Part I Chemistry and Biological Functions

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Part I

Chemistry and Biological FunctionsCO

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MATERIA

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The Contribution of Fruit and Vegetable Consumption to Human HealthElhadi M. Yahia,1∗ María Elena Maldonado Celis,2 and Mette Svendsen3

1Faculty of Natural Sciences, Autonomous University of Querétaro, Avenida de las Ciencias s/n, Juriquilla, Querétaro, Mexico2Nutrition and Dietetic School, University of Antioquia, Medellín, Colombia3Section for Preventive Cardiology, Centre of Preventive Medicine, Oslo University Hospital, Norway

1.1 Introduction

Increasing incidences of some chronic diseases, includingcancer, cardiovascular, and neurodegenerative diseases(Parkinson’s andAlzheimer’s diseases), especially in indus-trial countries, have raised awareness regarding the impor-tance of diet (Erbersdobler, 2003). It is estimated thatone-third of cancer cases and up to half of cardiovasculardisease rates are diet related (Goldberg, 1994).Clinical and epidemiological studies have justified

including antioxidants as dietary factors that affect brainfunction, promote aging, and contribute to the develop-ment of neurodegenerative diseases (Parkinson’s andAlzheimer’s) (Thomas and Beal, 2007). Numerous epide-miological studies have shown an inverse associationbetween fruit and vegetable consumption and chronicdiseases including different types of cancer, cardiovascular,and neurodegenerative diseases (Gan et al., 2015; IARC,2008; Devalaraja et al., 2011; Thompson, 2010; Mirmiranet al., 2013; Boeing et al., 2012; Albarracin et al., 2012;Hirayama, 1990; Block et al., 1992; Howe et al., 1992;Steinmetz and Potter, 1991, 1996; World Cancer ResearchFund, 1997; Joshipura et al., 2001; Bazzanoet al., 2002;Kris-Etherton et al., 2002, Yahia, 2009; Yahia, 2010; Yahia et al.,2011). These studies have shown mounting evidence thatpeople who avoid fruit and vegetables completely, orconsume very little, are indeed at increased risk of thesediseases. Therefore, interest in the health benefits of fruitand vegetable consumption is increasing. Moreover, inter-est in understanding the type, number, andmode of actionof the different components in fruits and vegetables thatconfer health benefits is also increasing.Fruits and vegetables have historically been considered

rich sources of some essential dietary micronutrients andof fibers, and more recently they have been recognized as

important sources for a wide array of phytochemicalsthat individually, or in combination, may benefit health(Stavric, 1994; Rechkemmer, 2001; Abuajah et al., 2015).Thus some people have conferred the status of “functionalfoods” on fruits and vegetables. There are many biologi-cally plausible reasons for this potentially protectiveassociation, including the fact that many of the phyto-chemicals act as antioxidants.Phytochemicals present in fruits and vegetables are very

diverse, such as ascorbic acid, carotenoids, and phenoliccompounds (Liu, 2004; Percival et al., 2006; Syngletaryet al., 2005; Yahia et al., 2001a, 2001b; Yahia, 2009; Yahia,2010; Yahia et al., 2011; Yahia and Ornelas-Paz, 2010).Plant polyphenols are ubiquitous in the diet, with richsources being tea, wine, fruits, and vegetables; they dem-onstrate considerable antioxidative activity in vitro whichcan have important implications for health (Duthie et al.,2000;Wootton-Beard and Ryan, 2011; Sindhi et al., 2013).Naturally occurring compounds such as phytochemi-

cals, which possess anticarcinogenic and other beneficialproperties, are referred to as chemopreventive agents,being classified as blocking and suppressive agents. Theblocking agents are based on their antioxidant activity andthe capacity to scavenge free radicals. Among the mostinvestigated antioxidant agents against cancer are somevitamins such as C, A, and E; flavonoids and phenolicacids, which account for 60% and 30%, respectively, ofdietary (poly)phenolic compounds (Ramos, 2007); andpigments such as carotenoids, chlorophylls, and betalains.Resolution of the potential protective roles of specificantioxidants and other constituents of fruits and vegeta-bles deserves major attention.Evidence indicates that for the effect of fruit and vege-

table consumption on health, thewholemay bemore thanthe sum of the parts. Individual components appear to actsynergistically, in that the influence of at least some ofthem is additive.∗Corresponding author.

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Fruit and Vegetable Phytochemicals: Chemistry and Human Health, Volume I, Second Edition. Edited by Elhadi M. Yahia.© 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd.

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Consumption of a high fruit and vegetable dietincreases antioxidant concentration in blood and bodytissues, and potentially protects against oxidative damageto cells and tissues. Olmedilla et al. (2001) described bloodconcentration of carotenoids, tocopherols, ascorbicacid, and retinol in well-defined groups of healthy non-smokers aged 25–45 years, across a sample of 175 menand 174 women from five European countries (France,Northern Ireland, Republic of Ireland, the Netherlands,and Spain). Analysis was centralized and performedwithin 18 months. Within gender, vitamin C showedno significant differences between countries. Females inFrance, Republic of Ireland, and Spain had significantlyhigher plasma vitamin C concentration than their malecounterparts. Serum retinol and α-tocopherol levels weresimilar, but γ-tocopherol showed great variability, beinglowest in Spain and France, and highest in theNetherlands. The provitamin A to non-provitamin Acarotenoid ratio was similar among countries, whereasthe xanthophylls (lutein, zeaxanthin, and β-cryptoxan-thin) to carotenes (α-carotene, β-carotene, and lycopene)ratio was double in southern areas (Spain) compared tonorthern areas (Northern Ireland and Republic ofIreland). Serum concentrations of lutein and zeaxanthinwere highest in France and Spain, and β-cryptoxanthinwas highest in Spain and theNetherlands. trans-Lycopenetended to be highest in Irish males and lowest in Spanishmales, while α-carotene and β-carotene were higher in theFrench volunteers. Due to the study design, the concen-tration of carotenoids and vitamins A, C, and E representphysiological ranges achievable by dietary means andmaybe considered as “reference values” in the serum ofhealthy, non-smoking middle-aged subjects from thefive European countries. Results suggest that lutein(and zeaxanthin), β-cryptoxanthin, total xanthophylls,γ-tocopherol, and β-tocopherol to γ-tocopherol ratiomay be important markers related to the healthy orprotective effects of a Mediterranean-like diet.The epidemiological evidence indicates that avoidance

of smoking, increased consumption of fruits and vegeta-bles, and control of infections can have a major effect onreducing rates of several chronic diseases includingcardiovascular disease and different types of cancer (Inter-national Agency for Research on Cancer, 2008; Cuenca-García et al., 2014; Stefani and Rigacci, 2014; Ames et al.,1995; Graham and Mettlin, 1981; Giovanelli, 1999; Liu,2004; Percival et al., 2006; Syngletary et al., 2005).The global average for vegetables (based on availability

and not including vegetable oils) and fruits consumptionis 2.6% and 2.7% of total daily energy intake, respectively.Thus, it is argued that increasing intake from 400 to 800 g/day of fruits and vegetables is a public health strategy ofconsiderable importance for individuals and communitiesworldwide. Vegetable consumption is highest in North

Africa, the Middle East, parts of Asia, the USA, Cuba, andsouthern Europe. On the other hand, fruit intakes arehighest in some parts of Africa, the Middle East, southernEurope, and Oceania, and lowest in other parts of Africaand Asia (WCRF/AICR, 2007).The World Health Organization (WHO) recommends

a daily intake of more than 400 g per person daily, andhealth authorities worldwide promote high consumptionof fruits and vegetables (Yahia, 2009; Yahia, 2010; Yahiaet al., 2011). Many of the putative chemoprotective phy-tochemicals in fruits and vegetables are colored (due todifferent pigments). The guidelines are based on selectingone serving daily of fruits and vegetables from each ofseven color classes (red, yellow-green, red-purple, orange,orange-yellow, green, white-green) so that a variety ofphytochemicals is consumed.Several promotional campaigns to increase fruit and

vegetable consumption have been proposed by developedcountries as the USA (5 a Day, now Fruits & Veggies),Australia (Go for 2&5), Canada (Canada’s Food Guide toHealthy Eating), UnitedKingdom (FoodDudes), Denmark(6 a Day), New Zealand (5+ a Day). Some results of thesecampaigns in theUSAbetween2004 and2009 showed thataverage consumption of fruits and vegetables for adultswas 1.8 cups/day, and that for children less than 6 years oldand children 6 to 12 years old consumption increased 4%and 2%, respectively, for adult females 18 to 44 years old itincreased by 1%, and for adult males it decreased by 7–9%(Produce for Better Health Foundation, 2010). The surveyof the Australian campaign on Western adults after threeyears through the Health Department’s Health and Well-being Surveillance System showed a mean increase of 0.2servings/day of fruits and 0.6 servings/day of vegetables(Pollard et al., 2008). In Denmark, in contrast to the resultsobtained in the USA and Australia, the Danish NationalSurvey of Dietary Habits and Physical Activity between1995 and 2004 showed an increase in consumption by the4- to 10-year-old group of 29% vegetables and 58% fruits,and by the 11- to 75-year-old group of 41% fruits and 75%vegetables (Danish National Centre for Social Research,2005). In Norway, delivery of fruits free of charge tochildren at school increased the daily intake of fruitfrom one to two portions between 2001 and 2008 (Bereet al., 2010).A study by Johnston et al. (2000) during 1994–1996, a

“continuing survey of food intakes by individuals,” wasused to examine the types of fruits and vegetables con-sumed in the USA. The sample populations consisted of4806 men and women (25–75 years old) who completedtwo non-consecutive 24 hour recalls, consuming3.6± 2.3 servings of vegetables and 1.6± 2.0 servingsof fruit daily. Iceberg lettuce, tomatoes, French friedpotatoes, bananas, and orange juice were the most com-monly consumed fruits and vegetables, accounting for

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nearly 30% of all fruits and vegetables consumed. Themost popular items, lettuce and tomatoes, were con-sumed by 39–42% of the sample population during thereporting period. Fewer respondents (16–24%) con-sumed French fried potatoes, bananas, or orange juice.Only 3% of the sample consumed broccoli during thereporting period. White potato consumption averaged1.1 servings daily, with French fried potatoes represent-ing 0.4 serving. Tomato products consumption averaged0.5 serving daily, dark green vegetable consumptionaveraged 0.2 serving daily, and citrus, berries, or melonconsumption amounted to nearly 0.8 serving daily.These data have indicated that people in the USA areconsuming more fruits and vegetables compared toprevious years but that dark green and cruciferousvegetable intake is low. Many studies suggest that con-sumption of fruit and vegetables is still low in manycountries (Naska et al., 2000; Agudo et al., 2002; USDA,2003; Blanck et al., 2008), and efforts are still needed toincrease it. This chapter will highlight the potentialhealth benefits of fruit and vegetable consumption onseveral diseases, as well as the nutritional and healthimportance of some fruits and vegetables.

1.2 Effect of Consumption of Fruit andVegetables on Some Diseases

1.2.1 Cancer

According to the study of Doll and Peto (1981) based onepidemiological studies, an average of 35% of the deathrate for cancer is associated with nutritional factors. It hasbeen proposed that absence in the diet of compoundspossessing cancer preventing properties, such as fruitsand vegetables, is responsible partially for this situation.In 2007, the World Cancer Research Fund (WCRF/

AICR, 2007) published its second expert report in whichthey found, from cohort studies since the mid 1990s, thatevidence of protection by vegetables or fruits consump-tion is convincing. Non-starchy vegetables probably pro-tect against cancers of the mouth, pharynx, and larynx,and those of the esophagus and stomach. There is limitedevidence suggesting that they also protect against cancersof the nasopharynx, lung, colorectum, ovary, and endo-metrium. Allium vegetables probably protect againststomach cancer. Garlic (an Allium vegetable, commonlyclassed as a herb) probably protects against colorectalcancer. Fruits in general probably protect against cancersof the mouth, pharynx, and larynx, and of the esophagus,lung, and stomach. There is limited evidence suggestingthat fruits also protect against cancers of the nasopharynx,pancreas, liver, and colorectum (WCRF/AICR, 2007).The chemopreventive properties of vegetables, fruits,

and pulses against some type of cancers is attributedto some micronutrients considered markers for con-sumption of vegetables, fruits, and pulses (legumes).For example, foods containing carotenoids probably pro-tect against cancers of the mouth, pharynx, larynx, andlung; whereas evidence of consumption of foods contain-ing beta-carotene and lycopene suggests that they proba-bly protect against esophageal and prostate cancer,respectively. On the other hand, in spite of the well-described quercetin mechanisms of action, there islimited evidence suggesting that consumption of foodscontaining this flavonoid, such as apples, tea, and onions,protects against lung cancer (WCRF/AICR, 2007). Epi-demiological evidence of cancer protective effects of fruitsand vegetables, as well as the basic mechanisms by whichphytochemicals in fruits and vegetables can protectagainst cancer development, has been previously surveyedby Wargovich (2000). Sometimes it was difficult to asso-ciate total fruit and vegetable consumption and cancerprevention; rather, there was an association with somespecific families or types of fruits and vegetables (Stein-metz and Potter, 1996; Voorips et al., 2000). For example,a high consumption of tomato or tomato-based productsis consistently associated with lower risk of differentcancer types as shown by meta-analysis, with the highestevidence found for lung, prostate, and stomach cancer(Giovannucci, 1999). The metabolism of chemical carcin-ogens has been shown to be influenced by dietary con-stituents (Wattenberg, 1975). Naturally occurringinducers of increased activity of the microsomal mixed-function oxidase system are present in plants; cruciferousvegetables are particularly potent in this regard. FromBrussels sprouts, cabbage, and cauliflower, three indoleswith inducing activity have been identified: indole-3-ace-tonitrile, indole-3-carbinol, and 3,3´-diindolylmethane.A second type of dietary constituent which affects themicrosomal mixed-function oxidase system is added:phenolic antioxidants, butylated hydroxyanisole (BHA),and butylated hydroxytoluene. The feeding of BHA hasresulted in microsomal changes in the liver. Spectralcharacteristics of cytochrome P450 were changed, andthe aryl hydrocarbon hydroxylase system of these micro-somes demonstrated increased sensitivity to inhibition byα-naphthoflavone. A decrease in the binding of metabo-lites of benzo[a]pyrene to DNA was noted upon incuba-tion of these microsomes with benzo[a]pyrene. BHA andbutylated hydroxytoluene exert a protective effect againstchemical carcinogens. Therefore, it seems that the con-stituents of the diet could be of consequence in theneoplastic response to exposure to carcinogens in theenvironment.Polyphenols have shown the capacity to block initiation

or to suppress the stages of promotion and progression ofcarcinogenesis. In this context, the groups of phenolic

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acids, flavonoids, stilbenes, and curcuminoids are themost important.Several in vitro studies have shown that phenolic com-

pounds in fruits and vegetables, such as ellagic acid frompomegranate, have an antiproliferative effect on differentcancer cell lines (Eberhardt et al., 2000; Chu et al., 2002;Sun et al., 2002; Liu et al., 2005; Mertens-Talcott et al.,2005; Percival et al., 2006; Bell and Hawthorne, 2008).Quercetin, a flavonoid found in many fruits and vege-

tables, has been shown to affect themetastatic potential ofmouse tumor cells (Suzuki et al., 1991). Mutagenicity ofquercetin was examined by means of DNA fingerprintanalysis using the Pc-1 probe which efficiently detectsmutations due to recombination. Treatment of BMT11and FM3A tumor cells with quercetin resulted in gain andloss of bands in the fingerprints in both cell lines. Thefrequencies of the clones having undergone mutationwere 3/11 and 6/26, respectively. This suggests thatquercetin is mutagenic and induces recombination, andthe results seem to provide a molecular basis for thephenotypic variations of BMT11 tumor cells inducedby quercetin. It has been shown that quercetin, otherthan the glycosylated form (rutin), exerts inhibition ofazoxymethane-induced colorectal carcinogenesis in rats(Murakami et al., 2008). Other flavonoids with chemo-preventive important activity are epigallocatechin gallatefrom green tea, genistein from soybean, and luteolinpresent in parsley, celery, pepper, and dandelion (Gon-zález-Vallinas et al., 2013).Resveratrol, the most important stilbene with demon-

strated chemopreventive properties,mainly present in redwine and grapes, is able to inhibit proliferation of a widerange of human cancer cells, and to suppress carcinogen-esis in several organ sites (head and neck, liver, thyroid,stomach, colorectum, pancreas, prostate, renal, bone,skin, breast, lung) by controlling proliferation, apoptosis,cell cycle progression, inflammation, angiogenesis, inva-sion, and metastasis (González-Vallinas et al., 2013).Chlorophyllin (CHL), a food-grade derivative of the

ubiquitous fruits and vegetables pigment chlorophyll,has been shown to be a potent, dose-responsive inhibitorof aflatoxin B1-DNA adduction and hepatocarcinogene-sis in the rainbow trout model when fed with carcinogen(Breinholt et al., 1995). Chlorophyllins are derivatives ofchlorophyll in which the central magnesium atom isreplaced by other metals, such as cobalt, copper, oriron. The relative efficacy of chlorophyll and chlorophyl-lin has been shown to modify the genotoxic effects ofvarious known toxicants (Sarkar et al., 1994). CHL neitherpromoted nor suppressed carcinogenesis with chronicpostinitiation feeding. By molecular dosimetry analysis,reduced aflatoxin B1-DNA adduction accounted quanti-tatively for reduced tumor response up to 2000 ppmdietary CHL, but an additional protective mechanism

was operative at 4000 ppm CHL. The finding of potentinhibition (up to 77%) at CHL levels well within thechlorophyll content of some green fruits and vegetablesmay have important implications in the intervention anddietary management of human cancer risks.Monoterpenes – natural plant products found in the

essential oils of many commonly consumed fruits andvegetables, and widely used as flavor and fragrance addi-tives in food and beverages – have been shown to possessantitumorigenic activities (Kelloff et al., 1996). Limonene,the simplest monocyclic monoterpene and found in somecitrus fruits, and perillyl alcohol, a hydroxylated limoneneanalog, have demonstrated chemopreventive and chemo-therapeutic activity against mammary, skin, lung, pan-creas, and colon tumors in rodent models (Crowell andGould, 1994; Wattenburg and Coccia, 1991; Stark et al.,1995).Experimental studies (Sugie et al., 1993; Dashwood

et al., 1989; Tanaka et al., 1990) have shown that indolesand isothiocyanates (found in Brassica vegetables), givento animals after a carcinogen insult, reduced tumor inci-dence and multiplicity at a number of sites including theliver, mammary gland, and colon. A possible inhibitoryactivity of isothiocyanates and indoles against tumori-genesis apparently stems from their ability to influencephase I and phase II biotransformation enzyme activities(Zhang and Talalay, 1994; Boone et al., 1990; McDannelland McLean, 1988). Sulforaphane, which is present inbroccoli, is a potent inducer of the phase II detoxificationenzymes quinine reductase and glutathione transferase,and an inhibitor of the carcinogen-activating cytochromeP450 2E1 (Zhang et al., 1992; Barcelo et al., 1996).Numerous studies (Rungapamestry et al., 2007) have

indicated that the hydrolytic products of at least threeglucosinolates, 4-methyl-sulfinylbutyl (glucoraphanin),2-phenylethyl (gluconasturtiin), and 3-indolylmethyl(glucobrassicin), have anticarcinogenic activity. Indole-3-carbinol, a metabolite of glucobrassicin, has showninhibitory effects in studies of human breast and ovariancancers. S-methyl cysteine sulfoxide and its metabolitemethyl methane thiosulfinate were shown to inhibitchemically induced genotoxicity inmice. Thus, the cancerchemopreventive effects of Brassica vegetables that havebeen shown in human and animal studies may be due tothe presence of both types of sulfur-containing phyto-chemicals (i.e. certain glucosinolates and S-methyl cys-teine sulfoxide).Curcumin, the major curcuminoid present in turmeric,

possesses anticancer properties against a wide range ofcancers (prostate, skin, bladder, oral, breast, bone, colon,stomach, liver, pancreas, cervical). In vitro studies haveshown that mechanisms include inhibition of NF-κB,arrest of cell cycle, inhibition of proliferation, survivalpathways, transcription factors and other molecules


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related to invasion and metastasis, and induction of apo-ptosis (González-Vallinas et al., 2013). Clinical studiesin colorectal and pancreatic cancers have demonstratedantitumor effects. However, in damaged lung epitheliumacts as a carcinogen agent, which must be taken intoaccount for smokers andex-smokers (Shehzadet al., 2010).

