, in isolation or as part of enriched foods, for effects on diverse

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Nuts are important sources of tocopherols and phenolic antioxidants, which protect against LDL oxidation [183]. Walnuts have been shown to contain substantial amounts of melatonin, which contributed to a significant antioxidant effect in an experimental rat model [193]. In addition, a substantial fraction of nut fat comes from MUFAs, which are not susceptible to oxidation. The PUFAs are contained mainly in walnuts and are more susceptible to oxidation. However, nuts are a rich source of many antioxidants, which protect the PUFA *in vivo* against

Plasma high-sensitivity CRP, an accepted measure for systemic low-grade inflammation, was a secondary outcome in several controlled nut feeding trials conducted in hypercholesterole‐ mic subjects with almonds [195-198] or walnuts [197, 199]. Some of them have demonstrated a CRP-lowering effect [196, 197, 198]. Zhao et al., who used walnuts and walnut oil to enrich the diet in PUFA and especially ALA, showed a decrease in inflammatory markers [197] and

Endothelial dysfunction is a critical event in atherogenesis and is implicated both in early disease and in advanced atherosclerosis [201]. Short-term feeding studies have shown consistently that diets rich in saturated fatty acids impair endothelial function [181, 202, 203] and that even a single fatty meal rich in saturated fatty acids is followed by transi‐ ent endothelial dysfunction [204, 205]. These detrimental effects can be counteracted by the

cardiovascular outcomes, including novel risk markers [189-192].

**Table 2.** Composition of Nuts (data from the US department of agriculture nutrient database)

proinflammatory cytokine production by mononuclear cells [197].

*2.2.1. Antioxidant effects*

oxidative modification [194].

*2.2.2. Anti-inflammatory effects*

*2.2.3. Effects on endothelial function*

### **2.2. Composition and health benefits of nuts**

Nuts are highly nutritious and of prime importance for people in several regions in Asia and Africa. Most nuts contain a great deal of fat (e.g., pecan 70%, macadamia nut 66%, Brazil nut 65%, walnut 60%, almonds 55% and peanut butter 55%). Most have a good protein content (in the 10–30% range) and only a few have a very high starch content [180]. Many nuts have also been identified as especially rich in antioxidants [181, 182]. Nuts therefore constitute one of the most nutritionally concentrated kinds of food available. Most nuts, left in their shell, have a remarkably long shelf life and can conveniently be stored for winter use [183]. Nuts are foods rich in fat, ranging from 46% in cashews and pistachios to 76% in macadamia nuts and provide 20–30 kJ/g per nut. Despite their high fat content, they are not harmful because they contain a low proportion (4–16%) of saturated fatty acids. Nearly one half of the fat content of nuts consists of unsaturated fatty acids, including both mono- (oleic acid) and poly- (linoleic and α-linolenic acid) unsaturated fatty acids (MUFA and PUFA respectively). The fatty fraction of nuts also contains plant sterols with anti-oxidants [184] and cholesterol-lowering effects [185]. Nuts are also rich sources of other bioactive macronutrients, such as protein (25% of energy) and dietary fibre, which ranges from 4 to 11g/100 g and in standard servings provide 5–10% of daily fibre requirements. They also contain significant micronutrients (Table 2), among them folate [185] antioxidant vitamins (e.g., tocopherols) and phenolic compounds [183].

By virtue of their unique composition, nuts are likely to benefit modern cardiovascular risk biomarkers, such as LDL oxidizability, soluble inflammatory molecules and endothelial dysfunction. The complex pathophysiology of atherosclerotic disease has evolved beyond the accumulation of cholesterol in the arterial wall. A series of circulating, functional, structural and genomic biological markers that reflect arterial vulnerability have been proposed as potential novel risk factors for the development of CVD (Vasan, 2006). Among them, bio‐ markers for oxidation [186], inflammation [187] and endothelial dysfunction [188] have received increasing attention.


**Table 2.** Composition of Nuts (data from the US department of agriculture nutrient database)

Studies had shown that whole, unprocessed and unpeeled nuts have a unique composition that consists of important macro- and micronutrients, which give nuts their multiple beneficial effects on cardiovascular outcomes [189-192]. Most nut constituents have shown beneficial effects when clinically tested, in isolation or as part of enriched foods, for effects on diverse cardiovascular outcomes, including novel risk markers [189-192].

