Dietary Phytochemicals and Human Health

Nutraceuticals are food product that provides health as well as medical benefits; including the prevention and treatment of disease. Few nutraceuticals are being used as pharmaceutical and a number of other being used and purchased by the general public as self-medication. Such products may range from dietary supplements to genetically engineered foods, herbal products and processed foods. Phytochemicals of nutraceuticals importance are bioactive constituentsthat sustain or promote health and occurs at the intersection of food andpharmaceutical industries. Such substances may range from isolatednutrients, dietary supplements and specific diets to geneticallyengineered designer foods, herbal products, processed foods andbeverages. Phytochemicals are broadly described as polyphenols,flavonoids, isoflavonoids, anthocyanidins, terpenoids etc,. Theyhave tremendous impact on the health care system and mayprovidemedical health benefits including the prevention and/ or treatment ofdiseases and physiological disorders. Majority of foods, such as wholegrains, beans, fruits, vegetables and herbs contain phytochemicals.Amongst these, fruits and vegetables contribute to the significantsources of phytochemicals. These phytochemicals, either alone and/orin combination, have tremendous therapeutic potential in curing variousailments. The respective health benefits are based on science andethics, for health claims, for functional foods, and presence of certainphytochemicals. They play certain pharmacological effects in humanhealth as

Many plants are traditional sources for food and pharma products. Since the difference of a therapeutic and a toxic effect depends on the dose, there are fluent transitions between consumption, therapy and toxicity of nutraceuticals in food, medicines, or plants. The following review provides a classification of phytochemicals into categories according to their biosynthesis from carbohydrates, lipids and amino acids as well as an overview of epidemiologically important toxic phytochemicals affecting human health including examples from the terpenoids, phenolic compounds, and alkaloids families. Despite evidence indicating that phytochemicals can reduce the risk of chronic non-communicable diseases, research is still needed using new and precise methodologies to unravel the multitude of beneficial roles played by phytochemicals in human health.

Earth is dominated by plants. It is estimated that there are about 250,000 500,000 species of plants on the earth, and nearly 10% of these are used as food and medicine by humans and other living things. Different compounds extracted from these plants possess various properties that which have significant effects on the health and nutrition of humans [1]. These compounds are known as phytochemicals, “phyto” means “plant” in Greek, which are nonnutritive, naturally occurring biochemicals.

Dietary Phytochemicals and Human Health Justyna Krzyzanowska,* Anna Czubacka and Wieslaw Oleszek Abstract T his chapter is a comprehensive review of the health promoting phytochemicals commonly found in our daily food. hese include carotenoids, phenolics, phytoestrogenes, polyun‑ saturated fatty acids, conjugated linoleic acids, tocols, allicin, glucosinolates, limonene and capsaicinoids. he review encompasses the main food sources of these chemicals in the diet, the possible mechanisms of their activity, evidence for potential health promoting activity and possible harmful efects. he newly emerged interest in these phytochemicals in animal nutrition as substitutes for synthetic antibiotic growth promoters has also been addressed. Introduction Living plants produce a great number of chemicals that are crucial for their function and devel‑ opment. Some of these chemicals are primary metabolites, which include proteins (aminoacids), carbohydrates, fats, nucleic acids etc. However, besides these primary chemicals, the plants also produce so‑called secondary metabolites, which are speciic to some taxonomic groups (families, genera). heir physiological function was questioned already in earlier work, but recent research has shown that they are important constituents of plants. hey are formed under environmental pressure and play a crucial function in protecting plants against some environmental stresses. his group includes classes of compounds such as phenolics, carotenoids, alkaloids, saponins, glucosinolates, cyanogenic glycosides, terpenes etc. Each of these groups contains compounds with diferent biological activities, which in traditional medicine and ethno‑pharmacology was used for centuries to cure or to protect from diseases. A correlation between diet and health has been known since Hippocrates (460‑377 BC), who recognised that “diferences of diseases depends on the nutriment”.1 During the centuries, numerous epidemiological studies have been performed, conirming Hippocrates