1.2.1.1 StomachGastric cancer is the secondmost common cause of deathdue to cancer. Although infectionwithHelicobacter pyloriis the strongest risk factor, epidemiological studies havesuggested that specific dietary components such as chili,processed meat, smoked foods, grilled or barbecuedfoods, salt and salty foods, and alcohol play an importantrole in the etiology of gastric cancer (Ferlay et al., 2010;IARC, 2008; Kim et al., 2010; Shikata et al., 2006;Tramacere et al., 2012).Reports on an inverse relationship between the con-

sumption of fresh vegetables and human gastrointestinalcancer have been followed by screening for the protectiveactivity of a large number of plant extracts, including leafyvegetables (Botterweck et al., 1998; Larsson et al., 2006).A meta-analysis (Wang Q. et al., 2014) showed that

consumption of fruit, but not vegetables, was inverselyassociated with gastric cancer risk. The risk decreaseswhen consumption of fruit is 10% in high versus lowanalysis, and by 5% per 100 g/day increment in fruitconsumption. Above that level, a slight further reductionwith higher intake is observed (an approximate 16%reduction for an intake of 500 g/day). This protectiveeffect is attributed to selenium, β-carotene, and vitaminsA, C, and E because of anti-inflammatory and antioxidantactions against H. pylori induced damage (Sezikli et al.,2012; Sjunnesson et al., 2001). Furthermore, dietary fiberplays an important role in preventing gastric cancer,acting as a nitrite scavenger like vitamin C (Molleret al., 1988); this is supported by the meta-analysis per-formed by Zhang et al. (2013), who concluded that a10 g/day increment in fiber intake was associated with areduction in the risk of gastric cancer of 44%. Results forhigh dietary fiber intake could indicate the value of a dietrich in whole grains, vegetables, fruit, and a variety ofnutrients which have been shown to prevent gastriccancer (González et al., 2006).Protection for all sites of digestive tract cancers (oral

cavity and pharynx, esophagus, stomach, colon, rectum)has been associated with an increased intake in tomato-based foods, and an increased supply of lycopene (Fran-ceschi et al., 1994). People who ate at least one serving oftomato-based product per day had 50% less chance ofdeveloping digestive tract cancer than those who did noteat tomatoes (Franceschi et al., 1994). The intake oflycopene has also been associated with a reduced risk

of cancers of sites other than the digestive tract, such asthe pancreas and the bladder (Gerster, 1997). Oldersubjects who regularly ate tomatoes were found to beless likely to develop all forms of cancer (Colditz et al.,1985). A significant trend in risk reduction of gastriccancers by high tomato consumption was also observedin a study which estimated dietary intake in low-riskversus high-risk areas in Italy (Buiatti et al., 1990). Asimilar regional impact on stomach cancer was alsoobserved in Japan (Tsugane et al., 1992) where out ofseveral micronutrients, including vitamins A, C, and Dand β-carotene, only lycopene was strongly inverselyassociated with stomach cancer. Franceschi et al.(1994) have shown a consistent pattern of protectionfor many sites of digestive tract cancer associated withan increased intake of fresh tomatoes.Habitual consumption of garlic has been reported to

correlate with a reduction in gastric nitrite content and areduction in gastric cancermortality (Mei et al., 1982; Youet al., 1989). Allium compounds present in garlic havebeen reported to inhibit the synthesis of N-nitroso com-pounds (Mei et al., 1989). In a human study, 5 g of freshgarlic consumption has shown to markedly suppressurinary excretion ofN-nitrosoproline in individuals givensupplemental nitrate and proline (Mei et al., 1989). Inaddition, two ecological studies (WCRF/AICR, 1997)showed that in areas where garlic or onion productionis very high, mortality rates from stomach cancer arevery low.

1.2.1.2 ColonColorectal cancer is the third most common cancer inmen (746,000 cases, 10.0% of the total) and the second inwomen (614,000 cases, 9.2% of the total) worldwide(IARC, 2012). It is accepted that about 70% of CRC casesare linked to diet (Michels et al., 2000). Thus, food is oneof the factors on which it is possible to act in order toincrease primary prevention (INCa, 2009). The mostconsistent finding on diet as a determinant of cancerrisk prevention is the consumption of vegetables andfruits. Convincing epidemiological evidence for this pre-ventive action exists for CRC attributed to foods contain-ing dietary fiber, and limited but suggestive evidence forfruits and non-starchy vegetables (WCRF/AICR, 2011).In 2011 the WCRF/AICR published an updated meta-

analysis concluding that consumption of 10 g/day dietaryfiber reduced risk by 10% and 11% for colon and rectalcancers respectively. Specifically for whole grains (3 serv-ings/day) there was a reduction in risk of 16–21%. Inrelation to non-starchy vegetables, there is a substantialamount of evidence, but it is inconsistent and did notreach conventional levels of statistical significance, inspite of findings that consumption of 100 g/day or 2


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servings/day reduced risk by 1–4%. A similar conclusionwas obtained for fruits in this report (WCRF/AICR, 2011).These findings were confirmed in 2015 by the EuropeanProspective Investigation into Cancer and Nutrition(EPIC). In general they found a lower risk of colon cancerwith higher self-reported consumption of fruits and veg-etables combined (HR Q4 vs. Q1 0.87, 95% CI 0.75–1.01,Ptrend 0.02). However, no consistent association wasobserved for separate consumption of fruits and vegeta-bles; an inverse association between colon cancer andcabbage consumption was observed (36.7 g/day reducedrisk of colon cancer by 7%), attributed to glucosinolates,while an increased risk of 5% was suggested for highmushroom consumption (8.8 g/day) (Leenders et al.,2015). Explanations for the attenuation of the risk esti-mates include the changes over time (11.2 years) of fruitsand vegetables consumption, the errors in measurementof the quantity of consumption of fruits and vegetables,which caused false negative results in the analyses regard-ing diet diversity, and the different dietary questionnairesused by EPIC centers; such aspects must be taken intoaccount in these types of analysis.Consumption of fruits and vegetables, and the associ-

ated vitamin C, carotene, and fiber, has been reported toreduce risk of colon cancer (Ziegler et al., 1981). Sinceplant sterols are plentiful in vegetarian diets, the effect ofβ-sitosterol on colon tumor formation in rats treated withthe carcinogen N-methyl-N-nitrosourea was studied byRaicht et al. (1980). They have demonstrated that β-sito-sterol nullified in part the effect of this direct-actingcarcinogen on the colon. They suggest that plant sterolsmay have a protective dietary action to retard colon tumorformation, and therefore the beneficial effects of vegetar-ian diets may be enhanced because of the presence ofthese compounds.An increased risk of colon cancer has been associated

with decreases in the frequency with which vegetableswere eaten in a study of 214 females with cancer of thecolon, and 182 females with cancer of the rectum yieldedsimilar results (Graham et al., 1978). The decrease in riskwas found to be associated with frequent ingestion ofvegetables, especially cabbage, Brussels sprouts, and broc-coli, and it is consistent with the decreased numbers oftumors observed in animals challenged with carcinogensand fed compounds found in these same vegetables.Associations between fruit, vegetable, and dietary fiber

consumption and colorectal cancer risk were investigatedin a population that consumes relatively low amounts offruit and vegetables and high amounts of cereals (Terryet al., 2001). Data were examined from a food-frequencyquestionnaire used in a population-based prospectivemammography screening study of women in centralSweden. Women with a diagnosis of colorectal cancerwere identified by linkage to regional cancer registries;

Cox proportional hazards models were used to estimaterelative risks, and all statistical tests were two-sided.During an average 9.6 years of follow-up of 61,463women, 460 incident cases of colorectal cancer wereobserved. In the entire studied population, total fruitand vegetable consumption was inversely associatedwith colorectal cancer risk, but subanalyses showedthat this association was largely due to fruit consumption.The association was stronger and the dose–responseeffect was more evident among individuals who con-sumed the lowest amounts of fruits and vegetables; indi-viduals who consumed less than 1.5 servings of fruit andvegetables per day had a higher relative risk of developingcolorectal cancer compared with individuals who con-sumed greater than 2.5 servings.Diets containing citrus fiber have been reported to

reduce the risk of intestinal cancer. The effect of dietarydehydrated citrus fiber on carcinogenesis of the colon andsmall intestine was studied in male F344 rats by Reddyet al. (1981). Weanling rats were fed semi-purified dietscontaining 5% fat and 15% citrus fiber; at 7 weeks of age,all animals, except vehicle-treated controls, receivedweekly injections of 8mg azoxymethane (AOM) per kgbody weight for 10 weeks; and the AOM- or vehicle-treated groups were autopsied 20 weeks after the lastinjection of AOM. The animals fed the citrus fiber dietand treated with AOM had a lower incidence (number ofanimals with tumors) andmultiplicity (number of tumorsper tumor-bearing animal) of colon tumors and tumors ofthe small intestine than did those fed the control diet andtreated with AOM. The number of adenomas, but not thenumber of adenocarcinomas, was reduced in rats fed onthe citrus pulp diet.Consumption of certain fruit juices has evidenced pro-

tective effects against colon cancer, such as pomegranate,citrus (Jaganathan et al., 2014), banana, passion fruit(Chaparro et al., 2015), and mango juice (Corrales-Bernalet al., 2014). These fruit juices contain polyphenols andother phytochemicals like carotenoids and vitaminsA andC; these help in reducing the growth of colon cancer cellsor the number of chemical carcinogen-induced pre-neo-plastic lesions in colonmucosa inmice Balb-c or rats F344by 91%, 65%, and 56% after consumption of pomegranate,mango, and banana and passion fruit juices (Boateng et al.,2007; Corrales-Bernal et al., 2014; Chaparro et al., 2015).These findings suggest that they can serve as a strategy toreduce the incidence of colon cancer. Pomegranate juicecontains ellagic acid, ellagitannins, luteolin glycosides,quercetin, and kaempferol; punicalagin is responsiblefor more than 50% of the antioxidant activity in the juice(Cerdá et al., 2003), and ellagic acid acts as a blockingagent by inhibiting the CYP1 activation of procarcinogensand induces phase II enzymes like glutathione S-transfer-ase (Barch et al., 1996). The pulp and juice of the citrus


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fruit contain flavonoids such as apigenin, naringenin,hesperidin, nobiletin, and limonoids (limonin glucoside,obacunone glucoside mixture) and the carotenoid cryp-toxanthin (Jaganathan et al., 2014), which may act assuppressor chemopreventive agents in colon carcinogen-esis because of the arrest of cell cycle colon adenocarci-noma HT-29, and the reduction in levels of cyclins A, D1,and E, iNOS, and COX-2 enzymes (Frydoonfar et al.,2003; Pan et al., 2002; Vanamala et al., 2006).The effect of a diet containing 10–40% lyophilized

cabbage or broccoli as cruciferous vegetable or 10–40%lyophilized potato as non-cruciferous vegetable fed for 14days on the colon mucosal glutathione (GSH) level wasstudied in male rats (Chen et al., 1995). The GSH levels ofthe duodenum mucosa and the liver were also measured.Cabbage and broccoli enhanced the colon and duodenummucosal GSH levels in a dose-related manner, but potatohad no effect. All three vegetables had no effect on theliverGSH level. The effect of GSH on colon tumorigenesisinduced by 1,2-dimethylhydrazine (DMH)was also exam-ined in rats. Male Sprague-Dawley rats were injectedweekly with DMH (20mg/kg body weight) for 20 weeks(Chen et al., 1995). DMH lowered the colonmucosal GSHlevel. GSH (100mg/day per rat) dissolved in the drinkingwater and given to rats during and after DMH injectionshad little or no effect on tumor incidence and totalnumber of colon tumors. Tumors were larger in ratsthat received GSH than in those that received water.Therefore, it seems likely that the colon mucosal GSHlevel can be enhanced by feeding rats a diet high incabbage or broccoli and that GSH added to the drinkingwater did not affect DMH-induced colon tumorigenesisunder the experimental conditions used.Steinmetz et al. (1994) have shown that risk of cancer in

the distal colon was 50% lower in women with the highestconsumption of garlic than in women who did not con-sume garlic.However, some large cohort studies (Michels et al.,

2000; Voorips et al., 2000) showed no appreciable associ-ation between fruit and vegetable intake and colon andrectal cancer.

1.2.1.3 BreastIARC (2012) estimated that breast cancer is the secondmost common cancer in the world, and themost frequentcancer among women, representing 25% of all cancers in2012.A meta-analysis of 26 prospective and retrospective

studies (Gandini et al., 2000) confirmed the reductionof the risk of breast cancer with enhanced intake of fruitand vegetables. Recently, in a meta-analysis on the risk ofbreast cancer and dietary factors, 13 and 11 studiesevidenced that vegetables (odds ratio OR= 0.77,

confidence interval 0.62–0.96, 95%) and fruits (OR= 0.66,CI 0.49–0.9, 95%) consumptions, respectively, are rele-vant protective factors against breast cancer. Moreover,the study found significant differences for those womenwho consumed soy foods (OR= 0.66, CI 0.50–0.93, 95%)rich in isoflavones that have a protective effect against thistype of cancer (Varinska et al., 2015). In contrast, a pooledanalysis of eight prospective studies indicated that fruitand vegetable consumption did not significantly reducethe risk of breast cancer (Smith-Warner et al., 2001). AEurope-wide prospective EPIC study with 285,526women demonstrated that a daily intake of 370 g fruitor 246 g vegetables is not associated with a reduced breastcancer risk (van Gils et al., 2005). Shannon et al. (2003)reported a protective effect of vegetables and fruit intakeat the highest quartile of consumption, suggesting athreshold effect in reducing breast cancer risk. However,reports indicated that 100 g of fresh apples have anantioxidant activity equivalent to 1700 mg of vitamin Cand that whole apple extracts prevent breast cancer in arat model in a dose-dependent manner at doses compa-rable to human consumption of one, three, and six applesa day (Liu et al., 2005). Whole apple extracts werereported to effectively inhibit mammary cancer growthin the rat model; thus consumption of apples was sug-gested as an effective means of cancer protection. FemaleSprague-Dawley rats treated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of agedeveloped mammary tumors with 71% tumor incidenceduring a 24 week study. However, a dose-dependentinhibition of mammary carcinogenesis by whole appleextracts was observed, where application of low, medium,and high doses of whole apple extracts, comparable to 3.3,10, and20 g of apples per kgof bodyweight, reduced tumorincidence by 17%, 39% (p< 0.02), and 44% (p< 0.01),respectively; this is comparable to human consumptionof one (200 g/60 kg), three, and six apples per day.García-Solís et al. (2008, 2009) studied the antineoplastic

properties of some fruits and vegetables using in vivo andin vitro models. The effect of ‘Ataulfo’ mango fruit con-sumption was studied on chemically induced mammarycarcinogenesis and plasma antioxidant capacity (AC) inrats treated with the carcinogen N-methyl-N-nitrosourea(MNU) (García-Solís et al., 2008). Mango was administeredin the drinking water (0.02–0.06 g/mL) during both short-term and long-term periods to rats, and plasma antioxidantcapacity was measured by ferric-reducing/antioxidantpower and total oxyradical scavenging capacity assays.Rats treated with MNU had no differences in mammarycarcinogenesis (incidence, latency, and number of tumors),and no differences in plasma antioxidant capacity. On theother hand, they (García-Solís et al., 2009) screened, usingmethylthiazolyldiphenyl-tetrazolium bromide assay, theantiproliferative activity of aqueous extracts of avocado,


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black sapote, guava, mango, cactus stems (cooked and raw),papaya, pineapple, four different prickly pear fruit, grapes,and tomato on the breast cancer cell line MCF-7. Only thepapaya extract had a significant antiproliferative effect andthere was no relationship between total phenolic contentandACwith antiproliferative effect. These results suggestedthat each plant food has a unique combination in quantityand quality of phytochemicals which could determine itsbiological activity.With respect to citrus fruits (oranges, tangerines, grape-

fruits, lemons, and limes), a systematic review and meta-analysis showed an inverse association between citrusfruits intake and the risk of breast cancer, with a 10%reduction in risk of breast cancer associated with highintake of citrus fruits (summary OR, 0.90; 95% CI0.85–0.96; p< 0.001) (Song and Bae, 2013). It is consid-ered that citrus fruits contain bioactive compounds suchas β-cryptoxanthin, β-carotene, folate, vitamin C, querce-tin, hesperetin, and naringenin (So et al., 1996).Indole-3-carbinol, 3,3´-diindolylmethane, and indole-3-

acetonitrile, three indoles occurring in edible cruciferousvegetables, have been studied for their effects on 7,12-dimethylbenz[a]anthracene-induced mammary tumorformation in female Sprague-Dawley rats and 77 onbenzo[a]pyrene-induced neoplasia of the forestomach infemale ICR/Hamice (Wattenberg and Loub, 1978). Whengiven by PO intubation 20 hours prior to 7,12-dimethyl-benz[a]anthracene administration, indole-3-carbinol and3,3´-diindolylmethane had an inhibitory effect on mam-mary tumor formation, but indole-3-acetonitrile wasinactive. Indole-3-carbinol, when added to the diet for 8days prior to challenge with 7,12-dimethylbenz[a]anthra-cene, inhibited mammary tumor formation, whereasindole-3-acetonitrile did not. Dietary administration ofall three indoles inhibited benzo[a]pyrene-induced neo-plasia of the forestomach in ICR/Ha mice.The consumption of a mixture of phenolic compounds

presented in apple or purple grape juice inhibited mam-mary carcinogenesis in DMBA-treated rats (Liu et al.,2005; Jung et al., 2006). Similar effects were observedusing polyphenolic extracts from peach and plum, whichshowed selective cytotoxic action against the estrogen-independentMDA-MB-435 breast cancer cells comparedto the estrogen-dependent MCF-7 cells, and small or noeffects on the MCF-10A non-cancerous breast cell line;chlorogenic acid and caffeic acid were the most activephenolic compounds (Vizzotto et al., 2014). However, theindividual antioxidants of these foods studied in clinicaltrials, including β-carotene, vitamin C, and vitamin E, donot appear to have consistent preventive effects compa-rable to the observed health benefits of diets rich in fruitsand vegetables, suggesting that natural phytochemicals infresh fruits and vegetables could be more effective than adietary supplement.