#### *2.2.1. Antioxidant effects*

Investigations concerning (n-3) PUFAs show that these forms of essential fatty acids reduce the risk of sudden cardiac death as well as fatal and nonfatal myocardial infarction [171-173]. A number of mechanisms have been implicated in the protective effects of (n-3) PUFAs [174, 175]. The (n-3) PUFAs have been demonstrated as altering the transcription of specific genes. These effects are mediated by a variety of mechanisms that involve indirect (i.e., by eicosa‐ noids, hormones) and direct nuclear effects on genes. The PUFAs (i.e., both (n-3) and (n-6) PUFAs) modulate the expression of genes involved in lipogenesis, glycolysis, production of glucose transporters, inflammatory mediators, early response genes and genes for cell

The primary source of MUFA that lowers cholesterol levels is olive oil [178, 179]. It is evident that olive oil, due to its micronutrient content and fatty acid composition, can play a vital role in maintaining beneficial serum lipid profiles. Together with its ability to reduce systemic oxidative stress, blood pressure and inflammation, it has become an appropriate dietary

Nuts are highly nutritious and of prime importance for people in several regions in Asia and Africa. Most nuts contain a great deal of fat (e.g., pecan 70%, macadamia nut 66%, Brazil nut 65%, walnut 60%, almonds 55% and peanut butter 55%). Most have a good protein content (in the 10–30% range) and only a few have a very high starch content [180]. Many nuts have also been identified as especially rich in antioxidants [181, 182]. Nuts therefore constitute one of the most nutritionally concentrated kinds of food available. Most nuts, left in their shell, have a remarkably long shelf life and can conveniently be stored for winter use [183]. Nuts are foods rich in fat, ranging from 46% in cashews and pistachios to 76% in macadamia nuts and provide 20–30 kJ/g per nut. Despite their high fat content, they are not harmful because they contain a low proportion (4–16%) of saturated fatty acids. Nearly one half of the fat content of nuts consists of unsaturated fatty acids, including both mono- (oleic acid) and poly- (linoleic and α-linolenic acid) unsaturated fatty acids (MUFA and PUFA respectively). The fatty fraction of nuts also contains plant sterols with anti-oxidants [184] and cholesterol-lowering effects [185]. Nuts are also rich sources of other bioactive macronutrients, such as protein (25% of energy) and dietary fibre, which ranges from 4 to 11g/100 g and in standard servings provide 5–10% of daily fibre requirements. They also contain significant micronutrients (Table 2), among them

folate [185] antioxidant vitamins (e.g., tocopherols) and phenolic compounds [183].

By virtue of their unique composition, nuts are likely to benefit modern cardiovascular risk biomarkers, such as LDL oxidizability, soluble inflammatory molecules and endothelial dysfunction. The complex pathophysiology of atherosclerotic disease has evolved beyond the accumulation of cholesterol in the arterial wall. A series of circulating, functional, structural and genomic biological markers that reflect arterial vulnerability have been proposed as potential novel risk factors for the development of CVD (Vasan, 2006). Among them, bio‐ markers for oxidation [186], inflammation [187] and endothelial dysfunction [188] have

adhesion molecules [176, 177].

218 Antioxidant-Antidiabetic Agents and Human Health

received increasing attention.

supplement for lowering the risk of CHD.

**2.2. Composition and health benefits of nuts**

Nuts are important sources of tocopherols and phenolic antioxidants, which protect against LDL oxidation [183]. Walnuts have been shown to contain substantial amounts of melatonin, which contributed to a significant antioxidant effect in an experimental rat model [193]. In addition, a substantial fraction of nut fat comes from MUFAs, which are not susceptible to oxidation. The PUFAs are contained mainly in walnuts and are more susceptible to oxidation. However, nuts are a rich source of many antioxidants, which protect the PUFA *in vivo* against oxidative modification [194].

#### *2.2.2. Anti-inflammatory effects*

Plasma high-sensitivity CRP, an accepted measure for systemic low-grade inflammation, was a secondary outcome in several controlled nut feeding trials conducted in hypercholesterole‐ mic subjects with almonds [195-198] or walnuts [197, 199]. Some of them have demonstrated a CRP-lowering effect [196, 197, 198]. Zhao et al., who used walnuts and walnut oil to enrich the diet in PUFA and especially ALA, showed a decrease in inflammatory markers [197] and proinflammatory cytokine production by mononuclear cells [197].

#### *2.2.3. Effects on endothelial function*

Endothelial dysfunction is a critical event in atherogenesis and is implicated both in early disease and in advanced atherosclerosis [201]. Short-term feeding studies have shown consistently that diets rich in saturated fatty acids impair endothelial function [181, 202, 203] and that even a single fatty meal rich in saturated fatty acids is followed by transi‐ ent endothelial dysfunction [204, 205]. These detrimental effects can be counteracted by the

administration of PUFA and other nutrients contained in nuts, such as antioxidant vitamins and arginine [179]. Another feeding trial showed that, compared with an isoenergetic Mediterranean diet with similar saturated fatty acid content, a walnut diet attenuated the endothelial dysfunction associated with hypercholesterolemia [199]. Moreover, changes in circulating levels of cellular adhesion molecules critical to leukocyte recruitment on the arterial wall also reflect endothelial dysfunction [201]. Several studies have shown that diets enriched with ALA from walnuts [197, 199, 206] reduce endothelial activation as assessed by decreased plasma cellular adhesion molecules. Walnut feeding also reduced the expression of endothelin-1, a potent endothelial activator in an animal model of accelerat‐ ed atherosclerosis [207].