statement, especially regarding the frequency of some diseases in relation to the intake of particular nutrients. One example might be the study of amine‑based substances discovered by Funk in rice bran and which for their importance were called “Vitamin” (Vita = life).2 Some epidemiological studies, in fact, clearly correlate the frequency of some diseases with diet, espe‑ cially those with a low consumption of fruit, vegetables and whole grain, which are rich sources of particular classes of phytochemicals. Many natural products are thought to have health promoting activities. he most promising and extensively studied compounds over recent years are listed in Table 1. his chapter provides an overview of data available on health beneits of some classes of listed phytochemicals. *Corresponding Author: Justyna Krzyzanowska—Institute of Soil Science and Plant Cultivation, Pulawy, Poland. Email: jkrzyzanowska@iung.pulawy.pl Bio‑Farms for Nutraceuticals: Functional Food and Safety Control by Biosensors edited by Maria Teresa Giardi, Giuseppina Rea and Bruno Berra. ©2010 Landes Bioscience and Springer Science+Business Media. ©2010 Copyright Landes Bioscience. Not for Distribution. Chapter 7 Active Compounds Food Source Potential Health Beneit Possible Mechanism and Function Carotenoids (‑carotene, lycopene, Tomatoes, carrots, yams, lutein) cantaloupe, spinach, sweet potatoes, citrus fruits Reduce coronary heart disease and cancer Antioxidants, singlet oxygen and free radical scav‑ engers, inhibit proliferation of acute myeloblastic leukemia Catechins (epigallo‑ and epigallocatechin gallate) Green tea, grapes/wine Reduce cancer and heart disease Inhibits initiation, promotion and progression of cancer, antioxidant, reduces free radical/oxidative damage Phytoestrogens: Isolavones (daidzein, genistein), Coumestans, Lignans (enterodiol, enterolactone) Soybeans, soybeanfood Pea (dried) Rapeseed, garlic, wheat bran, lentils, brown rice Inhibit the growth of human breast cancer cell Prevent menopausal symptoms, prevents osteoporosis, reduce cancer lines, decrease cholesterol, LDL cholesterol and triglicerides, stimulate calcium absorption and (breast, prostate) bone deposition Favones, lavonols and lavanols (quercetin, kaempferol, rutin, myricetin, anthocyanidin), procyanidins Apples, onion, tea, grapefruit and orange juice, broccoli, kale Reduce coronary heart disease and cancer Scavengers of reactive oxygen and nitrogen species, antioxidants, transition metal chelation Stilbenes (resveratrol) Red wine, yucca bark Reduce coronary heart disease and cancer, stimulate apoptosis, prevent blood clustering Antioxidants and free radical scavengers Tocopherols, tocotrienols Vegetable oils Antioxidant, lowers serum cholesterol, inhibits cancer, decreases heart diseases Inhibits cancer cell poliferation, inhibits HMG‑CoA reductase PUFA (omega‑3 fatty acids) Fish oil, algae, laxseed Reduce serum cholesterol and triacylglicerol, reduce heart diseases, immunosuppresants Lower the total and LDL/HDL ratios, increase serum HDL, inhibit arachadonic acid‑derived products such as PGE and leukotrienes ©2010 Copyright Landes Bioscience. Not for Distribution. 75 continued on next page Dietary Phytochemicals and Human Health Table 1. Bioactive food constituents that may prevent diseases (data modiied from ref. 3) 76 Table 1. Continued Food Source Potential Health Beneit Possible Mechanism and Function Conjugated linoleic acids Dairy products, processed vegetable oils Anticancer, antiatherosclerosis Inhibit cancer cell growth by interfering with the hormone regulated mitogenic pathway, reduce LDL/HDL ratio and total/HDL cholesterol in rabbits Diallyl disulide and allicin Garlic, onions Anticancers, stimulate immune func‑ tion, free radical scavengers, reduce serum cholesterol and triacylglyc‑ erols Inhibit the proliferation of human tumor cells in culture, inhibit metabolic activation of the toxicants and carcinogens, inhibit cholesterol biosynthesis Nitrogen and sulphur‑containing amino acid derivaties (glucosino‑ lates, alkaloids, capsaicinoids) Cruciferous vegetables, Green and red pepper Chemoprevention Chemopreventive activity, modulation of drug metabolizing enzymes, neuroactivity Limonene Citrus fruits Anticancer Regulator of malignant cell proliferation, inhibit posttranslational isoprenylation of cell growth‑regulatory proteins Lipoic acid (lipoyllysine) Spinach, broccoli, tomato, green pea, Brussel sprouts, rice bran Plays fundamental role in energy metabolism Antioxidant and redox regulatory activity, potentiates metabolism serving as cofactor in enzyme complexes Coumarins Vegetables, citrus fruits Prevent blood clotting, anticarcino‑ genic activity Anticoagulants, inhibitors and inactivators of carcinogen and mutagen, scavengers of superoxide anion radicals Nondigestable fermentable oligo‑ saccharides, fructans Garlic, asparagus, chicory Prebiotics‑effective substrates for