Associations between breast cancer and total and spe-cific fruit and vegetable group intakes were examinedusing standardized exposure definitions (Smith-Warneret al., 2001). Data sources were eight prospective studiesthat had greater than or equal to 200 incident breastcancer cases, included assessment of usual dietary intake,and had completed a validation study of the diet assess-ment method or a closely related instrument. They stud-ied 7377 incident invasive breast cancer cases among351,825 women whose diet was analyzed at baseline.For highest versus lowest quartiles of intake, weak non-significant associations were observed for total fruits, totalvegetables, and total fruits and vegetables. There was noapparent additional benefit for the highest and lowestdeciles of intake. There were no associations for greenleafy vegetables, eight botanical groups or 17 specificfruits and vegetables. The study concluded that consump-tion of fruits and vegetables during adulthood is notsignificantly associated with reduced risk of breast cancer.Some research has suggested that diets high in mush-

rooms may modulate aromatase activity and be useful inchemoprevention against breast cancer by reducing thein situ production of estrogen. The white button mush-room (Agaricus bisporus) suppressed aromatase activitydose dependently (Grube et al., 2001). Enzyme kineticsdemonstrated mixed inhibition, suggesting the presenceof multiple inhibitors or more than one inhibitory mech-anism. Aromatase activity and cell proliferation were thenmeasured using MCF-7aro, an aromatase-transfectedbreast cancer cell line. Phytochemicals in the mushroomaqueous extract inhibited aromatase activity and prolif-eration of MCF-7aro cells.The role of intake of dietary fiber and sources of fiber for

protection in an earlier stage of breast cancer has beenconsidered in adolescents with breast benign disease,because of significant inverse associations between con-sumption of fiber and risk of proliferative initiated cells(Su et al., 2010). This result was attributed partly to theanti-estrogenic effects of lignans and isoflavonoid com-pounds, which occur naturally in fiber-rich foods (Var-inska et al., 2015; Adlercreutz et al., 2007). Green teacomponents, especially catechins, have been consideredfor prevention and treatment of breast cancer based onnumerous in vitro and preclinical studies, with promis-sory results including reducing tumor volume, interferingwith estrogen receptor function, inhibiting estrogen-induced breast cancer cells proliferation, and potentiatingeffect of curcumin, paclitaxel, and tamoxifen (Li et al.,2014; Yiannakopoulou, 2014).

1.2.1.4 ProstateProstate cancer is the second most common cancer inmen. An estimated 1.1 million new cases worldwide were


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diagnosed in 2012, accounting for 15% of the cancersdiagnosed in men IARC 2015.Some studies have suggested that ingestion of some

fruits and vegetables may potentially reduce the risk ofprostate cancer (Giovannucci et al., 2003; Campbell et al.,2004; Stram et al., 2006). Several epidemiological studieshave reported associations between fruit and vegetableintake and reduced risk of prostate cancer, but the find-ings are inconsistent and data on clinically relevantadvanced prostate cancer are limited (Kirsh et al., 2007).A study at the Harvard School of Public Health done on

48,000 men for 4 years reported that men who ate 10 ormore servings of tomato products (such as tomatoes,tomato sauce, pizza sauce) per week had up to 34% lesschance of developing prostate cancer (Giovannucci et al.,1995). They showed that lycopene intake from tomato-based products is related to a low risk of prostate cancer,but consumption of other carotenoids (β-carotene, α-car-otene, lutein, β-cryptoxanthin) or retinol was not associ-ated with the risk of prostate cancer. Etminan et al.published a meta-analysis in 2004 which confirmed theprotective effect of lycopene and/or tomato intake. Theyfound that serum lycopene intake (relative risk RR= 0.71,95% CI 0.59–0.92), lycopene intake (RR= 0.89, 95% CI0.81–0.98), and cooked tomato intake (RR= 0.81, 95% CI0.71–0.92) (six studies), but not raw tomato intake (RR= 0.89, 95% CI 0.80–1.00) (nine studies), were associatedwith a significant decrease in prostate cancer risk. Inpreclinical studies in animals where prostate cancerwas induced by chemical agents or xenograft cancer cells,it has been observed that tomato powder (250mg/kg diet)was more effective than lycopene alone (100, 200, or300mg/kg diet) (Boileau et al., 2003, Tang et al., 2005).Although in general this carotenoid alters prostate cancerdevelopment and/or tumor growth, this suggests that thecancer chemopreventive action of lycopene is effectivetogether with that of other compounds of tomato.Activities of various carotenoids present in foods

against human prostate cancer cell lines have been inves-tigated (Kotake-Nara et al., 2001). The effects of 15carotenoids on the viability of three lines of humanprostate cancer cells, PC-3, DU 145, and LNCaP, wereevaluated. When cancer cells were cultured in a carot-enoid-supplemented medium for 72 hours at 20mmol/L,5,6-monoepoxy carotenoids, namely, neoxanthin fromspinach and fucoxanthin from brown algae, significantlyreduced cell viability to 10.9% and 14.9% for PC-3, 15.0%and 5.0% forDU 145, and nearly zero and 9.8% for LNCaP,respectively. Acyclic carotenoids such as phytofluene,ξ-carotene, and lycopene, all of which are present intomato, also significantly reduced cell viability. However,phytoene, canthaxanthin, β-cryptoxanthin, and zeaxan-thin did not affect the growth of the prostate cancer cells.DNA fragmentation of nuclei in neoxanthin- and

fucoxanthin-treated cells was detected by in situ TdT-mediated dUTP nick end labeling (TUNEL) assay. Neo-xanthin and fucoxanthin reduced cell viability throughinduction of apoptosis.Epigallocatechin-3-gallate (EGCG), resveratrol, curcu-

min, and the isoflavones (genistein and daidzein) from soyhave shown chemopreventive effects against prostatecancer. Epidemiological studies have suggested thatincreasing intake of green tea is correlated with significantdecrease in the development of prostate cancer (Johnsonet al., 2010). However, recent epidemiological studieshave revealed inconclusive results (Zheng et al., 2011;Montague et al., 2012; Lin et al., 2014), contrary to thoseobserved in laboratory studies where EGCG, green teaextract, or black tea extract induce apoptosis, cell cyclearrest, inhibition of COX-2 and metalloproteinase-9 and-2 enzymes, and reduction of vascular endothelial growthfactor (VEGF) levels in prostate cancer cell lines (Ciminoet al., 2012). The contradiction may be attributed to theblood–prostate barrier which reduces penetration ofactive compounds from tea. An additional factor is thelower quantities of human tea consumption compared tothe doses used in experimental studies (Fulmer andTurner, 2000). Resveratrol and curcumin are consideredpromising molecules because of findings (overcomeresistance, enhance radiosensitivity, antioxidant in pre-malignant cells, antiproliferative, and pro-apoptotic) inmany in vitro and preclinical experimental studies. Fur-thermore, curcumin (2–5 μM) in combination with radi-ation showed significant enhancement of radiation-induced clonogenic inhibition and apoptosis in PC-3(Cimino et al., 2012; Chendil et al., 2004). However, thereare no results from human clinical trials that justify arecommendation for the administration of resveratrol orcurcumin in healthy or prostate cancer patients (Ciminoet al., 2012; Jasin ́ski et al., 2013).It has been suggested that soy isoflavones and their

metabolites may be beneficial for the prevention or treat-ment of prostate cancer, and some epidemiologic studieshave shown that total soy isoflavone levels in serum areassociated with a reduced risk of this cancer (Hwang et al.,2009). In prostate tissue, levels of total soy isoflavones(2.3 μmol/L) exceed serum levels (0.7 μmol/L) by sixfoldin people daily consuming soy after dietary supplementa-tion (82mg/day aglycone equivalents) for two weeks(Gardner et al., 2009). The inhibition of prostate cancercells by soy isoflavones involves inhibition of cell growthbymodifying the expression of some central genes for cellsurvival, cell cycle, apoptosis, androgen receptor, andreduction of prostate-specific antigen levels, inducingthe expression of several enzymes involved in the anti-oxidant defense system and capable of reversing promoterhypermethylation in some tumor suppressor genes(including Ras association domain family 1 (RASSF1A),


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B-cell translocation gene 3, PTEN, cyclin D, p53,FOXO3a, p21 (WAF1/CIP1) and p16) under high phar-macological doses in prostate cancer cell lines (Mahmoudet al., 2014).

1.2.1.5 LungIncreased fruit and vegetable consumption may protectagainst lung cancer, although epidemiologic findings areinconclusive. Dosil-Díaz et al. (2008) analyzed the effect offruit and vegetable intake on lung cancer risk in a popu-lation in northwest Spain, using data from a hospital-based case-control study including 295 histologicallyconfirmed cases and 322 controls. Controls were patientsattending the hospital for minor surgery. After adjust-ment for sex, age, tobacco use, and occupation, they foundno protective effect of overall consumption of fruit (OR1.49, 95% CI 0.81–2.73), but green leafy vegetables con-ferred a protective effect (OR 0.50, 95% CI 0.30–0.83).The association of fruit and vegetable consumption and

lung cancer incidence was evaluated by Linseisen et al.(2007) using data from the EPIC study, applying a refinedstatistical approach (calibration) to account for measure-ment error potentially introduced by using food fre-quency questionnaire data. Between 1992 and 2000,detailed information on the diet and lifestyle of 478,590individuals participating in EPIC was collected, and dur-ing a median follow-up of 6.4 years, 1126 lung cancercases were observed. In the whole study population, fruitconsumption was significantly inversely associated withlung cancer risk while no association was found forvegetable consumption. In current smokers, however,lung cancer risk significantly decreased with higher vege-table consumption, and this association became morepronounced after calibration, the hazard ratio (HR) being0.78 (95% CI 0.62–0.98) per 100 g increase in daily vege-table consumption. In comparison, the HR per 100 g fruitwas 0.92 (0.85–0.99) in the entire cohort and 0.90(0.81–0.99) in smokers. Cancer incidence decreasedwith higher consumption of apples and pears (entirecohort) as well as root vegetables (in smokers).Wright et al. (2008) prospectively examined associa-

tions between lung cancer risk and intakes of fruit,vegetables, and botanical subgroups in 472,081 partici-pants aged 50–71 years in the National Institutes ofHealth–American Association of Retired Persons(NIH–AARP) Diet and Health Study. Diet was assessedat baseline (1995–6) with a 124-item dietary question-naire. A total of 6035 incident lung cancer cases wereidentified between 1995 and 2003. Total fruit and vegeta-ble intake was unrelated to lung cancer risk in both menand women, but higher consumption of several botanicalsubgroups was significantly inversely associated with riskonly in men. Association between lung cancer risk and

fruit and vegetable consumption was also investigated byFeskanich et al. (2000) in 77,283 women in a Nurses’Health Study and 47,778 men in a Health Professionals’Follow-Up Study. Diet was assessed using a food fre-quency questionnaire including 15 fruits and 23 vegeta-bles. Relative risk of lung cancer within each cohort wasestimated using logistic regression models; all statisticaltests were two-sided. Totals of 519 and 274 lung cancercases were documented among women and men, respec-tively. Total fruit consumption was associated with amodestly lower risk among women but not amongmen. RR for highest versus lowest quintile of intakewas 0.79 (95% CI 0.59–1.06) for women and 1.12 (95%CI 0.74–1.69) for men after adjustment for smokingparameters. Total fruit and vegetable consumption wasassociated with lower risk of lung cancer among men andwomen who had never smoked, but the reduction was notstatistically significant (RR= 0.63, 95%CI 0.35–1.12 in thehighest tertile). It is suggested that the inverse associationamong women was confounded by unmeasured smokingcharacteristics.Goodmanet al. concluded in1992 that someβ-carotene-

rich fruits such as papaya, sweet potato,mango, and yelloworange show little influence on survival of lung cancerpatients, and the intake of β-carotene before diagnosis oflung cancer does not affect the progression of the disease.These authors have also concluded that a tomato-rich diet(which contributes high lycopene content but little β-car-otene) had a strong positive relationship with survival,particularly among women. However, other studies (LeMarchand et al., 1989; Steinmetz et al., 1993) concludedthat lycopene intake was unrelated to lung cancer.

1.2.2 Cardiovascular Disease (CVD)

CVD is the number one cause of death in developed anddeveloping nations (Go et al., 2014), and prevention is atthe top of the public health agenda (Retelny et al., 2008).In 2008, 17 million deaths worldwide were due to cardio-vascular diseases; this represents 48% of non-communi-cable disease deaths (WHO, 2011). Evidence shows thatreducing the incidence of coronary heart disease (CHD)with diet is possible (Retelny et al., 2008). This wasrecently shown in the Prevención con DietaMediterránea(PREDIMED) study, a randomized controlled trial includ-ing 7447 obese men and women with a mean age of67 years at high risk for cardiovascular disease (50% of theparticipants had diabetes type 2, more than 70% haddyslipidemia, and more than 80% had hypertension).After a median follow-up of 4.8 years, the study showedthat a Mediterranean diet supplemented with extra virginolive oil or a mix of nuts (almonds, walnuts, and hazel-nuts) reduced incidence of CVD (myocardial infarction,


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stroke, or cardiovascular death) by 30% in the olive oilgroup (HRadj= 0.70, 95% CI 0.54, 0.92) and 28% in the nutgroup (HRadj= 0.72, 95% CI 0.54, 0.96) compared to thecontrol group, which was instructed to eat a more fatreduced diet (Estruch et al., 2013). Moreover, in theprospective part of the PREDIMED study, the baselineintake of fruit was inversely associated with all-causemortality (HR for the fifth compared with the first quintile= 0.59, 95% CI 0.44, 0.78) and the associations werestronger for CVDmortality than for other causes of death(Buil-Cosiales et al., 2014).Two important meta-analyses by Dauchet in 2006 and

by He in 2007, which included nine and 13 cohort studies,concluded that a higher fruit and vegetable consumptionwas inversely associated with the risk of CHD. Thesefindings were coherent with followingmeta-analyses suchas the EPIC Heart Study (Crowe et al., 2011) and theMorgan Study (Oude Griep et al., 2010); the exception isthe Italian study within EPIC where no association wasfound for fruit and vegetable in total, but only for leafyvegetables (Bendinelli et al., 2011). A recent meta-analy-sis, which included 23 studies involving 937,665 partic-ipants and 18,047 patients with CHD, concluded that fruitand vegetable intake >5 servings/day was significantlyassociated with a lower risk of CHD in Western popula-tions, but not in Asian populations. This meta-analysisfound that in dose–response studies the relative risk ofCHD decreased by 12%, 16%, and 18% for daily 477 g oftotal fruit and vegetables, 300 g of fruit, and 400 g ofvegetables, respectively (Yu et al., 2014).Some biological mechanisms have been proposed to

explain these protective effects by using in vivo models,such as inhibition of lipid oxidation, an increase in theantioxidant capacity of serum or plasma (Harasym andOledzki, 2014), protection against the oxidation of cho-lesterol and other lipids in cell membranes (da SilvaPereira et al., 2014), reduction in oxidative stress (Thomp-son, 2010), an anti-inflammatory effect (Loke et al., 2008),prevention of platelet aggregation, reduction in vasculartone (Wang X. et al., 2014), and induction of glutathione,endothelial NO synthase (eNOS), and inducible NOS(iNOS) (Mukai and Sato, 2009). Using rat cardiomyoblastH9c2 cells (Park et al., 2009; Angeloni et al., 2007), humanumbilical vein endothelial cells (HUVECs) (Gong et al.,2010), J774A.1 macrophages (Hwang et al., 2003), andmonocyte-derivedmacrophages (La et al., 2009), cell linestreated withmethanolic onion extract (0.05 and 0.1 g/mL),quercetin (30 μM), rutin (200 μM), resveratrol (20μM),and cranberry proanthocyanidins (25 and 50 μg/mL)induced anti-apoptotic effects, evidenced by inhibitionof cytochrome C release to cytoplasm and inactivationof H2O2-induced caspases-3, increase in bioavailability ofnitric oxide (NO), and reduction in matrix metalloprotei-nases 9, 7, 8, and 13 production.

Numerous epidemiological studies have provided evi-dence that a diet rich in fruits and vegetables may protectagainst CVD (Ness and Powles, 1997; Law and Morris,1998; Ness et al., 1999; Liu et al., 2000, 2001; Joshipuraet al., 2001; Bazzano et al., 2002). The positive effect hasbeen accomplished by 3 servings/day of vegetables andfruits, and the relative risk could be minimized to a greatextent by enhancing the vegetable and fruit consumptionby up to 10.2 servings/day. A study on 2682 men inFinland has also indicated that high intake of fruits andvegetables correlates with reduced risk of cardiovasculardisease (Rissanen et al., 2003). The inverse relationshipbetween vegetable intake and cardiovascular disease wasmore evident with smokers consuming at least 2.5 serv-ings/day in comparison with less than 1 serving/day (Liuet al., 2001). Legume consumption was significantly andinversely associated with cardiovascular disease, loweringthe risk by about 11% (Bazzano et al., 2001).The Japan Collaborative Cohort Study for Evaluation of

Cancer Risk (Nagura et al., 2009), with 25,206 men and34,279 women aged 40–79 years, whose fruit, vegetable,and bean intakes were assessed by questionnaire at base-line in 1988–90 and followed for 13 years, concluded thatintakes of plant-based foods, particularly fruit intake, areassociated with reduced mortality from CVD and allcauses among Japanesemen andwomen.However, Naka-mura et al. (2008) assessed the intake of fruit and vege-tables in 13,355 men and 15,724 women in Takayama,Gifu, Japan using a validated food frequency question-naire (FFQ), and found that for women, the highestquartile of vegetable intake compared with the lowestwas marginally significant and was inversely associatedwith CVD mortality after adjusting for total energy, age,and non-dietary and dietary covariates, whereas for men,CVD death was not associated with fruit or with vegetableintake.Radhika et al. (2008) examined the relationship between

fruit and vegetable intake (g/day) and CVD risk factors inurban south Indians. The study population comprised983 individuals aged>20 years selected from the ChennaiUrban Rural Epidemiological Study (CURES), a popula-tion-based cross-sectional study on a representative pop-ulation of Chennai in southern India, and fruit andvegetable intake (g/day) was measured using a validatedsemi-quantitative FFQ. Linear regression analysisrevealed that after adjusting for potential confounderssuch as age, sex, smoking, alcohol, BMI, and total energyintake, the highest quartile of fruit and vegetable intake(g/day) showed a significant inverse association withsystolic blood pressure (BP), total cholesterol, and low-density lipoprotein (LDL) cholesterol concentrationwhen compared with the lowest quartile. A higher intakeof fruit and vegetables explained 48% of the protectiveeffect against CVD risk factors.


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It has been reported that death attributed to cardiovas-cular and coronary heart diseases showed strong andconsistent reductions with increasing nut or peanut but-ter consumption (Blomhoff et al., 2006). Nuts, includingpeanuts, have been recognized as having the potential toimprove the blood lipid profile and, in cohort studies, nutconsumption has been associated with a reduced risk ofCHD (Jenkins et al., 2008; Kris-Etherton et al., 2008).These findings have recently been confirmed in system-atic reviews andmeta-analyses (Afshin et al., 2014; Grossoet al., 2015). Afshin et al. (2014) found that fatal ischemicheart disease (IHD) was inversely associated with nutconsumption (per 4 weekly servings of 28 g nuts, RR= 0.76, 95% CI 0.69, 0.84), as was non-fatal IHD (RR= 0.78, 95% CI 0.67, 0.92). Likewise, Grosso et al.(2015) reported a 27% reduced risk of all-cause mortality(RR= 0.73, 95% CI 0.60, 0.88) for 1 serving of nuts per dayand a 39% risk for CVDmortality (RR= 0.61, 95% CI 0.42,0.91) per daily serving of nuts. However, as the authorspointed out, confounding factors such as body massindex, smoking status, increased intake of fruit and veg-etables, as well as intake of alcohol have to be taken intoaccount when considering the findings (Grosso et al.,2015).Both in meta-analysis and in clinical studies, the bene-

ficial effects of different nuts and peanuts on lipids, lip-oproteins, and various CHD risk factors, includingoxidation, inflammation, endothelial function, and arte-rial stiffness, have been shown (Kris-Etherton et al., 2008;Sabaté et al., 2010; Kasliwal et al., 2015). In the meta-analysis by Sabaté et al. (2010) it was shown that a meandaily consumption of 67 g nuts reduced total cholesterolconcentrations by 5%, reduced LDL cholesterol by 7%,and improved the LDL cholesterol to high-density lipo-protein (HDL) cholesterol ratio. Moreover, a reduction insmall dense LDL particles after consumption of 57 gpistachios has been shown among subjects with pre-diabetes (Hernández-Alonso et al., 2015).The LDL cholesterol lowering response of nut and

peanut studies is generally greater than expected onthe basis of blood cholesterol lowering equations thatare derived from changes in the fatty acid profile of thediet. Thus, in addition to a favorable fatty acid profile, nutsand peanuts contain other bioactive compounds thatexplain theirmultiple cardiovascular benefits. Othermac-ronutrients include plant protein and fiber; micronu-trients such as potassium, calcium, magnesium, andtocopherols; and phytochemicals such as phytosterols,phenolic compounds, resveratrol, and arginine. Kris-Etherton et al. (2008) have indicated that nuts and peanutsare food sources that are a composite of numerouscardioprotective nutrients and, if they are routinely incor-porated in a healthy diet, the population risk of CHDwould be expected to decrease markedly.