**3. Conclusions and future directions**

brane protein function and gene expression.

flavonols [49].

with populations are warranted.

Investigation of the mechanisms underlying CVD showed that the disease has a complex cause beyond the accumulation of cholesterol on the arterial wall, with enhanced oxidative stress and a prominent inflammatory response. Diet has been shown to be associated with cardio‐ vascular events. PUFAs are essential in our diet because we cannot synthesize them. They are also essential nutrients for optimal health of the cardiovascular, nervous and undoubtedly other organ systems. Dietary (n-3) PUFAs are incorporated into the cellular membranes of all tissues. The extent of incorporation into tissue membranes is dependent on dietary intake. The enrichment of membranes with (n-3) PUFAs can modulate cellular signalling events, mem‐

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Interest in the possible health benefits of flavonoids has increased owing to their potent antioxidant and free-radical scavenging activities observed *in vitro*. There is growing evidence from human feeding studies that the absorption and bioavailability of specific flavonoids is much higher than originally believed. However, epidemiologic studies exploring the role of flavonoids in human health have been inconclusive. Some studies support a protective effect of flavonoid consumption in CVD and cancer; other studies demonstrate no effect and a few studies suggest potential harm. More recently, results from human studies provide evidence that rooibos can offer protection against oxidative stress conditions such as CVD [131,219]. In a study by Pantsi et al., the beneficial effects of dietary rooibos flavonoids were observed *ex vivo* in isolated perfused rat hearts. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruit and vegetables are in part mediated by their flavonoid content, with particular benefits provided by one member of this family, the

Polyphenols are abundant micronutrients in our diet and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Because there are many biological activities attributed to the flavonoids, some of which could be beneficial or detrimental depending on specific circumstances, further studies in both the laboratory and

However, the fatty acid components of nuts may differently influence oxidation processes and this needs to be considered for the synergy or opposition to the effects of constituent antioxi‐ dants. There is growing evidence that dietary polyphenols in nuts, tea and wine may have anti-inflammatory effects, mediated by both their antioxidant action and modulation of signal transduction pathways, such as the nuclear transcription factor kB, with ensuing downregulation of inflammatory genes in endothelial cells and macrophages [220]. The increased diversity and availability of sources of dietary fatty acids will likely allow the continued expansion of food products fortified with these fatty acids, a trend that may result in the

Future studies in oils should be carried out in order to elucidate the effects of oils in various models in which effects remain unknown. Little is known about the effects of nuts on a diseased

attainment of the recommended dietary intake of these nutrients.

#### *2.2.4. Effects on body weight changes*

As the interest in incorporating nuts into the diet grows, it is important that consumers understand how to include them in a healthy diet without promoting weight gain. They are high-fat, energy dense foods and are therefore a potential threat for contributing to positive energy balance. Numerous epidemiological and clinical studies have shown that nuts are not associated with higher body weight [208, 209] or weight gain [210-215]. This could be attributed along with other potential mechanisms for the high satiety properties of nuts [216]. The enhanced satiety, which is also achieved via other mechanisms such as the decreased eating rate [217], leads to reduced energy consumption and therefore a decreased risk of weight gain and obesity.

Blomhoff et al. [190] argued that the inverse association between nut intake and cardiovascular and coronary heart diseases in epidemiological studies may, or may not, be associated with antioxidants. According to these authors, epidemiologic studies are not ideally suited for studying the role of specific nuts or biological mechanisms. Nevertheless, they are in agree‐ ment with findings supporting the theory that a complex and rich mix of nut constituents is able to offer protection against CVD and perhaps other chronic diseases [183].

#### *2.2.5. Possible mechanism(s) of action*

Epidemiologic and clinical trial evidence has demonstrated the beneficial effect of nut consumption on coronary heart disease and its associated risk factors. The cardioprotective properties of nuts, due partially to their favourable lipid fatty acid profile (rich in unsaturated fatty acids), exceed the LDL-C lowering. Nuts, especially walnuts, contain (n-3) PUFAs, which have been shown to have a favourable impact on multiple factors related to CVD, such as inflammation, platelet function, arrhythmias, hypertriglyceridemia and nitric oxide-induced endothelial relaxation [218]. Nuts are also excellent sources of other bioactive compounds such as vegetable protein, dietary fibre, potassium, calcium, magnesium, tocopherols, phytosterols, phenolic compounds, resveratrol and arginine [179]. This unique nutrient composition explains the benefits of nut consumption for the prevention of CVD through mechanisms of oxidation, inflammation and vascular reactivity.