biidobacteria, Intestinal fortiication, stimulate im‑ mune function, inhibit tumorigenesis, modulate lipid metabolism reduce serum cholesterol ©2010 Copyright Landes Bioscience. Not for Distribution. Bio‑Farms for Nutraceuticals Active Compounds 77 Some natural products found in plants have recently also found application in animal nutrition. For some time, a number of antibiotics have been used as growth promoting factors in animal production, especially in poultry and pigs. However, this practice has had serious consequences in increasing the resistance of some microorganisms dangerous to human health. hus, some countries have introduced regulations prohibiting the use of antibiotics in animal production. In addition, starting from 2006, the European Community has banned using antibiotics as growth promoters. hese new regulations may cause loses in income for some companies. Natural products seem to be good substitutes to replace synthetic antibiotics in animal production. Natural plant remedies are being developed and classes of active natural principles are being identiied. Carotenoids Carotenoids are natural fat‑soluble yellow, orange, or red pigments that are synthesised in plants, algae, fungi, yeasts and bacteria. In addition, the characteristic yellowish colours of many birds, insects, ish and crustaceans are due to the presence of carotenoids in their bodies; however, animals and humans cannot synthesise carotenoids de novo and are dependent on the dietary sources.4,5 In nature, the total production of carotenoids has been estimated at 108 ton per year, moreover this mass is concentrated mainly in four carotenoids: lutein, violaxanthin and neoxanthin in green leaves and fucoxanthin, which predominates in marine algae. Over 600 of these compounds have been identiied in nature; however, only about 40 are present in a typical human diet. Human plasma and tissues contain only 20 carotenoids, which are represented mainly by β‑carotene, lycopene, lutein, β‑cryptoxanthin and α‑carotene.6,7 Carotenoids belong to the tetraterpenes family and these are characterised by a polyisoprenoid structure with a long conjugated chain of double bond and a near bilateral symmetry around the central double bond. According to their chemical composition, they are classiied in two classes: carotenes, which contain only carbon and hydrogen atoms and xanthophylls (oxycarotenoids) that have carbon, hydrogen and at least one oxygen atom. Due to the presence of the conjugated double bonds, carotenoids can undergo cis‑trans isomerisation.7,8 Carotenoids usually occur in their all‑trans coniguration, which make them the thermodynamically more stable isomer. However, there is some evidence for the presence of cis‑isomers in plants (e.g., palm oil fruit, algae), espe‑ cially in chlorophyll‑containing tissues but also in a number of fruit. Cis‑isomers may also arise as a result of processing.9,10 hey are present in various types of food, but the major sources of dietary carotenoids include orange and yellow fruits and vegetables as well as green leafy vegetables. Smaller amounts can be extracted from milk and foods containing dairy fat, egg yolks, sea ish and carotenoids added as colorants to foods during processing.11 Table 2 presents some of the richest dietary sources of these compounds in a human diet. he intake of carotenoids in the human diet is more variable than the intake of many other dietary constituents. However, the total carotenoid intake by humans is estimated to be between 6‑11 mg per day (based on ive major carotenoids consumed in US). he dietary intake of ly‑ copene is about 2‑5 mg per day, whereas the intakes of β‑carotene and lutein are slightly lower, approximately 3 and 2‑3 mg per day respectively, with the remainder from β‑cryptoxanthin and α‑ carotene.11,12 Carotenoids are important components of the human diet because they have been linked to a multitude of health beneits. hey play an important role in the cell communication and protection against photooxidative processes by acting as singlet molecular oxygen, as well as, peroxyl radical scavengers and can interact synergistically with other antioxidants.14 In mammals, some of them can be metabolised to retinol and function as vitamin A precursors. Positive efects between high dietary consumption and tissue concentration of carotenoids and reduced risk of chronic diseases such as age‑related macular degeneration were also observed. here is also strong evidence showing that a rich diet in carotenoids prevents cardiovascular diseases and certain cancers like lung, colon, breast and prostate cancer.7,14,15 ©2010 Copyright Landes Bioscience. Not for Distribution. Dietary Phytochemicals and Human Health Bio‑Farms for Nutraceuticals Carotenoids have been shown to possess antioxidant activity and their antioxidant properties are thought to be the main mechanism by which they exert their beneicial efects. Recent studies have