Hung et al. (2003) evaluated the association of con-sumption of fruits and vegetables with peripheral arterialdisease in a cohort study of 44,059 men initially free ofcardiovascular disease and diabetes, reporting no evi-dence that fruit and vegetable consumption protectsagainst peripheral arterial disease, although a modestbenefit cannot be excluded. In the age-adjusted model,men in the highest quintile had a relative risk of 0.55 (95%CI 0.38–0.80) for overall fruit and vegetable intake, 0.52(0.36–0.77) for fruit intake, and 0.54 (0.36–0.81) forvegetable intake, compared with those in the lowestquintile of intake. However, the associations were greatlyweakened after adjustment for smoking and other tradi-tional cardiovascular disease risk factors.Pure β-carotene supplementation (30–50mg/day) had

no depressive effects on cardiovascular disease risk (Hen-nekens et al., 1996; Omenn et al., 1996; Lee et al., 1999).Mono-unsaturated fats in avocados have been shown to

reduce blood cholesterol while preserving the level ofhigh-density lipoproteins (Yahia, 2012b). Avocadoenriched diet produced a significant reduction in LDLand total cholesterol in patients with high cholesterollevels, while diets enriched with soy and sunflower did notchange the total cholesterol concentrations (Carranzaet al., 1997). These findings were confirmed in a random-ized, crossover controlled feeding study among 45 over-weight or obese hyperlipidemic men and women. In thisstudy the inclusion of one avocado per day reduced LDLcholesterol, non-HDL cholesterol, and the overall LDLparticle number (Wang et al., 2015).Lycopene from tomato fruit was found to prevent the

oxidation of LDL cholesterol and to reduce the risk ofdeveloping atherosclerosis and coronary heart disease(Agarwal and Rao, 1998), and a daily consumption oftomato products providing at least 40 mg of lycopene wasreported to be enough to substantially reduce LDL oxi-dation. Lycopene is recognized as the most efficientsinglet oxygen quencher among biological carotenoids(Di Mascio et al., 1989, 1991). Lycopene has also beenreported to increase gap-junctional communicationbetween cells and to induce the synthesis of connexin-43 (Zhang et al., 1992).

1.2.2.1 HypertensionBlood pressure (BP) is a continuous, consistent, andindependent risk factor for CVD that is modifiablethrough lifestyle. Indeed, a recent meta-analysis reportedamoderate average BP reduction of 3.5 and 2.0mmHg forsystolic and diastolic BP, respectively, which was associ-ated with a 24% reduction in stroke (Aburto et al., 2013).In the PREDIMED study the reduced incidence of CVDwasmainly driven by reduced incidence of stroke (Estruchet al., 2013) and favorable effects of both Mediterranean


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diets were seen on BP (Martinez-Gonzales, 2015). Ameta-analysis including 21 randomized clinical trialsshowed that nut consumption was associated with areduction in systolic BP among participants withoutdiabetes type 2 (�1.3mmHg, 95% CI �2.3, �0.22) andthat pistachios had the strongest effect on systolic (�1.8mmHg, 95% CI�3.0,�0.7) and diastolic BP (�0.8mmHg,95% CI �1.4, �0.2) (Mohammadifard et al., 2015).Diet plays a major role in BP control, and the Dietary

Approaches to Stop Hypertension (DASH) studies clearlyshowed that eating vegetables, fruit, and low-fat dairyproducts lowered BP (Zhao et al., 2011). In particular, theevidence for recommending vegetables and fruit toreduce BP is convincing (Boeing et al., 2012; Bupathirajuand Tucker, 2011). Indeed, a recentmeta-analysis, includ-ing clinical trials and a total of 311 participants, showedthat a vegetarian diet was associated with a reduction inmean systolic BP (�4.8mmHg, 95% CI �6.6, �3.1) anddiastolic BP (�2.2mmHg, 95% CI �3.5, �1.1) (Yokoyamaet al., 2014).The BP lowering effects of fruits and vegetables may

involve several mechanisms, but fruits and vegetables aregenerally high in antioxidants (Halvorsen et al., 2006).Oxidative stress has been postulated to have a possiblerole in the pathogenesis of hypertension (Ceriello, 2008),and higher intake of antioxidants may increase the bio-availability of NO by decreasing endogenous oxidantformation (McCarty, 2008). Another possibility may beincreased intake of potassium. Potassium has been shownto promote vasodilation and to reduce renin, renalsodium reabsorption, reactive oxygen production, andplatelet aggregation (McDonough and Nguyen, 2012).Also, inhibition of the angiotensin-converting enzyme(ACE) activity by fruit and vegetables has been postulated,and dietary involvement of the renin–angiotensin systemby the DASH diet has been shown (Conlin et al., 2003).

1.2.2.2 Chronic Heart FailureChronic heart failure (CHF) has a prevalence of about 80%among individuals aged more than 80 years worldwide,and is seen as the end-stage of CVD and the final pathwayof diseases such as hypertension and CVD (Rich, 2001;Lloyd-Jones et al., 2010). CHF has many causes, butoxidative stress has also been proposed as a risk factor(Ingelsson et al., 2005). In a population-based prospectivecohort study, more than 30,000 women aged 49–83 yearswere followed for 11.3 years, and total antioxidant capac-ity of the diet measured by oxygen radical absorbancecapacity was inversely associated with heart failure (themultivariable adjusted relative risk in the highest quintilecompared to the lowest was 0.58, 95% CI 0.47, 0.72)(Rautiainen et al., 2013). Among Swedish men a dietarypattern in accordance with theDASHdiet rich in fruit and

vegetables has been associated with reduced incidence ofCHF (22%, 95% CI 5%, 35%) (Levitan et al., 2009).

1.2.3 Diabetes Mellitus

The prevalence of type 2 diabetes mellitus is increasingworldwide. In 2013 it was reported to be 382 million, andit is expected to rise to 592 million by 2035 (Guariguataet al., 2014). Because diabetes is characterized by eitherresistance to the blood glucose regulating hormone insu-lin or its relative deficiency (WHO, 2006), it has beenproposed that antioxidants may play a role in increasingor reducing insulin sensitivity (Bryans et al., 2007). Thus,fruit and vegetable consumption has been considered as astrategy to lower markers of oxidative stress and inflam-mation present in 54 type 2 diabetes (T2D) patients asobserved by Asgard et al. (2007) in a cross-sectional study,where fruit and vegetable intake was negatively correlatedwith DNA oxidation and lipid peroxidation. These effectswere negatively correlated with dietary vitamin C, andplasma carotenoids were negatively correlated withinflammation, measured as IL-6 (Asgard et al., 2007).Similar results were obtained in the study of Hegdeet al. (2013), where 60 patients were assigned to receiveadditional dietary therapy and 63 received standard diet(control). The dietary intervention resulted in significantreduction in malondialdehyde, plasma glucose, and gly-cated hemoglobin, and improvement in antioxidants likevitamin C and reduced glutathione when compared withthe control group. Mean plasma levels of vitamin Cincreased by 64% (p< 0.001) (Hegde et al., 2013).On the other hand, Hamer and Chida (2007) have

suggested that the consumption of 3 or more daily serv-ings of fruit or vegetables was not associated with asubstantial reduction in the risk of T2D, but the intakeof antioxidants was associated with a 13% reduction inrisk, mainly attributed to vitamin E. Five cohort studies offruit and vegetables intake and the risk of diabetes using167,128 participants and 4858 incident cases of T2D, witha mean follow-up of 13 years, were reviewed by Hamerand Chida (2007). The relative risk of T2D was 0.96 (95%CI 0.79–1.17, P= 0.96) for consuming 5 or more servingsof fruit and vegetables daily, 1.01 (0.88–1.15, P= 0.88) for3 or more servings of fruit, and 0.97 (0.86–1.10, P= 0.59)for 3 or more servings of vegetables. Nine cohort studiesof antioxidant intake and the risk of diabetes were alsoidentified, incorporating 139,793 participants and 8813incident cases of T2D, with a mean follow-up of 13 years(Hamer and Chida, 2007); these indicated that the pooledrelative risk was 0.87 (0.79–0.98, P= 0.02) for the highestcompared with the lowest antioxidant intake. Villegaset al. (2008) examined the associations between fruitand vegetable intake and the incidence of T2D in a


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population-based prospective study of 64,191 Chinesewomen with no history of T2D or other chronic diseasesat study recruitment and with valid dietary information.Individual vegetable groups were all inversely and signifi-cantly associated with the risk of T2D, but there was noassociation with fruit intake.This suggests that the association between the intake of

fruit and vegetables and the risk of T2D is unclear.However, it has been proposed that this inconsistencybetween studies examining the association between fruitsand vegetables intake and risk of diabetes could be due tothe extent of measurement error associated with the FFQbecause people overestimate their fruit and vegetableconsumption. In addition, these studies include con-sumption of fruit juices, which contain both an importantsugar load and fructose which contribute to the develop-ment of diabetes and insulin resistance (Bazzano et al.,2008). Recently, Wu et al. (2015) carried out a dose–response meta-analysis to quantitatively assess the asso-ciation of T2D risk with consumption of vegetables (sevenstudies), fruits (nine studies), and total fruits and vegeta-bles (seven studies). They found that there was a thresholdaround 2–3 servings/day of vegetable and 2 servings/dayof fruit, after which the T2D risk did not reduce further;these findings are consistent with the general recommen-dation to consume 5 servings of fruit and vegetables a day(3 of vegetable and 2 of fruit), but the effect of specifictypes of fruit and vegetable on T2D risk is unknown (Wuet al., 2015).Randomized controlled trials of patients with T2D have

confirmed the beneficial effects of nuts on blood lipids,also seen in non-diabetic subjects, but the trials have notreported improvement in A1c or other glycated proteins(Jenkins et al., 2008). Therefore, Jenkins et al. (2008)concluded that there is justification to consider the inclu-sion of nuts in the diets of individuals with diabetes in viewof their potential to reduce CHD risk, even though theirability to influence overall glycemic control remains to beestablished.Nettleton et al. (2008) characterized dietary patterns

and their relation to incident T2D in 5011 participantsfrom the Multi-Ethnic Study of Atherosclerosis (MESA)and found that high intake of whole grains, fruit, nuts/seeds, green leafy vegetables, and low-fat dairy was asso-ciated with a 15% lower diabetes risk.Bazzano et al. (2008) concluded that consumption of

green leafy vegetables and fruit was associated with alower hazard of diabetes, whereas consumption of fruitjuices may be associated with an increased hazard amongwomen. A total of 71,346 female nurses aged 38–63 yearswho were free of cardiovascular disease, cancer, anddiabetes in 1984 were followed for 18 years, and dietaryinformation was collected using a semi-quantitative FFQevery 4 years (Bazzano et al., 2008). During follow-up,

4529 cases of diabetes were documented, and the cumu-lative incidence of diabetes was 7.4%; an increase of 3servings/day in total fruit and vegetable consumption wasnot associated with development of diabetes, whereas thesame increase in whole fruit consumption was associatedwith a lower hazard of diabetes. An increase of 1 serving/day in green leafy vegetable consumption was associatedwith a modestly lower hazard of diabetes, whereas thesame change in fruit juice intake was associated with anincreased hazard of diabetes.Experimental evidence showed that consumption of

prickly pear cladodes (nopal) could reduce blood glucoselevels (Frati et al., 1990a). The intake of broiled Opuntiastems for 10 days improved glucose control in a smallgroup of adults with non-insulin-dependent diabetesmellitus (NIDDM) (Frati et al., 1983, 1990b). The risein serum glucose levels which follows the intake of a sugarload (oral glucose tolerance test) was lower with previousingestion ofOpuntia stems compared towhen the sugar isingested alone (Frati et al., 1990a). In patients withNIDDM, the ingestion of some species of nopal (O.streptacantha, O. ficus-indica) in fasting condition isgenerally followed by a decrease in serum glucose andserum insulin levels (Frati, 1992). These positive healtheffects of Opuntia stems might be associated with dietaryfibers, since similar results can be achieved with Plantagopsyllium or other sources of dietary fiber (Frati, 1992).Ingestion of raw and cooked O. ficus-indica extractsresulted in beneficial effects on total cholesterol, withoutany secondary effect on glucose and lipoprotein amountsin blood (Medellin et al., 1998).Some flavonoids, such as procyanidins, have antidia-

betic properties because they improve altered glucose andoxidative metabolisms of diabetic states (Pinent et al.,2004). Extract of grape seed procyanidins (PE) adminis-tered orally to streptozotocin-induced diabetic ratsresulted in an antihyperglycemic effect, which was signif-icantly increased if PE administration was accompaniedby a low insulin dose (Pinent et al., 2004). The antihy-perglycemic effect of PE may be partially due to theinsulinomimetic activity of procyanidins on insulin-sensitive cell lines.

1.2.4 Obesity

Obesity is characterized by the accumulation of excess fatin adipose tissues. It is considered a major public healthissue, especially in most developed countries nowadaysbecause of its wide spread across population groups, aswell as its contribution to the development of chronicdiseases, particularly cardiovascular diseases, type 2 dia-betes, and some types of cancer (i.e. colorectal, breast)(IARC, 2008). These result from a sedentary lifestyle and


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unhealthy dietary practices, which mean high energyintake and low energy expenditure.Despite the alarming increase in the prevalence of

obesity across the world, epidemiologic studies on therelation between fruit and vegetable consumption andweight gain (WG) are still insufficient. In a systematicreview, Fogelholm et al. (2012) showed that a high intakeof fiber-rich foods and nuts predicted less WG andreduced waist circumference. Indeed, a recent analysisfrom the National Health and Nutrition ExaminationSurvey 2004–2010 showed that nut consumers who atea mean of 44 g nuts per day had lower BMI and waistcircumference than non-nut consumers (p< 0.01 forboth) (O’Neil et al., 2015). The mechanism for the bene-ficial effect of nuts on body weight may be due to theirsatiating effect and subsequent food compensation(Mattes et al., 2008).The evidence accumulated indicates that the combina-

tion of an increased fruits and vegetables intake, togetherwith other dietary recommendations, might promotesatiety and weight loss in overweight and obese individ-uals. Fruits and vegetables are low in fat but high in watercontent, indigestible fiber, and soluble dietary fiber whichcontribute to reduce the energy intake of meals, or thecalorie intake, and consequently the body weight. It hasbeen proposed that soluble dietary fiber delays gastricemptying of ingested food and forms a gel-like environ-ment in the small intestine that partly diminishes theactivity of enzymes involved in the digestion of macro-nutrients and absorption. This prolongs the contact of thenutrients with receptors in the small intestine such asfructose, causing the release of putative satiety peptidesand creating a hyperosmolar environment in the colon –leading, for example, to a decrease in insulin secretion andan improvement in glucose control, an attraction of fluidsinto the gut lumen, and a loss of interest in further foodconsumption (Mirmiran et al., 2013).Vioque et al. (2008) explored the associations between

fruit and vegetable intake andWGover a 10 year period inan adult Mediterranean population of 206 aged 15–80years at baseline in 1994, who participated in a nutritionsurvey in Valencia, Spain. They concluded that dietarypatterns associated with a high intake of fruits and veg-etables in Mediterranean populations may reduce thelong-term risk of subsequent WG and obesity amongadults.Svendsen et al. (2007) assessed the effect of increased

consumption of vegetables and fruit on body weight, riskfactors for CVD, and antioxidant defense in obese patientswith sleep-related breathing disorders (SRBD). They con-cluded that targeted dietary advice to increase the intakeof vegetables and fruit among subjects with SRBD con-tributed to weight reduction and reduced systolic anddiastolic BP, but had no effect on antioxidant defense

measured by ferric-reducing/antioxidant power (FRAP)assay.He et al. (2004) examined the changes in intake of fruits

and vegetables in relation to risk of obesity and weightgain among middle-aged women through a prospectivecohort study with 12 years of follow-up, conducted in theNurses’Health Study with a total of 74,063 female nursesaged 38–63 years, whowere free of cardiovascular disease,cancer, and diabetes at baseline in 1984. During the 12year follow-up, participants tended to gain weight withaging, but those with the largest increase in fruit andvegetable intake had a 24% lower risk of becoming obesecompared with those who had the largest decrease inintake after adjustment for age, physical activity, smoking,total energy intake, and other lifestyle variables. Formajorweight gain (>25 kg), women with the largest increase inintake of fruits and vegetables had a 28% lower riskcompared to those in the other extreme group.Bes-Rastrollo et al. (2006) assessed the association

between fiber intake and fruit and vegetable consumptionwith the likelihood of weight gain in a Mediterranean(Spain) population with a cross-sectional analysis of 5094men and 6613 women in a multipurpose prospectivecohort (Seguimiento Universidad de Navarra Study).There was a significant inverse association between totalfruit and vegetable consumption andweight gain, but onlyamong men; it was more evident among those with a highintake of total fiber, and the benefit of total fiber wasmoreevident among those with a high consumption of fruitsand vegetables.De Carvalho et al. (2006) evaluated the dietary fiber

intake of adolescents in the metropolitan area of SãoPaulo city and the association between low dietary fiberintake and constipation and overweight. The studyincluded 716 adolescents, and evaluation of fiber intakewas based on a 24 hour daily intake record and a fre-quency questionnaire. Adolescents who did not eat beanson more than 4 days per week presented a higher risk offiber intake below that recommended, and dietary fiberintake below that recommended was associated with agreater risk toward overweight in students attendingpublic schooling.

1.2.5 Pulmonary Health

Several studies have suggested a positive associationbetween fruit and vegetable intake (particularly fruit)and pulmonary function (Walda et al., 2002; Watsonet al., 2002; Celik and Topcu, 2006). Fruit and vegetableconsumption has been suggested to maintain a healthypulmonary function in well-adult populations, and toimprove lung function in those with established pulmo-nary disorders. Phytochemicals, especially of antioxidant


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potential, have been suggested to be important in pro-tecting lungs from oxidative stress. In a study of 2917menin seven European countries, higher fruit intake wasfound to be consistently associated with lowered mortal-ity from chronic obstructive pulmonary disease (COPD)related causes, and the trend was statistically significantwhen age, country of residence, and smoking were con-sidered (Walda et al., 2002). This study has shown thatvegetables and the antioxidant nutrients vitamins C andβ-carotene did not correlate with COPD mortality, butvitamin E intake did appear to be protective when datawere adjusted for age, country, and smoking. Fruit intakesof over 121 g/day and increased vegetable consumptionwere reported to be associated with significantly reducedCOPD (Watson et al., 2002; Celik and Topcu, 2006).It has been suggested that reduced antioxidant intake is

one critical factor associated with increased susceptibilityto asthma (Devereux and Seaton, 2005), and thereforefruit and vegetable intake has been suggested to reduce it(Patel et al., 2006) by improving ventilatory function andrespiratory symptoms (Romieu et al., 2006). Fruits andvegetables that were found to be associated with reducedincidence of asthma included green leafy vegetables(intake of >90 g/day; 22% risk reduction), tomato (intakeof >28.2 g/day; 15% risk reduction), carrots (intake of>24.9 g/day; 19% risk reduction), and apples (intake of>31.2 g/day; 10% risk reduction). These studies havesuggested that high carotenoid content in the food couldaccount for the effect, although results of studies focusedon β-carotene have not been consistent. The consump-tion of fruit and vegetables was reported to be significantlyassociated with reduced occurrence of wheezing andshortness of breath in 2103 boys and 2001 girls aged6–7 years from Italy (Farchi et al., 2003), and inmore than20,000 children aged 7–11 from 25 areas in Central andEastern Europe (Antova et al., 2003). Kelly et al. (2003)suggested an association between fruit and vegetableintake and improved respiratory function in more than6000 healthy adults in Scotland. However, contradictingdata have also been reported, such as in the study of Lewiset al. (2005) which reported no association betweenasthma prevalence and fruit intake in 11,562 childrenaged 4–6 years living in the United Kingdom, based ondata provided by parents of the study subjects; and in 598Dutch children aged 8–13 years (Tabak et al., 2006).

1.2.6 Bone Health

The loss of bone mass is a global epidemic associated withosteoporosis (Lanham-New, 2006). Fruit and vegetableconsumption has been suggested to improve bone (Lan-ham-New, 2006; Bueline et al., 2001; Pryne et al., 2006; Liet al., 2013; Liu et al., 2015). Higher fruit and vegetable

intake was associated with improved markers of bonestatus in males and females between 16 and 83 years old(Pryne et al., 2006). Tylavsky et al. (2004) showed that fruitand vegetable intakemight be important in bone health inwhite girls aged 8–13 years. The effect was high with 3servings/day or more and low with less than 3 servings/day, with 4.0 servings (1.6 fruit, 2.4 vegetables) in the highgroup and 1.7 servings (0.6 fruit, 1.1 vegetables) in the lowgroup. Girls in the high fruit and vegetable intake grouphad significantly larger bone area across the whole bodyand the wrist, and higher mineral content for whole bodyand at the wrist. A study of 1407 premenopausal farmwomen from five rural districts in Japan has concludedthat fruit and vegetable intake is positively correlated withbone health (Okabo et al., 2006). In a study conductedwith 85 boys and 67 girls aged 8–20 years in Saskatche-wan, Canada (Vatanparast et al., 2005), fruit and vegetableintake was reported to be an important independentpredictor of accrued total body bone mineral contentin boys but not in girls. In a study with adolescents aged 12and 15 years in Northern Ireland (n= 1345), 12-year-oldsconsumed the highest quantity of fruit and a positiveassociation has been demonstrated between bone densityand fruit intake (Gartland et al., 2004).Antioxidants in fruits and vegetables, including vitamin

C and β-carotene, reduce oxidative stress on bonemineraldensity, in addition to the potential role of some nutrientssuch as vitamin C and vitamin K that can promote bonecell and structural formation (Lanham-New, 2006). Manyfruits and vegetables are rich in potassium citrate andgenerate basic metabolites to help buffer acids andthereby may offset the need for bone dissolution andpotentially preserve bone. Potassium intake was signifi-cantly and linearly associated with markers of bone turn-over and femoral bone mineral density (Macdonald et al.,2005).Lin et al. (2003) indicated that high potassium, magne-

sium, and calcium content in addition to antioxidants,phytochemicals, and lower acidity of fruits and vegetablescould be important factors for bone health.In a study with 40 healthy men and women, average age

63.7 years, who were randomized to either an “alkali” diet(meat plus fruits and vegetables) or an “acid” diet (meatplus cereal grains) (Jajoo et al., 2006), altering the renal netacid excretion over a period of 60 days impacted severalbiochemical markers of bones turnover and calciumexcretion. The acidity of the diet had a significant effecton increasing NTX, a urinary marker of bone breakdown,and increasing the amount of calcium excreted in theurine.Li et al. (2013) reported a significantly positive associa-

tion between fruit intakes and bone mineral density(BMD) and bone mineral content (BMC) in all partic-ipants, including boys and girls (11–14 years), young


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women (20–34 years including postpartum within 2weeks), and postmenopausal women (50–70 years), in across-sectional studywhere themean fruit intake was 185,206, 380, and 174 g/day in boys, girls, young women, andpostmenopausal women, respectively. About 40% of thefruit intake was from the group of apple, pear, peach,pineapple, and plum, and 20% from the group of orange,grapefruit, and lemon. In addition, Liu et al. (2015)recently found that a daily increase of 100 g/kcal totalfruit intake was associated with 4.5% and 6.4% increase ofBMD across the whole body, and 3.9% and 4.8% increaseat the femoral neck, in Hong Kong Chinese men andwomen aged 65 years and older, respectively. Similar tothe study of Li et al. (2013), these authors did notfind significant association between vegetable intakeand bone mass.

1.2.7 Cataracts and Eye Health

Oxidative mechanisms have been implicated in the eti-ology of cataracts in humans, and fruit and vegetablesintake has been associated with this problem. A studyinvolving 35,724 healthy professional women over the ageof 45 years in the USA was conducted to determine thepotential association between fruit and vegetable intakeand subsequent risk of cataract development over a 10year follow-up period (Christen et al., 2005). Relative riskof developing cataracts during the 10 year study was onlyslightly reduced in womenwith the highest intake of fruitsand vegetables (10 servings/day) compared to those withthe lowest intake (2.6 servings/day). A study of 479women with an average fruit intake of 2.5 servings/dayand average vegetable intake of approximately 4 servings/day also indicated that fruit and vegetable intake did notdiffer between women with and without nuclear opacities(Moeller et al., 2004). The authors concluded that multi-ple aspects of the diet are more important in reducing therisk of cataracts than emphasizing one particular foodgroup or component over another. A study with 98participants, 68% women, ranging in age between 45and 73 years, using macular pigment optical density(MPOD) as a marker to correlate diet and serum carot-enoid levels with the amount of molecular pigment in theretina, showed that high (�5 servings/day) intake of fruitand vegetables was associated with significantly higherMPOD compared with measurement in subjects withlower (<3 servings/day) intake (Burke et al., 2005).

1.2.8 Arthritis

Dietary antioxidants and anti-inflammatory componentsin food are thought to be important in reducing the risk or

improving the course of rheumatoid arthritis (RA), andtherefore fruit and vegetable consumption has been asso-ciated with reduced risk of RA (Pattison et al., 2004b). Astudy with 29,368 married women from the USA, pre-dominately white, average age 61.4 years, over 11 years,indicated that total fruit consumption (>83 servings/month) was associated with reduced risk of RA (Cerhanet al., 2003). Oranges were the only individual fruit linkedto reduced incidence of RA, and β-cryptoxanthin, acarotenoid found in this fruit, was consistently highlyprotective. Total vegetable intake was not associated withreduced incidence of RA, but intake of cruciferous veg-etables (>11 servings/month), particularly broccoli (>3servings/month), was associated with a moderate effecton RA. In a study where dietary intake for 73 cases wascompared to intake of 146 controls (mean age 60–61years; 70% women), results indicated that lower but notstatistically significant intake of fruits and vegetables wasweakly associated with higher incidence of inflammatorypolyarthritis (IP) (Pattison et al., 2004a). Subjects with thelowest intake (<55.7mg/day) of vitamin C were threetimesmore likely to develop IP than thosewith the highestintake (>94.9mg/day). A related study to determine therelationship with carotenoid intake, in which the diets of88 cases were compared to those of 176 controls (meanage 61 years; 69% women), found that intake of vitamin Cand dietary carotenoids, particularly β-cryptoxanthin andto a lesser extent zeaxanthin, were significantly correlatedwith reduced risk of IP (Pattison et al., 2005).

1.2.9 Birth Defects

The effect of folic acid supplementation on reducing therisk of neural tube defects of the brain and spine, includ-ing spina bifida and anencephaly, is well documented(Eichholzer et al., 2006). Fruits and vegetables are animportant source of dietary folate and their consumptionhas been associated with increased plasma levels of folate.Plasma folate concentration increased by 13% to 27% aftershort-term feeding experiments with fruits and vegetables(Brevick et al., 2005), and red blood cell folate alsoincreases with increasing fruit and vegetable intake(from 1 to 7 servings/day) (Silaste et al., 2003).

1.2.10 Diverticulosis

Diverticulosis, or the presence of several diverticula,affects 50% or more of the population over the age of60 years in several countries (Ye et al., 2005). Studies haveestablished an association between low-fiber diets and thepresence of diverticulosis (Aldoori and Ryan-Harshman,2002). The intake of fruit and vegetable fiber was inversely


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associated with risk of diverticulosis in a large prospectivestudy of male health professionals, and therefore a high-fiber diet including fruits and vegetables remains animportant aspect of therapy for diverticulosis (AmericanDietetic Association, 2002).

1.2.11 Skin Diseases

Skin is the largest organ that is exposed constantly toenvironmental factors able to induce oxidative stress,such as ultraviolet radiation (UVR), air pollutants, andchemical oxidants favoring skin aging, an inevitable nor-mal process. However, premature skin aging may occurdue to non-healthy lifestyle (smoking, unbalanced nutri-tion, excessive caloric restrictions, and mental stress)(Biesalski et al., 2003). In vitro and in vivo studies suggestthat antioxidants regulate the biomarkers associated withpremature aging by reducing oxidative stress in skin.Lycopene had a protective effect on the oxidative stress-

mediated damage of the human skin after irradiation withUV light (Ribaya-Mercado et al., 1995).A formulation of a synergistic blend named OptiBerry

that contains wild blueberry, bilberry, cranberry, elder-berry, strawberry, and raspberry seed extracts developedby Bagchi et al. (2006) showed whole-body antioxidantprotection in vitamin E deficient rats after exposure topressure of 2 atmospheres (atm) for 2 hours with hyper-baric oxygen (HBO). The animals were supplemented for8 weeks, significantly reducing GSH levels compared toplacebo-fed rats (Bagchi et al., 2006). In addition, VEGFexpression induced in keratinocytes by treatment withH2O2 and tumor necrosis factor alpha (TNF-α, an inflam-matory cytokine) was inhibited after 12 hours of treat-ment with OptiBerry; and pretreatment of cells withOptiBerry inhibited ROS- and inflammation-inducedVEGF protein expression (Roy et al., 2002; Bagchiet al., 2004).Promising results have been obtained for the preven-

tion of UV-induced skin alterations and premature skinaging by using extracts of pomace from Riesling grapes,which showed a dose-dependent inhibitory activityagainst both enzymes with IC50 values of 20.3 μg/mLand 14.7 μg/mL for collagenase and elastase activity,respectively, these being the most active in the freephenolic acids fraction (Wittenauer et al., 2015). Humandermal fibroblasts incubated with strawberry extract at0.5mg/mL and stressed with H2O2 showed an increase incell viability, a smaller intracellular amount of ROS, and areduction of membrane lipid peroxidation and DNAdamage; they were also able to improve mitochondrialfunctionality, increasing the basal respiration ofmitochondria, and to promote a regenerative capacityof cells after exposure to pro-oxidant stimuli (Giampieri

et al., 2014). These findings promote the use of naturalsources of antioxidants like fruits and plant extracts(green and black tea, carotenoids, coffee) for protectingskin against premature aging. Moreover, vitamins A, B, C,and E, CoQ10 and its analogs, and flavonoids are currentlyincorporated into a variety of anti-aging skin care systemsby oral administration and topical application. However,many controlled clinical studies are needed to determinethe efficacy and risks of plant-derived products in der-matology. Safety aspects, especially related to sensitiza-tion and photodermatitis, have to be taken into accountfor dermatologic disorders and cosmetic purposes (Bruce,2008; Reuter et al., 2010).

1.2.12 Aging and Cognition

Oxidative stress and inflammation are considered signifi-cant mediators in healthy aging of the brain and in age-related neurodegenerative diseases such as Alzheimer’sand Parkinson’s diseases (Shukitt-Hale et al., 2006). Ani-mal and human studies have suggested that fruits andvegetables have the potential to reduce some age-relatedprocesses, primarily due to the antioxidant and anti-inflammatory properties of several phytochemicals. Anin vitro study has suggested that some classes of phyto-chemicals also act in cell signaling and thus may protectagainst aging by mechanisms other than oxidative andinflammatory processes (William et al., 2004). Fruit andvegetable extracts have been demonstrated to reverse orretard various age-related cognitive and motor deficits inrats (Lau et al., 2005).Strawberry and spinach extracts attenuated age-related

cognitive and neuronal decline in rats over 6–15 months,and blueberry extracts were effective in reversing existingcognitive deficits and improving motor function in agedrats (Joseph et al., 2005a, 2005b). Examination of the braintissue from these animals showed evidence of reducedinflammatory and oxidative processes in the supple-mented groups. Transgenic mice models of Alzheimer’sdisease fed blueberry extract exhibited cognitive perform-ance equivalent to that of normal non-supplementedmice and were significantly improved compared tonon-supplemented transgenic mice (Joseph et al.,2003). Blueberry supplementation in the transgenicmice increased concentration of cell signaling kinasesthought to be involved in converting short-term memoryto long-term memory, and increased other aspects of cellsignaling including increased muscarinic receptor activ-ity, which is also known to be important in cognitivefunction (Casadesus et al., 2004). Aging rats providedwithConcord grape juice at low concentration (10%) for 9weeks improved cognitive performance, while high (50%)concentration improved motor performance (Shukitt-


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Hale et al., 2006). Concord grape and juice contain avariety of flavonoids, and 10% grape juice supplemen-tation was reported to be associated with the mosteffective increase in muscarinic receptor sensitivity inaging rats.A study that interviewed 13,388 women living in 11

states in the USA over a period of 10–16 years (Kang et al.,2005) showed that baseline cognitive performance wasstronger in women who reported the highest intake ofcruciferous vegetables compared to those with lowerintake.It is believed that oxidative stress plays a key role in the

development of Alzheimer’s disease because of the char-acteristic lesions associated with free radical damage andthe attenuation of these processes with supplementationof some antioxidants. To date, there are no clinical trialsthat specifically address the role of dietary fruits andvegetables, although there are trials to investigate theassociation between dietary antioxidants in food andthe risk of Alzheimer’s disease. A study involving 5395men with an average age of 67.7 years, living in theNetherlands and followed for 6 years (Engelhart et al.,2002), reported that baseline dietary intake of vitamins Cand E as well as the use of antioxidant supplements wasassociated with reduced risk of developing Alzheimer’sduring the follow-up period, with a stronger protectiveeffect in subjects who were smokers, and that flavonoidsand β-carotene intake was protective in smokers but notin non-smokers.Themechanisms proposed are based on the antioxidant

action of curcumin by increasing glutathione levels,reducing lipid peroxidation in 3-nitropropionic acid (3-NP) induced neurotoxicity in rats and improving learningand memory (Mythri et al., 2011; Harish et al., 2010;Kumar et al., 2007). Epigallocatechin gallate is able toprotect neuronal cell lines submitted to glucose or gluta-mate toxicity (Romeo et al., 2009; Kang et al., 2010) andage-associated oxidative damage in rat brain by increasingactivities of superoxide dismutase, catalase, glutathioneperoxidase, and glucose-6-phosphate dehydrogenase(Srividhya et al., 2008). Another mechanism observedwith epigallocatechin gallate, genistein, kaempferol, andquercetin is the inhibition of cholinesterase activity,which improves cognitive functions like learning andmemory (Zhang et al., 2009; Huang and Zhang, 2010;Liu et al., 2010; Tota et al., 2010; Kim et al., 2011). It hasalso been observed that curcumin (Wang et al., 2009),grape extracts and resveratrol (Vislocky and Fernandez,2010; Vingtdeux et al., 2010; Karuppagounder et al.,2009), and epigallocatechin gallate (Avramovich-Tiroshet al., 2007) have the capacity to reduce amyloid-beta (Aβ)deposition and Aβ protein in preclinical animal modelsand in hippocampus neuronal cells and neuroblastomacells.

Thus, there is a growing body of evidence on thepotential of natural polyphenols to combat neuro-degenerative diseases. Nevertheless, application to clini-cal routine has been limited because it is necessary tounderstand systemic metabolism, pharmacokinetics,brain bioavailability, local metabolism, and modificationwithin the central nervous system.

1.3 Nutritional and Health Importance ofSome Fruits and Vegetables

Fruits and vegetables are rich sources of phytochemicals,as well as of other components thatmay act synergisticallywith phytochemicals to contribute to the nutritional andhealth benefits of these food commodities.

1.3.1 Apples and Pears

Apples are a widely consumed, rich source of phytochem-icals, including phenolic compounds, pigments, and vita-min C among others. There are six classes of polyphenolsin apple fruit (Thompson et al., 1972; Lea andTimberlake,1974; Whiting and Coggins, 1975a, 1975b; Lea, 1978;Oleszek et al., 1988; Spanos et al., 1990). The anthocya-nins and flavonol glycosides are mainly found in the skin.The phenolic acids are mainly chlorogenic and p-cou-maroylquinic acid. The dihydrochalcones are phloretinglucoside (phloridzin) and xylo-glucoside. The main cat-echin is (�)-epicatechin, and the procyanidins are the(4β→ 8)-linked epicatechin series with some mixed(+)-catechin/(�)-epicatechin. There is no significantamount of glutathione in apple fruit, and none in applejuice (Jones et al., 1992). Fresh apple fruit may contain upto 100 ppm of vitamin C, but during processing into juicethis is rapidly lost (Lea, 1992). The phytochemical com-position of apples varies greatly between different vari-eties, and changes during maturation, ripening, storage,and processing (Curry, 1997). The accumulations ofantioxidants in apple peels before harvest were foundto be affected more by ripening and light intensity than bylow temperature (Barden and Bramlage, 1994). Totalantioxidant activity in four apple cultivars were in theorder ‘Golden Delicious’> ‘Empire’> ‘Delicious’> ‘Cort-land’ (Ju and Bramlage, 1999). Ascorbate and non-proteinthiols (glutathione) content significantly decreased withincreasing pear (Pyrus communis L. ‘Conference’) matu-rity (Lentheric et al., 1999). Concomitantly, the activity ofsuperoxide dismutase and catalase decreased about five-fold and twofold, respectively, when the fruit was pickedmore mature. Pears were reported to have lower antiox-idant activity compared to pigmented fruits (Priorand Cao, 2000). The antioxidant potentials measured


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by 1,1-diphenyl-2-picrylhydrazyl (DPPH), β-carotenebleaching, and nitric oxide inhibition radical scavengingtests in apple peel and pulp were significantly higher thanin pear peel and pulp (Leontowicz et al., 2003). Theethanol extract of apple peels showed the strongest inhi-bition of lipid peroxidation as a function of its concen-tration, pear pulp had the weakest antioxidant ability,whereas apple pulp and pear peel were equal (Leontowiczet al., 2003). Diets supplemented with peels of both fruitsexercised a significantly higher positive influence onplasma lipid levels and on plasma antioxidant capacityof rats than diets with fruit pulps (Leontowicz et al., 2003).Apple extracts with 70% acetone tested on the basis of

their dry weight showed strong antioxidant activitiestowards oxidation of methyl linoleate, although appleswere reported to be low in total phenolics (Kahkonenet al., 1999). In apple juice, vitamin C activity representeda minor fraction of the total antioxidant activity, withchlorogenic acid and phloretin glycosides as the majoridentifiable antioxidants (Miller and Rice-Evans, 1997).Chlorogenic acid was found to contribute 27% of the totalactivity of apple extract to scavenge hydroxyl radicals(Plumb et al., 1996b). It has been reported (Eberhardtet al., 2000; Lee et al., 2003) that the antioxidant andantiproliferative activities of apples are the consequencesof synergistic activities of phenolics rather than vitamin C.In pear fruit, the contribution of phenolic compounds toantioxidant activity has also been reported to be muchgreater than that of vitamin C (Galvis-Sanchez et al.,2003). Phenolics in apple skin showed a much higherdegree of contribution to the total antioxidant and anti-proliferative activities of whole apple than those in appleflesh (Eberhardt et al., 2000; Wolfe et al., 2003). Some ofthe important antioxidant phenolics found in applesinclude chlorogenic acid, epicatechin, procyanidin B2,phloretin, and quercetin (Burda et al., 1990; Mayr et al.,1995). The relative antioxidant activities of some of thesephenolic compounds in apples were in the order ofquercetin> epicatechin> procyanidin> phloretin> vita-min C> chlorogenic acid (Lee et al., 2003).Epidemiological studies have linked the consumption of

apples with reduced risk of cardiovascular disease,asthma, and diabetes (Liu et al., 2005) and some typesof cancer. A meta-analysis of multicenter case-controlstudies conducted in Italy revealed that consumption of�1 apple/day in comparison with �1 apple/day signifi-cantly reduced the odds ratio for colorectal cancer (OR0.80, 95% CI 0.71–0.90) as well as for cancers of the oralcavity (OR 0.79, 95% CI 0.62–1.00), larynx (OR 0.58, 95%CI 0.44–0.76), breast (OR 0.82, 95% CI 0.73–0.92), andovary (OR 0.85, 95% CI 0.72–1.00) (Gallus et al., 2005). IntheNurses’Health Study, a large prospective cohort studyconducted in the USA reported that the 20% of womenwho consumed almost 2 apples/day had a significantly

reduced risk of developing colorectal adenomas (OR 0.83,95% CI 0.70–0.98) in comparison to the 20% with thelowest intake (OR 1.00, Ptrend 0.05) (Michels et al., 2006).In a South Korean case-control study, fruit consumption(apples combined with banana, pear, and watermelon)lowered the risk for colon cancer in men (adjusted OR0.36, 95% CI 0.16–0.84) but not in women (adjusted OR1.14, 95% CI 0.54–2.40) (Lee et al., 2005).In the laboratory, apples have been found to reduce lipid

oxidation, to lower cholesterol, and to have very strongantioxidant activity (Boyer and Liu, 2004). Apple constit-uents such as procyanidins (PCy) have been shown toinhibit proliferation of HT29 (Veeriah et al., 2006),SW480, and SW620 colon cancer cells (Gossé et al.,2005; Maldonado-Celis et al., 2009) at subcytotoxicconcentrations.One study has addressed the toxicology and safety of a

polyphenol-rich extract from unripe apples (Apple-phenon®), which is sold in Japan as a food additive andnutritional supplement and contains high levels of PCy(64%, dimers to 15-mers), 12% flavan-3-ol monomers, 7%flavonoids, and 18% non-flavonoids (Ohnishi-Kameyama,1997). One gram of extract was reported to containpolyphenols equivalent to approximately four apples(Akazome, 2004). In the Ames mutagenicity test, onlyone out of five bacterial strains showed a slight increase inrevertants indicative of mutagenic potential. No signs ofmutagenicity were detected in the chromosomal aberra-tion test in Chinese hamster lung cell culture and themicronucleus test in Sprague-Dawley rats. Also, no signsof toxicity at a dose of 2000mg/kg body weight wereobserved in an acute and subchronic toxicity test. Theextract was therefore regarded as safe (Shoji et al., 2004).As a first indication of cancer chemopreventive efficacy

in vivo, apple products have been tested in experimentalanimal models for chemically or genetically inducedtumors of colon (Gossé et al., 2005), as well as in xenograftmodels for solid tumors and melanoma (Miura et al.,2008). Apple PCy applied at 1% in drinking water inhib-ited the growth of transplanted B16 mouse melanomacells in vivo, and increased the survival rate of the hostmice transplanted with B16 cells (Miura et al., 2008).

1.3.2 Citrus

Citrus fruit and their juices are rich sources of vitamin C;an 8 fl oz serving was reported to supply the entirereference daily intake (RDT) amount for vitamin C (Rou-seff and Nagy, 1994). There is considerable variation inthe vitamin C content of juices of different citrus fruits.Grapefruit, tangerine, and lemon generally containbetween 20 and 50mg per 100mL juice. However, it isimportant to take into account that vitamin C content in


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oranges, tangerines, and grapefruits decreases with matu-rity. Conversely, thiamin, niacin, B6, and folic acid vita-mins increase with ripening; folic acid is susceptible tooxidation but is protected by vitamin C in fresh fruit.Orange juice contains more niacin, thiamin, riboflavin,and B6 than tangerine and grapefruit; of these vitamins,niacin is the highest at 200–600 μg, followed by thiamin at30–80 μg, B6 at 18–66 μg, and riboflavin at 20–40 μg. In aglass (177mL) of each of orange, tangerine, and grapefruitjuice, the content of folic acid is 34 μg, 21 μg, and 8 μg.With respect to minerals content, citrus fruit is high inpotassium and low in sodium. For example, 178mL ofeach of orange and grapefruit juice contains 300mg and200mg of potassium, whereas sodium content is 3–4mgand 5.5mg respectively in the same volume (Ladaniya,2008).Citrus limonoids (such as limonin and nomilin), one of

the two main classes of compounds responsible for thebitter taste in citrus fruits, have certain biological activitiesthat may be used as chemopreventive agents (Lam et al.,1994). The main flavonoids in oranges and grapefruits arehesperidin and naringin, respectively, and hesperidin isalso found in mandarins, lemons, and limes. The poly-methoxyflavones and the glycosylated flavones – onlyfound in citrus fruits, and their pattern is specific toeach species – have been shown to have a broad spectrumof biological activities such as anti-inflammatory, anti-cancer, and anti-atherogenic properties (Li et al., 2009).Citrus flavonoids have been reported to possess anti-cancer activity both in vitro and in vivo (Middleton andKandaswami, 1994), in addition to antiviral and anti-inflammatory activities, and the ability to inhibit humanplatelet aggregation (Huet, 1982; Benavente-García et al.,1997) and to reduce cholesterol levels and increase HDLin serum (Aptekmann and Cesar, 2013; Cesar et al., 2010).Citrus fruits are particularly rich sources of pectin, whichoccurs both in the edible portion and in the inedibleresidues such as peel, rag, and core (Baker, 1994). Dietaryincorporation of citrus pectins appears to affect severalmetabolic and digestive processes, such as the effect onglucose absorption, and cholesterol levels (Baker, 1994). Ithas been found that pectin of lemons is able to inhibit thebinding of fibroblast growth factor 1 to the receptor in thepresence of 0.1 μg/mL heparin (Liu et al., 2000); thuspectin may be used as an anti-growth factor agent infibroblasts.Orange (Citrus sinensis) was found to be more active

than pink grapefruit (C. paradisi) in scavenging peroxylradicals. while grapefruit juice was more active thanorange juice, when the oxygen radical absorbance capac-ity (ORAC) assay was used (Wang et al., 1996). Grapefruitextracts inhibited ascorbate-iron-induced lipid peroxida-tion of liver microsomes in a dose-dependent way, butwere less effective antioxidants towards an NADH-iron-

induced system (Plumb et al., 1996b). The total antioxidantactivity in orange juice was thought to be accounted for byhesperidin and narirutin (Miller and Rice-Evans, 1997).Seeds of lemons, sour oranges, sweet oranges, mandarins,and limes had greater antioxidant activity than the peels(Bacco et al., 1998). Antioxidant activity is generally higherin the seeds than in the peels (Bocco et al., 1998).

1.3.3 Grapes and Berries

Grapes and berries are rich sources of phytochemicalsincluding phenolic compounds, pigments, and ascorbicacid.Fresh grapes and grape juices are excellent sources of

phenolic antioxidants (Frankel and Meyer, 1998). Grapesand other dietary constituents derived from them, likegrape juice and wine, have attracted a great deal ofattention in recent years, and therefore the compositionand properties of grapes have been extensively investi-gated. Grapes are considered one of the major sources ofphenolic compounds among fruits (Macheix et al., 1990).The phenolic compounds found in Vitis vinifera includephenolic acids, stilbenes, and flavonoids, which includeflavonols, flavanols, and anthocyanins, and play an impor-tant role in the quality of grapes and wines (Downey et al.,2006). Anthocyanins are directly responsible for the colorof grape fruit and young wines; astringency and structureof wines are related to catechins and proanthocyanidins,and flavonols contribute to bitterness (Hufnagel andHoffman, 2008). The diverse classes and large amountsof phenolic compounds found in grapes (Somers andZiemelis, 1985; Macheix et al., 1990; Ricardo-da-Silvaet al., 1990) were reported to play an important role inhuman health, such as lowering of low-density lipoprotein(LDL) (Frankel et al., 1993; Tussedre et al., 1996). It hasbeen demonstrated that products derived from grapeshave high antioxidant capabilities (Alonso et al., 2002). Inaddition, viniferin, a potent antifungal agent, and antho-cyanins, which are strong antioxidants that inhibit plateletaggregation, are also present in grapes (Escarpa andGonzalez, 2001). Extracts of fresh grapes inhibited humanLDL oxidation from 22% to 60% and commercial grapejuice from 68% to 75% when standardized at 10 μM gallicacid equivalents (GAE) (Frankel et al., 1998). The LDLantioxidant activity correlated highly with the concentra-tion of total phenolics for both grape extracts and com-mercial grape juices, with the level of anthocyanins andflavonols for grape extracts, with the levels of anthocya-nins for Concord grape juices, and with the levels ofhydroxycinnamates and flavan-3-ols for the white grapejuice samples (Frankel et al., 1998).Berries contribute significant numbers and amounts of

phytochemicals such as ascorbic acids, carotenoids,


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flavonoids, phenolic acids, and tocopherols. Some wildberries with very high antioxidant activities includecrowberries (Empetrum nigrum), cloudberry (Rubus cha-maemorus), whortleberry (Vaccinium uliginosum), ling-onberry (V. vitis-idaea), aronia (Aronia melanocarpa),cranberry (V. oxycoccos), and rowanberry (Sorbus aucu-paria), but some of the cultivated berries such as straw-berries (Fragaria ananassa), redcurrant (Ribes rubrum),blackcurrant (Ribes nigrum), and raspberry (Rubusidaeus) exerted lower antioxidant activity (Kahkonenet al., 1999). Different blueberries (V. corymbosum) andbilberries (V. myrtillus) were reported to exhibit goodantioxidant activity in the ORAC assay (Prior et al., 1998;Kalt et al., 1999). The antioxidant capacity of blueberrieswas about threefold higher than either strawberries orraspberries, with only a small contribution of ascorbicacid to the total antioxidant capacity compared to totalphenolics and anthocyanins (Kalt et al., 1999). Berry(poly)phenols may exert potential inside the initiatedcell anticancer effects by chelating redox active metals(such as iron) or by directly scavenging intracellular ROS,although this mechanism may be an oversimplification ofthe processes involved. It may be that berry (poly)phenolsinteract with cell receptors or enzymes resulting in alteredcell redox status, which activates redox-dependentreactions (Forman et al., 2002).On the other hand, it is important to consider the effect

of intestinal digestion and bacterial fermentation on theantioxidant properties of berries, because ileostomy feed-ing studies have demonstrated that substantial amountsof (poly)phenolic compounds in berries are not absorbedinto circulation from the small intestine but rather passinto the large intestine, where they come into directcontact with the colonic epithelium and exert beneficialeffects (antioxidant, antigenotoxic, anti-inflammatory,anticarcinogenic) (Johnson, 2004; Del Rio et al., 2010)in healthy populations and in colorectal cancer patientswho consumed whole fruit or juice (blueberry, bilberry,blackberry, blackcurrant, chokeberry) (Wang et al., 2011;Mentor-Marcel et al., 2012; Thomasset et al., 2009; Del Boet al., 2013; Riso et al., 2013).Strawberries are good sources of natural antioxidants

(Heinonen et al., 1998; Wang et al., 1996). The extract ofstrawberries (F. ananassa) had the highest total antiox-idant activity compared with extracts of plums, orange,red grapes, kiwifruit, pink grapefruit, white grapes,banana, apple, tomato, pears, and honeydew melonswhen the ORAC assay was used (Wang et al., 1996),but ranked among the least compared to some otherberries when lipid oxidation model (methyl linoleate,LDL) assays were used (Heinonen et al., 1998; Kahkonenet al., 1999). Strawberry extracts exhibited high enzymaticactivity for oxygen detoxification (Wang et al., 2005) and ahigh level of antioxidant capacity against free radical

species including peroxyl radicals, superoxide radicals,hydrogen peroxide, hydroxyl radicals and singlet oxygen(Wang and Lin, 2000; Wang and Jiao, 2000). The majorpigments of wild strawberries (F. vesca) were pelargoni-din-3-monoglucoside and cyanidin-3-monoglucoside,while in cultivated strawberries the main pigment wasonly pelargonidin-3-monoglucoside (Sondheimer andKarash, 1956). Strawberry extracts exhibited chemopre-ventive and chemotherapeutic activities in vitro andin vivo (Carlton et al., 2001; Meyers et al., 2003; Wanget al., 2005). They also inhibited proliferation of thehuman lung epithelial cancer cell line A549 and reducedtetradecanoylphorbol-13-acetate (TPA) induced neoplas-tic transformation of JB6 P+ mouse epidermal cells(Wang et al., 2005).

1.3.4 Avocados

Avocado fruit is a high-fat fruit, contains rare sugars ofhigh carbon number, and is relatively rich in certainvitamins, dietary fiber, minerals, and nitrogenous sub-stances (Yahia, 2012b). It has a high oil content with awide range (3–30%) and low sugar (about 1%); hence it isrecommended as a high-energy food for diabetics (Yahia,2012b). It is a rich source of potassium, containing 1.6times as much as bananas. A 100 g serving has about 177calories, contains no cholesterol, and has about 17 g of fat,which is primarily of the mono-unsaturated type. Oilcontent is a key part of the sensory quality of the fruit.Oil quality is very similar to that of olive oil, with a highproportion of the oil being approximately 75% mono-unsaturated, 15% saturated, and 10% polyunsaturatedfatty acids. The high mono- and poly-unsaturation andlow saturated content makes it a “healthy” oil in terms ofeffect on heart disease. In addition, avocado oil contains arange of other health-promoting compounds such aschlorophyll, carotenoids, α-tocopherol, and β-sitosterol.The edible portion of the fruit is rich in oleic, palmitic,linoleic, and palmitoleic acids, while stearic acid is presentonly in trace amounts. The fatty acid composition of thelipids of avocado fruit and avocado oil differs greatly withcultivar, stage of ripening, anatomical region of the fruit,and geographic location (Itoh et al., 1975). However, themajor fatty acid is always oleic followed by palmitic andlinoleic acids, while the fatty acids present in traceamounts are myristic, stearic, linolenic, and arachidonic(Itoh et al., 1975; Gutfinger and Letan, 1974; Tangoet al., 1972; Mazliak, 1971; Swisher, 1984). The cuticularwax contains C20 to C27 long-chain fatty acids(Mazliak, 1971). Avocados are rich in vitamin B6

(3.9–6.1 μg/g pyridoxine) and contain lesser amountsof biotin, folic acid, thiamine, and riboflavin (Hall et al.,1955), calciferol (vitamin D), α-tocopherol (vitamin E),


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and 2-methyl-1,4-naphthoquinone (vitamin K) (Yahia,2012b). Therefore, besides being a source of energy andvitamins, avocados also contain several phytochemicalsthat are thought to be beneficial for health, and areconsidered by some as “functional food” (Mazza, 1998).Some nutraceutical ingredients that have been found inavocado pulp are antioxidants such as tocopherols(about 4.3 IU/100 g) and glutathion (18mg/100 g). Ithas also been reported that avocado is a source of lutein(up to 248mg/100 g). Lutein is included in the subclassof carotenoids known as xanthophylls, which are oxy-gen-containing fat-soluble antioxidants with low pro-pensity for pro-oxidant activity (McNulty et al., 2008).In this regard it is important to have in mind that theabsorption of carotenoids depends on the presence ofdietary fat and that the avocado fruit with its fatty acidcontent is naturally designed to enhance the absorptionof carotenoids (Dreher and Davenport, 2013). Amongall fruit and vegetables, avocados are one of the highestin lipophilic total antioxidant capacity (Wu et al., 2004)and may be important for reducing the oxidation of LDL(Hozawa et al., 2007). Avocados are also one of therichest fruit sources of phytosterols (Duester, 2001).The amount of β-sitosterol in this fruit is comparableto that found in soy and olives. Pigments are importantcontributors to the appearance and healthful propertiesof both avocado fruit and avocado oil. Ashton et al.(2006) identified the following in the skin, flesh, and oilof avocado fruit: lutein, β-carotene, neoxanthin, viola-xanthin, zeaxanthin, antheraxanthin, chlorophylls a andb, and pheophytins a and b, with the highest concen-trations of all pigments in the skin. Chlorophyllides aand b were identified in the skin and flesh tissues only.

1.3.5 Stone Fruits

Yellow flesh peaches (Prunus persica L.), such as thecultivar Fay Alberta, contain 54 retinol equivalents (RE)per 100 g of provitamin A carotenoids (USDA, 1982),predominantly as β-carotene and β-cryptoxanthin (Gross,1987). The two dominant polyphenols in sweet cherries(P. avium L.) are caffeoyltartaric acid and 3-p-coumar-oylquinic acid (Robards et al., 1999). However, sweetcherries are characterized to have anthocyanins as themajor phenolic compounds, the aglicon cyanidin boundto the glycosides 3-rutinoside and 3-glucoside being themain compounds, with pelargonidin-3-rutinoside, peo-nidin-3-rutinoside, and peonidin-3-glucoside as minorcontributors (Gao and Mazza, 1995; Chaovanalikit andWrolstad, 2004). Ascorbic acid, total phenolic com-pounds, and total antioxidant activity decreased duringthe early stages of sweet cherries fruit development, butexponentially increased coinciding with the stage of

anthocyanin accumulation and fruit darkening (Serranoet al., 2005). Prunes (P. domestica) and prune juice wereantioxidant toward oxidation of human LDL (Donovanet al., 1998). Prunes ranked highest, with more than twicethe level of antioxidants of other high-scoring fruits,when the ORAC assay was used (Wang et al., 1996).The inhibition of LDL oxidation by raw and cannedpeaches (P. persica) ranged between 56% and 87%, withoxidation activity mainly attributed to the presence ofhydroxycinnamic, chlorogenic, and neochlorogenic acids,but not to carotenoids such as β-carotene and β-cryptox-anthin. However, Plumb et al. (1996b) reported thathydroxycinnamic acids do not contribute to the inhibitionof lipid peroxidation of liver and cell microsomes by fruitextracts including plums and peaches, although thesefruits had the ability to scavenge hydroxyl radicals.

1.3.6 Kiwifruit

Kiwifruit contains high levels of potassium (290mg/100 g), vitamin C (59mg/100 g), and lutein (160 μg/100 g), and has high antioxidant capacity (91mmol/100 g) measured with FRAP. In particular, the kiwifruitis rich in lutein, an oxycarotenoid with high antioxidantcapacity (Calvo, 2005; Wolber et al., 2013). Moreover, thekiwifruit has been shown to exert cardioprotective prop-erties (Duttaroy, 2013) and reduce ACE activity (Dizdar-evic et al., 2014) and intake of kiwifruit has shown to up-regulate genes involved in stress defense and DNA repair(Bøhn et al., 2010). Intakes of kiwifruits have shownpromising effects on BP reduction in smoking men(Karlsen et al., 2012) and in men and women with highnormal BP (Svendsen et al., 2015). In the study by Karlsen(2012) 102 smoking men were randomized to a kiwifruitgroup that received three kiwifruit a day, an antioxidant-rich diet group that received about 50% of their dietaryintake from antioxidant-rich foods, and a control groupthat continued with their habitual diet for 8 weeks.Compared to controls, a reduction of 10mmHg in systolicBP (p= 0.019) and 9mmHg in diastolic BP (p= 0.016) wasseen in the kiwifruit group. In addition, a 15% reduction(p= 0.009) in platelet aggregation and 11% reduction inACE activity (p= 0.034) was shown in the kiwifruit group.In the antioxidant diet group a reduction in BP was seenonly among the hypertensive participants and no effectswere seen with regard to platelet aggregation or ACEactivity (Karlsen et al., 2012). The effect of kiwifruit on BPwas investigated in a similar manner among men andwomen with stage 1 hypertension (Svendsen et al., 2015).In parallel groups, 118 subjects with systolic BP130–159mmHg and/or diastolic BP 85–99mmHg wererandomized to daily intakes of three kiwifruits or oneapple. After 8 weeks, 24 hour ambulatory BP was lower in


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the group assigned to kiwi versus apple intake (between-group difference: �3.6mmHg, 95%CI �6.5, �0.7, P=0.017, and �1.9mmHg, 95%CI �3.6, �0.3, P= 0.040, forsystolic and diastolic BP, respectively). In this study applewas chosen as the comparing fruit because of the differentmicronutrient composition with regard to potassium,vitamin C, lutein, and antioxidant capacity measuredwith FRAP. In these studies, the kiwifruit showed BPlowering effects among subjects that may have higherlevels of stress due to smoking and hypertension. In linewith this, inflammatory status has been shown tomodulatethe response of kiwifruit consumption on plasma lipidsand inflammatory markers (interleukin-6 and high-sensi-tivity C-reactive protein), indicating the beneficial effectsof regular consumption of kiwifruits among men withhigher level of inflammation (Gammon et al., 2013). How-ever, Gammon et al. (2014) did not find any effect ofkiwifruit on BP among normotensives.

1.3.7 Tropical Fruits

Tropical fruits are produced in various tropical countrieslocated in the geographical zone stretching from latitudes30°S to 30°N, where temperature ranges from 16 °C to36 °C. The most common are papaya, guava, coconut,pineapple, mango, watermelon, mangosteen, bananas,passion fruit, and feijoa (Dembitsky et al., 2011). Tropicalfruits are important sources of nutrients (Yahia, 2006) andbioactive compounds, and are considered potential nutra-ceutic foods partly because of the antioxidant activityattributed to the content of polyphenols and/or ascorbicacid (Contreras-Calderon et al., 2011; Zapata et al., 2014;Park et al., 2015). The Colombian tropical fruits that havebeen described as having the highest phenolic content(1011–1018mg GAE/100 g fresh weight (fw)) and ascor-bic acid (AA) (102–257mg AA/100 g fw) are Brazilianguava, guava apple, and cashew; the last presents a highantioxidant activity (FRAP 125 and ABTS 115 μmol Tro-lox equivalents (TE) per gram fw) and vitamin C values(228mg AA/100 g fw). Banana passion fruit (Passifloramollissima) provides an example of high content ofphenolic compounds (1018mg GAE/100 g fw) and anti-oxidant activity (FRAP 114 and ABTS 131 μmol TE/g fw)but did not present the highest value of AA (61.5mg AA/100 g fw) compared to the AAmedium value per 100 g fw(26.7–51.1) present in other tropical fruits (giant grana-dilla, pejibaye, mountain papaya, yellow mombin (Con-treras-Calderon et al., 2011). Zapata et al. (2014) alsodetermined the phenol content and antioxidant capacityby ORAC assay of Colombian tropical fruits includingbanana passion fruit, mango ‘Tommy Atkins’, passionfruit, banana, guava apple, pineapple, papaya, guava, andkiwifruit. They found that phenols and ORAC values

ranged from 30.5 to 10584.7mg GAE/100 g dry weight(dw) and from 685.7 to 207850.4 μmol TE/100 g fw;banana passion fruit had the highest phenolscontent (10584.7mg GAE/100 g dw) and ORAC value(207850.4 μmol TE/100 g fw), supporting previous studies.It has been proposed that consumption of 100 g or 3000 to5000 ORAC/day of these fruits could have a positive effectin plasma antioxidant status (Rojano et al., 2012; Prioret al., 2003).Bananas, plantains, and breadfruit are widely used as a

source of starch; acerola fruit contains the highest knownascorbic acid content among all fruits (1000–3300mg/100 g fw), and some other good sources of vitamin Cinclude guava, lychee, papaya, and passion fruit (Yahia,2006). Mango and papaya are good sources of vitamin A;breadfruit and cherimoya contain relatively high amountsof niacin and thiamin; and most tropical fruit are goodsources of minerals, especially potassium and iron (Yahia,2006). Tropical fruits are thought to contain more carot-enoids compared to temperate fruits, which containmoreanthocyanins. Mango and papaya are among the tropicalfruits rich in carotenoids (Rivera-Pastarna et al., 2009;Ornelas-Paz et al., 2007, 2008a, 2008b).Mango fruit is a rich source of vitamin C and carot-

enoids, some of which function as provitamin A (Sid-dappa and Bhatia, 1954; Thomas, 1975, Yahia et al., 2006).β-carotene (all-trans), β-cryptoxanthin (all-trans and cis),zeaxanthin (all-trans), luteoxanthin isomers, violaxanthin(all-trans and cis), and neoxanthin (all-trans and cis) wereidentified in several mango cultivars (Mercadante et al.,1997; Ornelas-Paz et al., 2007, 2008a, 2008b). Mangoretinol was found to be highly bioavailable by estimatingvitamin A and carotene reserves in the liver and plasma ofrats. Information on the tocopherol content in mango isvery scarce, but it seems to be low (Burns et al., 2003;Ornelas-Paz et al., 2007). The major (poly)phenols interms of antioxidative capacity identified in mango aremangiferin, catechins, quercetin, kaempferol, rhamnetin,anthocyanins, gallic and ellagic acids, propyl and methylgallate, benzoic acid, and protocatechuic acid; gallicacid is the most predominant phenolic acid (Dembitskyet al., 2011).Some chemical components of Carica papaya fruit

pulp have been reported by Oloyede (2005), suggestingthat the astringent action of the plant encountered innumerous therapeutic uses is due to the presence of somephytochemicals like saponins and cardenolides. Liquidchromatography or mass spectrometry analyses of ripeand green papaya showed few candidate phenols, otherthan catechin conjugates (Mahattanatawe et al., 2006),which is consistent with the small number of compoundsreported previously in this fruit (Agrawal and Agrawal,1982). Quercetin and kaempferol, previously reported inleaves and shoots of C. papaya (Canini et al., 2007), were


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found only in trace amounts in fruit peel extracts (Caniniet al., 2007; Miean and Mohamed, 2001). Corral-Aguayoet al. (2008) reported that the antioxidant capacity ofpapaya extract ranked one of the lowest among eightdifferent fruits.Dopamine, a strong water-soluble antioxidant, was

identified in banana fruit (Musa cavendishii) by Kanazawaand Sakakibara (2000). Banana fruit contained high levelsin the pulp and peel, at 2.5–10mg/100 g and 80–560mg/100 g, respectively. A banana water extract was reportedto suppress the autoxidation of linoleic acid by 65–70%after a 5 day incubation in an emulsion system, as deter-mined from peroxide value and thiobarbituric acidreactivity (Kanazawa and Sakakibara, 2000).Pineapple fiber showed higher (86.7%) antioxidant

activity than orange peel fiber (34.6%), and myricetinwas the major polyphenol identified in pineapple fiber(Larrauri et al., 1997). On the other hand, the anti-inflammatory and anticarcinogenic properties attributedto the fruit are based on bromelain content – a mixture ofdifferent thiol endopeptidases and enzymes of type phos-phatase, glucosidase, peroxidase, cellulase, escharase, andseveral protease inhibitors – and 40% of bromelain isabsorbed by the gastrointestinal tract in a functionallyintact form (Pavan et al., 2012). Clinical studies haveshown that bromelain may be used in cardiovasculardiseases by fibrinolytic activity and inhibition of plateletaggregation, and in inflammatory and autoimmune dis-eases such as rheumatoid arthritis by modulating theactivation of TCD4+, macrophages, and natural killercells and secretion of IL-6, IL-1β and TNF-α. Bromelaininduces apoptosis and reduces tumor formation in xeno-graft human cancer cells in mouse (leukemia, sarcoma,skin, lung, and breast cancer cells) (Pavan et al., 2012).Ma et al. (2004) isolated and identified seven phenolic

compounds in Pouteria campechiana, P. sapota, and P.viridis, namely gallic acid, (+)-gallocatechin, (+)-catechin,(�)-epicatechin, dihydromyricetin, (+)-catechin-3-O-gal-late, and myricitrin. The highest level of the seven phe-nolic compounds was found in P. sapota, the secondhighest in P. viridis, and the lowest in P. campechiana.

1.3.8 Nuts

Nuts (almonds, Brazil nuts, cashews, hazelnuts, macad-amia nuts, pecans, pine nuts, pistachios, and walnuts) andlegume seeds (peanuts and baru) are rich sources ofunsaturated fatty acids, L-arginine, minerals (magnesium,zinc, selenium, potassium), phenolic compounds, andphytosterols that are consistently shown to have cardio-protective effects (Ros, 2015; Souza et al., 2015). A dailyserving of 15 g walnuts, 7.5 g almonds, and 7.5 g hazelnutswas associated with a reduced incidence of diabetes and

stroke of about 50%, in addition to 28% reduction in CVD(Ros, 2015). Several nuts are among the dietary plantswith a high content of total antioxidants. Of the tree nuts,walnuts, pecans, and chestnuts have the highest contentsof antioxidants. Walnuts contain more than 20mmolantioxidants per 100 g, mostly in the walnut pellicles.Peanuts also contribute significantly to dietary intake ofantioxidants (Blomhoff et al., 2006). Almonds are richsources of proteins, dietary fats, fibers, and several min-erals (Ren et al., 2001; Turnball et al., 1993). Nine phenoliccompounds have been identified in almonds by Sang et al.(2002), of which eight exhibited strong antioxidant activ-ity. Almond skins were found to contain high levels of fourdifferent types of flavanol glycosides, which are thought tohave powerful effects as antioxidants (Frison and Sporns,2002). Polyphenolic compounds in almonds werereported to be absorbed well in the body, and are activein preventing the oxidation of LDL cholesterol, and vita-min E in almonds acts in synergy with phenolic com-pounds to reduce oxidation (Millburry et al., 2002).Research has suggested a possible effect of almond con-sumption on cancer (Davis and Iwahashi, 2001), includingcolon cancer (Davis et al., 2003).

1.3.9 Tomatoes

Tomato and tomato-based products are consideredhealthy foods because they are low in fat and calories,cholesterol free, and a good source of fiber, vitaminsA andC, β-carotene, lycopene, and potassium (Yahia andBrecht, 2012). Interest in the nutritional and healthbenefits of tomato fruit and their products has increasedgreatly (Geeson et al., 1985; Giovannucci and Clinton,1998; Guester, 1997; Yahia and Brecht, 2012). Vitamin Ccontent in tomato (23mg/100 g) is not as high as in severalother fruits, but its contribution is very important due tothe common use of tomato in the diet of many cultures. A100 g tomato can supply about 20% and 40% of the adultUS recommended daily intake of vitamins A and C,respectively. The selection of tomato genotypes that arerich in vitamins A and C has been accomplished, andcultivars with very high vitamin A content have beendeveloped, but their orange color was not well accepted byconsumers. Epidemiological studies have indicated thattomato fruit has one of the highest inverse correlationswith cancer risk and cardiovascular disease, includingstroke (Giovannucci et al., 1995). Lycopene, the principalpigment responsible for the characteristic deep red colorof ripe tomato fruit and tomato products, is a naturalantioxidant that can prevent cancer and heart disease (Shiand Le Maguer, 2000). Although lycopene has no pro-vitamin A activity, as is the case with some other carot-enoids, it does exhibit a physical quenching rate constant


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with singlet oxygen almost twice as high as that ofβ-carotene.Increasing clinical evidence supports the role of lyco-

pene as a micronutrient with important health benefits,due to its role in protection against a broad range ofepithelial cancers (Shi and Le Maguer, 2000). The serumlevel of lycopene and the dietary intake of tomatoes havebeen inversely correlated with the incidence of cancer(Helzlsouer et al., 1989; Van Eenwyk et al., 1991).Fresh tomato fruit contains about 0.72 to 20mg of

lycopene per 100 g of fresh weight, which accounts forabout 30% of the total carotenoids in plasma (Stahl andSies, 1996). Yellow tomato species are less rich inlycopene, with a content of only about 0.5mg/100 g(Holzapfel et al., 2013). In contrast to other pigmentssuch as β-carotene, lutein, violaxanthin, auroxanthin,neoxanthin, and chlorophylls a and b, which accumulatein inner pulp and in the outer region of the pericarp,lycopene appears only at the end of thematuration period,and almost exclusively in the external part of the fruit(Laval-Martin et al., 1975). Other tomato componentsthat can contribute to health include flavonoids, folic acid,and vitamin E (Dorais et al., 2001a, 2001b).Absorption of lycopene is in the cis conformation; this

occurs through dietary lipid micelles passing into themucosa of the small intestine, then being transported bychylomicrons to the liver in the lymph system, fromwhere they are distributed to their target organs (testes,prostate, and adrenal glands). By contrary, all-transisomers have a greater disposition to aggregate in theintestine, building crystals, which may reduce theiruptake through micelles (Parker, 1996; Boileau et al.,2002).Tomato was reported to exert antioxidant activity in

some studies (Vinson et al., 1998; Kahkonen et al.,1999), but to show no antioxidant activity or even toact as pro-oxidant in others (Gazzani et al., 1998). Inserum samples from individuals fed with tomato prod-ucts or tomato extracts, there was observed a delaychemically induced in LDL oxidation. This effect wasnot observed with lycopene supplementation alone(30mg/day). However, lymphocyte DNA damage wasreduced (Devaraj et al., 2008; Neyestani et al., 2007;Zhao et al., 2006) Thus, the antioxidant effect of tomatois most probably due to synergism between severalcompounds and not due to lycopene content alone,as pure lycopene and several other carotenoids act aspro-oxidants in a lipid environment (Al-Saikhan et al.,1995; Haila et al., 1996). On the other hand, lycopenehas biological effects independent of antioxidant activ-ity such as apoptosis, arrest of cycle, inhibition ofandrogen and estrogen activity, induction of hepaticphase II enzymes, and decrease in C reactive protein andserum cholesterol levels (Erdman et al., 2009).

1.3.10 Cruciferous Vegetables

Sulfur-containing phytochemicals of two different kindsare present in allBrassica oleracea (Cruciferae) vegetables(cabbage, broccoli, cauliflower, Brussels sprouts, kale).They are glucosinolates (previously called thioglucosides)and S-methyl cysteine sulfoxide. These compounds,which are derived in plant tissue by amino acid bio-synthesis, show quite different toxicological effects andappear to possess anticarcinogenic properties (Stoew-sand, 1995). Glucosinolates have been extensively studiedsince the mid nineteenth century. They are present inplant foods other than Brassica vegetables, with especiallyhigh levels in a number of seed meals fed to livestock.About 100 different kinds of glucosinolates are known toexist in the plant kingdom, but only about 10 are present inBrassica. The first toxic effects of isothiocyanates andother hydrolytic products from glucosinolates that wereidentified were goiter and a general inhibition of iodineuptake by the thyroid. Numerous studies have indicatedthat thehydrolytic products of at least three glucosinolates,4-methyl-sulfinylbutyl (glucoraphanin), 2-phenylethyl(gluconasturtiin), and 3-indolylmethyl (glucobrassicin),have anticarcinogenic activity. Indole-3-carbinol, ametab-olite of glucobrassicin, has shown inhibitory effects instudies of human breast and ovarian cancers. S-Methylcysteine sulfoxide and its metabolite methyl methanethiosulfinate have been shown to inhibit chemicallyinduced genotoxicity in mice. Thus, the cancer chemo-preventive effects of Brassica vegetables that have beenshown in human and animal studies may be due to thepresence of both types of sulfur-containing phytochem-icals (i.e. certain glucosinolates and S-methyl cysteinesulfoxide).The effect of consumption of Brussels sprouts on levels

of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG) inhuman urine was investigated in 10 healthy, male, non-smoking volunteers by Verhagen et al. (1995). Following a3 week run-in period, five volunteers continued on a dietfree of cruciferous vegetables for a subsequent 3 weekintervention period (control group), while the other five(sprouts group) consumed 300 g of cooked Brusselssprouts per day, at the expense of 300 g of a glucosino-late-free vegetable. In the control group there was nodifference between the two periods in levels of 8-oxodG(P= 0.72), but in the sprouts group the levels of 8-oxodGwere decreased by 28% during the intervention period(P= 0.039); these results support the results of epidemio-logic studies that consumption of cruciferous vegetablesmay result in a decreased cancer risk.Extracts from broccoli (B. oleracea L. ‘Italica’), Brussels

sprouts (B. oleracea L. ‘Rubra’), white cabbage (B. oleraceaL. ‘Alba’) and cauliflower (B. oleracea L. ‘Botrytis’) showedsignificant antioxidant properties against lipid


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peroxidation (Plumb et al., 1996a). However, it is thoughtthat most of the direct antioxidant action of the crucifervegetables is not due to the glucosinolate content, butprobably involves the hydroxylated phenols and poly-phenol content, as has been identified in broccoli (Plumbet al., 1997b). Cabbage, cauliflower, and Brussels sproutswere reported to be pro-oxidants toward lipid peroxida-tion inmicrosomes containing specific cytochrome P450s(Plumb et al., 1997a). Kale (B. oleracea L. ‘Acephala’),Brussels sprouts, and broccoli were found to exert higherantioxidant activity than cauliflower and some othervegetables (Al-Saikhan et al., 1995; Cao et al., 1996;Ramarathnam et al., 1997; Vinson et al., 1998).

1.3.11 Leafy Vegetables

Some contradictory results have been reported regardingthe antioxidant activities of leafy vegetables. For example,among 23 vegetables, spinach (Spinacia oleracea L.)ranked 18th and head lettuce (Lactuca sativa L. ‘Capita’)22nd when assayed for inhibition of LDL (Vinson et al.,1998). However, theORACantioxidant activity of spinachwas reported to be very high, while that of leaf lettuce andiceberg lettuce was poor (Cao et al., 1996).

1.3.12 Root and Tuberous Vegetables

Carrots (Daucus carota) are excellent sources of β-caro-tene and vitamin A, although they have been reported toexert low antioxidant activity compared to some othervegetables (Al-Saikhan et al., 1995; Cao et al., 1996;Ramarathnam et al., 1997; Vinson et al., 1998; Beomet al., 1998). However, boiling carrots for 30 minutessignificantly improved their antioxidant activity towardscoupled oxidation of β-carotene and linolenic acid (Gaz-zani et al., 1998).In addition to being an excellent source for some

carbohydrates, potatoes (Solanum tuberosum) are con-sidered a source for some antioxidants such as ascorbicacid, α-tocopherol, and polyphenolic compounds (Al-Saikhan et al., 1995; Velioglu et al., 1998). Potato peelshave been reported to show high antioxidant activity(Rodriguez de Siotillo et al., 1994). Purple potatoes andpeel have been shown to exhibit greater antioxidantactivities than the white and yellow varieties (Veliogluet al., 1998), which is due to the presence of anthocyaninssuch as pelargonidin-3-rutinoside-5-glucoside (Rodri-guez-Saona et al., 1998). Potato is not considered to bea rich source of carotenoids, but some have been identi-fied. Pendlington et al. (1965) tentatively identified eightcarotenoids (e.g. β,β-carotene, lutein) asmost abundant inmost cultivars, although Muller (1997) reported that

violaxanthin is the main potato carotenoid, followed bylutein, antheraxanthin, and others. Iwanzik et al. (1983)compared the carotenoid content between 13 potatocultivars in the same habitat, and reported violaxanthinas the main carotenoid, followed by lutein, lutein-5,6-epoxide, and neoxanthin. Breithaupt and Bamedi (2002)investigated the pattern of four yellow-fleshed and fourwhite-fleshed potato cultivars, and reported that it isdominated by violaxanthin, antheraxanthin, lutein, andzeaxanthin, whereas neoxanthin, β-cryptoxanthin, andβ,β-carotene generally are only minor constituents. Thecolor of orange-fleshed potato was suggested to originatefrom large amounts of zeaxanthin (Brown et al., 1993).In addition to having some important phytochemicals

such betalains, beetroot (Beta vulgaris L.) and sugar beet(B. vulgaris subsp. esculenta) peels showed remarkablyhigh antioxidant activities (Kahkonen et al., 1999). Forexample, beet ranked eighth among 23 vegetables assayedfor inhibition of LDL oxidation (Vinson et al., 1998).

1.3.13 Peppers

Fresh peppers are excellent sources of vitamins A and C,as well as neutral and acidic phenolic compounds(Howard et al., 2000). Levels of these can vary by genotypeand maturity, and are influenced by growing conditionsand processing (Mejia et al., 1988; Howard et al., 1994; Leeet al., 1995; Daood et al., 1996; Simmone et al., 1997;Osuna-García et al., 1998; Markus et al., 1999; Howardet al., 2000). Peppers have been reported to be rich in theprovitamin A carotenoids β-carotene, α-carotene andβ-cryptoxanthin (Minguez-Mosquera andHomero-Men-dez, 1994; Markus et al., 1999), as well as xanthophylls(Davies et al., 1970;Markus et al., 1999). Bell peppers havebeen shown to exert low antioxidant activity (Al-Saikhanet al., 1995; Cao et al., 1996; Vinson et al., 1998), or mayeven act as pro-oxidants (Gazzani et al., 1998).

1.3.14 Alliums

Edible alliums, especially onions and garlic, have been animportant part of the daily diet of several cultures forhundreds of years. In many cultures alliums were thoughtto have medicinal properties. Allium vegetables, such asonions, garlic, scallions, chives, and leeks, include highconcentrations of compounds such as diallyl sulfide andallyl methyl trisulfide (Steinmetz and Potter, 1996). Thesecompounds have been shown to inhibit cell proliferationand growth, enhance the immune system, alter carcino-gen activation, stimulate detoxification enzymes, andreduce carcinogen–DNA binding (Hatono et al., 1996;Lin et al., 1994; Lee et al., 1994; Amagase and Miller,


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1993). Hageman et al. (1997) studied the effects of sup-plemental garlic consumption on ex vivo production ofbenzo[a]pyrene–DNA adducts in lymphocytes in a non-randomized pilot study of nine men, and observed thatisolated lymphocytes from the blood of participants eat-ing garlic (3 g raw garlic per day for 8 days) developedfewer adducts when incubated with benzo[]pyrene.Selenium has been shown to possess antitumor

activity in humans. Efforts to produce Se-enrichedvegetables (including garlic and broccoli) with anti-carcinogenic activity have been successful. A numberof studies (Ip et al., 1992; Ip and Lisk, 1994) have shownthat selenium-enriched garlic is an effective anti-carcinogen. Whanger et al. (2000) have suggestedthat Se-enriched ramps (A. tricoccum, a wild leek spe-cies) appear to have potential for reduction of cancer inhumans. There was approximately 43% reduction inchemically induced mammary tumors when rats werefed a diet with Se-enriched ramps. Bioavailability stud-ies with rats indicated that Se in ramps was 15–28%more available for regeneration of glutathione peroxi-dase activity than inorganic Se as selenite.Yellow and red onions (A. cepa) were reported to be

poor antioxidants towards oxidation of methyl linoleate(Kahkonen et al., 1999) in contrast to their high antiox-idant activity towards oxidation of LDL (Vinson et al.,1998). Garlic (A. sativum L.) was reported to have fourtimes more antioxidant activity than onions when usingthe ORAC assay (Cao et al., 1996).

1.3.15 Prickly Pear Fruit and Cladodes

Prickly pear fruit and cladodes are valued because of theirhigh nutrient content, vitamins, and other health compo-nents (Yahia, 2012a; Hegwood, 1990).Cladodes (called nopal in Mexico) are low in calories

and high in fiber, and are traditionally consumed as avegetable in Mexico and the southern region of the USA.Nopal contains about 920 g/kg water, 40–60 g/kg fiber,10–20 g/kg proteins, and about 10 g/kg minerals, primar-ily calcium. Vitamin C content is about 100–150mg/kgand β-carotenes (provitamin A) are about 300 μg/kg.Cladodes are used in various pharmaceutical applicationsfor their therapeutic, dermatological, and medical prop-erties. Ethanol extract of Opuntia ficus-indica showspotential analgesic and anti-inflammatory effects (Parket al., 1998). Galati et al. (2001) reported preventive andcurative effects of O. ficus-indica cladodes preparationson rats affected by ethanol-induced ulcers. The cactusconsumption gives rise to cytoprotection phenomena bybreaking up the epithelial cells and stimulating anincrease in mucus production. When O. ficus-indicacladodes are administered as a preventive therapy, they

keep the gastric mucosa in the normal condition bypreventing mucus dissolution caused by ethanol andfavoring mucus production. An increase of mucus pro-duction is also observed during the course of the curativetreatment. The treatment with O. ficus-indica cladodesprovokes an increase in the number of secretory cells.Probably, the gastric fibroblasts are involved in the anti-ulcer activity.The consumption of prickly pear cactus fruit is recom-

mended for their beneficial and therapeutic properties(Yahia, 2012a). Aqueous extracts of cactus pear fruit(O. ficus-indica L. Mill.) were reported by Butera et al.(2002) to possess a high total antioxidant capacity,expressed as Trolox equivalents, and to exhibit a markedantioxidant capacity in several in vitro assays, includingthe oxidation of red blood cell membrane lipids and theoxidation of human LDLs induced by copper and 2,2´-azobis(2-amidinopropane-hydrochloride). Antioxidantcomponents reported by these authors includedvitamin C, negligible amounts of carotenoids, and vitaminE. However, Corral-Aguayo et al. (2008) reported that theantioxidant capacity of extracts of prickly pear fruitranked the lowest compared to seven other fruits.Some prickly pear fruit contain two betalain pigments,the purple-red betanin and the yellow indicaxanthin, bothwith radical-scavenging and reducing properties (Forniet al., 1992; Fernandez-Lopez and Almela, 2001; Stintzinget al., 2002; Castellanos-Santiago and Yahia, 2008). Qual-itative and quantitative analysis of betalains pigments in10 cultivars and lines of prickly pear (Opuntia spp.) fruitwere conducted with reverse phase high-performanceliquid chromatography with diode array detection(HPLC-DAD) coupled with electrospray mass spectrom-etry (ESI-MS) (Castellanos-Santiago and Yahia, 2008).Betacyanins and betaxanthins were identified by compar-ison with UV/Vis and mass spectrometric characteristicsas well as the retention times of semi-synthesized refer-ence betaxanthins. Carotenoids and chlorophylls werealso identified and quantified based on their molecularmass determined by applying HPLC-DAD coupled withpositive atmospheric pressure chemical ionization massspectrometry (APCI-MS). A total of 24 known andunknown betalains were present in the studied pricklypear fruit, including 18 betaxanthins and 6 betacyanins.The ratio and concentration of betalain pigments areresponsible for the color in the different cultivars; thehighest betalains content is shown in fruit of purple color,comparable to that found in red beet (Beta vulgaris L.‘Pablo’). All cultivars/lines had a similar carotenoid profile;lutein was the most abundant compound in ‘Camuesa’,while neoxanthinwas themost abundant compound in theline ‘21441’. Chlorophyll a was the most abundant in allcultivars/lines, with the highest quantity in ‘21441’. Dailysupplementation with 500 g cactus fruit (O. ficus-indica)


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pulp for 2 weeks greatly improved the oxidation stressstatus of healthy humans (Tesoriere et al., 2004). Theeffects included remarkable reduction in plasma markersof oxidative damage to lipids, such as isoprostanes andmalondialdehyde (MDA), an improvement in theoxidativestatus of LDL, considerably higher concentrations ofmajorplasma antioxidants, and improvement in the redox statusof erythrocytes. The fruit also enhances renal function(Cacioppo, 1991).Reports indicate that other parts of prickly pear cactus

are also used in folk medicine as emollient, moisturizing,cicatrizant, hypocholesterolemic, and hypoglycemic age-nts, and in gastric mucosa diseases (Hegwood, 1990; Fratiet al., 1990a, 1990b; Cruse, 1973; Meyer and McLaughlin,1981; Harvala et al., 1982; Camacho-Ibanez et al., 1983;Brutsch, 1990; Fernandez et al., 1992, 1994; Yahia, 2012a).In Sicilian folk medicine, a flower infusion has an effectgenerally defined as depurative, and in particular it is usedbecause of its diuretic and relaxant action on the renalexcretory tract (Arcoleo et al., 1961, 1966; Sisini, 1969).Therefore, it is stipulated that a flower infusion may helpthe expulsion of renal calculus. Galati et al. (2002)reported that flower infusion shows a modest increasein diuresis and natriuresis. Treatment with cladode infu-sions increases diuresis but does not significantly influ-ence the uric acid pattern. The fruit infusion instead haddiuretic and antiuric activity. The diuretic action observedmay depend on stimulation of the urinary tract and islinked to the activation of the neurohumoral mechanism,mediators of stimuli acting on glomerulus, and tone acidon the pyeloureteral peristalsis. These effects might bedue to the influence that the electrolytes, present inconsiderable quantities in the plant, exert on the renalepithelium. In particular,O. ficus-indica is rich in K+ ions,which are present at concentrations of 548mg/kg in thecladodes, 21.7mg/kg in the flowers, and 18mg/kg in thefruit (D’Aquino, 1998).

1.3.16 Mushrooms

Some types of mushrooms contain moderate quantitiesof good quality protein and are good sources of dietaryfiber, vitamins C and B, and minerals (Breene, 1990).Extensive clinical studies have demonstrated that somespecies have medicinal and therapeutic value, by injec-tion or oral administration, in the prevention andtreatment of cancer, viral diseases (influenza, polio),hypercholesterolemia, blood platelet aggregation, andhypertension (Breene, 1990). It has been reported thatthe inclusion of cultivated mushrooms, particularlyshiitake and enokitake, in the diet is likely to providesome protection against some manifestation of cancer(Mori et al., 1987).

1.3.17 Pickled Vegetables

Roussin’s red (dimethylthiotetranitrosodiiron) has beenidentified as a non-alkylating N-nitroso compound pres-ent in pickled vegetables from Linxian County, a high-riskarea for esophageal cancer in China (Cheng et al., 1981).In vitro experiments showed that Roussin’s red had nosignificant mutagenic and transforming activities atthe doses used, but it did enhance transformation inC3H/10TI/2 cells initiated with 3-methylcholanthrene(0.1 μg/mL), and it reduced the number of sebaceousglands and increased the epidermal thickness in short-term skin tests. This indicated that Roussin’s redresembled 12-O-tetradecanoyl-phorbol-13-acetate andmay be a new naturally occurring tumor promoter.Examination of dietary data in relation to incidence ratesspecific to place of birth showed positive associations ofstomach cancer with consumption of rice, pickled vege-tables, and dried/salted fish, and a negative associationwith vitamin C intake (Kolonel et al., 1981); the results areconsistent with the particular hypothesis that stomachcancer is caused by endogenous nitrosamine formationfrom dietary precursors, and that vitamin C may protectagainst the disease. Extracts of pickled vegetables com-monly consumed in Linhsien County, a high-incidencearea for esophageal cancer in northern China, werestudied for mutagenicity (Lu et al., 1981). The liquidresidue from ethereal extracts produced a dose-depen-dent increase of mutants in Salmonella typhimuriumTA98 and TA100 strains; mutagenicity required thepresence of a fortified liver microsomal activationsystem induced by Aroclor 1254 in adult male BD VIinbred rats. An amount of extract equivalent to 2.8 gfresh pickled vegetables produced sixfold (75 rever-tants/g) and twofold (45 revertants/g) increases inrevertant frequencies in strains TA98 and TA100,respectively. Roussin’s red methyl ester, a tetranitrosocompound [(NO)2Fe(CH3S)]2, was isolated and identi-fied from the ethereal extracts, and shown to be muta-genic in strain TA100 in the presence of a liveractivation system, producing 25 revertants/mmol. Atype of Japanese mixed vegetable pickle was found to bemutagenic to S. typhimurium strains TA100 and TA98with S9 mix (Takahashi et al., 1979). Its activity was one-sixth that of a similar Chinese pickle from LinhsienCounty, China. Mutagens in the Japanese pickle wereisolated, purified, and identified; the main componentwas kaempferol and a minor component was isorhamne-tin. As flavonoids are ubiquitous in vegetables, kaempferoland isorhamnetin do not seem to be specific to the pickle.Whole pickles of each kind of vegetable used in theJapanese pickle were extracted with methanol and sub-jected to mutagenicity tests; extracts of all vegetablesexcept carrots were slightly mutagenic, with green leaves


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of vegetables and yellow chrysanthemum flowers showingthe highest specific activity.

1.4 Enhancement of Phytochemicals inFruits and Vegetables

In addition to increasing the consumption of fruits andvegetables, the enhancement of the nutritional and healthquality of fruits and vegetables is an important goal in theeffort to improve global health and nutrition. Erbersdobler(2003) and Boeing et al. (2004) advocated the intake offunctional foods that are enriched with phytochemicals.A number of crop production techniques have been

reported to enhance phytochemical content in severalfruits and vegetables (Schreiner, 2005). Various postharv-est practices and techniques can also affect the content ofphytochemicals (Beuscher et al., 1999; Goldmann et al.,1999; Huyskens-Keil and Schreiner, 2004).Genetic engineering can make a substantial contribu-

tion to improved nutrition in crops. The most famousexample of using biotechnology to improve nutrition isthe development of vitamin A enriched “golden” rice (Yeet al., 2000). Biotechnology has also been applied toimprovements in the nutritional quality of a range of fruitand vegetables (Dalal et al., 2006), targeting proteinquality and quantity, desirable fatty acids, vitamins, min-erals, and antioxidants. Many vegetables and fruits con-tain significant amounts of protein, but are deficient inparticular amino acids, such as potato which is deficient inlysine, tyrosine, methionine, and cysteine, and thereforethe introduction of a transgene encoding a seed albuminprotein into potato resulted in tubers with sufficientquantities of all essential amino acids (Chakrabortyet al., 2000). Cassava has also been improved by introduc-ing an artificial protein encoding a maximal content of allessential amino acids (Sautter et al., 2006). Conventionalbreeding has resulted in similar successes, such as maizewith higher-quality protein that is enriched for lysine andtryptophan (Hoisington, 2002). Polyunsaturated fattyacids have been implicated as being beneficial to humanhealth. Enhancement of the γ-linoleic acid content oftomato was achieved through introduction of a geneencoding a Δ6 desaturase enzyme (Cook et al., 2002).Plants, including fruits and vegetables, naturally contain alarge array of antioxidants, including carotenoids, vita-mins C and E, and flavonoids, and efforts to increase theantioxidant content of fruits and vegetables have takenboth breeding-based and transgenic approaches. Naturalhigh-pigment mutants are available in tomato that can beused in breeding strategies (Long et al., 2006) and wildaccessions of tomato exhibit substantial metabolic diver-sity that may similarly be exploited (Fernie et al., 2006). Aseries of introgression lines has been generated in

cultivated tomato containing genomic segments of awild tomato relative, and the population exhibited a broadrange of phenotypes, including characteristics that havepotentially important attributes related to health andnutrition. Analysis of these lines identified more than800 quantitative trait loci (QTL) underlying levels ofvarious metabolites including ascorbate and γ-tocopherol(Schauer et al., 2006). Using structural flavonoid genes(encoding stilbene synthase, chalcone synthase, chalconereductase, chalcone isomerase, and flavone synthase) fromdifferent plant sources, Schijlen et al. (2006) were able toproduce transgenic tomatoes accumulating new phyto-chemicals. Biochemical analysis showed that the fruit peelcontained high levels of stilbenes (resveratrol and piceid),deoxychalcones (butein and isoliquiritigenin), flavones(luteolin-7-glucoside and luteolin aglycon) and flavonols(quercetin glycosides and kaempferol glycosides). Theyhave demonstrated that, due to the presence of the novelflavonoids, the transgenic tomato fruits displayed alteredantioxidant profiles. In addition, total antioxidant capacityof tomato fruit peel with high levels of flavones andflavonols increased more than threefold. These resultson genetic engineering of flavonoids in tomato fruit dem-onstrate the possibilities for changing the levels and com-position of health-related polyphenols in a crop plant(Fraser et al., 2007). Introduction of transgenes has beenshown to increase antioxidant content (Bovy et al., 2002;Fraser et al., 2002). QTL for lycopene content and β-caro-tene content have been identified in carrot (Santos andSimon, 2002) and varietal differences in antioxidant con-tent of onion suggest the presence of genetic diversity thatcould be exploited by selective breeding (Yang et al., 2004).Diaz de la Garza et al. (2004) used genetic engineering togenerate a 10-fold increase in the folic acid content of ripetomatoes. Substantial improvements can be made usingmarker-assisted and traditional breeding. The use of anon-transgenic approach such as targeted induced locallesions in genomes (TILLING) can allow for relatively easyidentification of novel alleles in either mutagenized ornatural populations. This technology was initially usedin reverse genetic studies by plant biologists and it isnow being applied to crop improvement (Slade andKnauf,2005). Naturally occurring germplasm can provide a richsource of genetic variation, and it is likely that newstrategies for improving the nutritional value of fruitsand vegetables will result from screening for variation innutritional and health composition in wild crops and thebroadest possible spectrum of existing cultivars.

1.5 Conclusions

Accumulating evidence demonstrates that fruit and veg-etable consumption has health-promoting properties.


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Fruits and vegetables are rich sources of diverse phyto-chemicals. The majority of evidence linking fruit andvegetable intake to health continues to be observational,and data in some areas are still contradictory. Therefore,although it is evident that fruit and vegetable consump-tion is important for health, there is still a need for further

controlled clinical intervention trials in order to investi-gate and to confirm the effect of the consumption offruits and vegetables on different diseases, as well as forstudies to reveal the mechanisms behind the effects ofthe different phytochemical components of fruits andvegetables.

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Part I Chemistry and Biological Functions