also shown that they may mediate their efects via other mechanisms such as gap junction communication, cell growth regulation, modulating gene expression and immune response and as modulators of Phase I and II drug metabolising enzymes.7,16 A considerable pool of data shows a relationship between the risk of cancer and dietary carotenoid intake. Some studies conirmed their protective role, whereas others found no cor‑ relation or even describe an adverse activity. A case‑control study (2.706 cases of cancer of the oral cavity, pharynx, oesophagus, stomach, colon and rectum vs 2.879 controls) indicated that a high intake of tomatoes and tomato‑based food, both of which are rich sources of lycopene, was strongly associated with reduced risk of digestive tract cancers, especially stomach, colon and rectal.17 Another study reported that a diet supplemented with β‑carotene at a dose of 50 mg per day over ive years showed no efect on the occurrence of new basal‑ or squamous‑cell carcinoma in well‑nourished patients who previously had skin cancer. On the other hand, it was also shown that administration of 25 mg of β‑carotene per day with or without vitamin C (1 g per day) and α‑tocopherol (400 mg per day) for 5‑8 years did not reduce the occurrence of colorectal adenoma in patients who had a prior history of adenomas.11 A large‑scale study— he Alpha‑Tocopherol, Beta‑Carotene (ATBC) study suggested that β‑carotene, under certain circumstances, enhances carcinogenesis. his research involved 29.133 male smokers from Finland, whose diet was supplemented with β‑carotene (20 mg per day) or α‑tocopherol (50 mg per day), or both, or placebo for 5‑8 years. Surprisingly, the subjects who received β‑carotene alone or in a combination with α‑tocopherol showed 18% increased incidence of lung cancer and 8% increased in total mortality.16,18 here are several reports that lycopene intake is correlated with a decreased risk of prostate cancer. An important study monitored dietary habits and the incidence rate of prostate cancer in approximately 48.000 men for four years. Researchers observed that subjects who ate ten or more servings of tomato products per week (tomatoes, tomato sauce and pizza sauce) were up to 34% less likely to develop prostate cancer. Men, whose intake was 4‑7 servings per week, were 20% less likely to develop the cancer. Tomato sauce was the strongest dietary predictor of reduced prostate cancer risk (66%) and the major predictor of serum lycopene levels. On the other hand, other studies found no protective efect of serum level and dietary lycopene intakes on prostate cancer risk.17 Some of the epidemiological studies, which considered the role of carotenoids in the devel‑ opment of Cardiovascular Disease (CVD) supported the hypothesis that these compounds had preventive activity. here is evidence that the consumption of processed tomato products causes a reduction in lipoprotein sensitivity to oxidative damage.4 A study that compared Lithuanian and Swedish populations showed that low lycopene levels were connected with an increased risk and mortality from Coronary Heart Disease (CHD). Another study also conirmed the positive role of lycopene. his substance caused a reduction of total serum cholesterol levels and thereby decreased the risk of CVD7. However, there are also studies that found no association between carotenoid dietary intake, their plasma concentration and the risk of CVD as well as CHD.12 Vitamin A is an essential nutrient for human health and is responsible for the promotion of growth, cellular diferentiation, morphogenesis, embryonic development and visual function. Some carotenoids can be converted into active forms of this vitamin and, in doing so, may prevent vitamin A deiciency. hey are termed provitamin A compounds. β‑carotene, α‑carotene and similarly β‑cryptoxanthin as well as nearly 50 other carotenoids with β‑ring end groups belong to this family, whereas lycopene is not a provitamin A compound. It has been estimated that carote‑ noids from fruits and vegetables provide more that 70% of the vitamin A intake in hird World countries, whereas in Western societies, the contribution is much lower.4,5,11 he macula of the eye contains only two carotenoids: lutein and zeaxanthin. hese molecules are thought to protect the eye by acting as ilters for damaging blue light and quenching reactive oxygen species (ROS). here is some evidence that dietary carotenoids afect the human eye and ©2010 Copyright Landes Bioscience. Not for Distribution. 78 79 Dietary Phytochemicals and Human Health Table 2. Concentrations of selected carotenoids in fruit, vegetables and food products (data modiied from refs. 4,7,12,13) Food Source α‑Carotene β ‑Carotene Lycopene Lutein Zeaxanthin Pepper 16.7 ‑ ‑ 50.30 160.80 Green bean 7.0 ‑ ‑ 49.4 ‑ Sweet corn 6.0 5.9 ‑ 52.20 43.7 Banana 5.0 ‑ ‑ 3.3 0.40 Apricot 3.7 2.6 ‑ 10.1 3.10 Carrots, cooked 3.7 ‑ ‑ ‑ ‑ Carrots, raw ‑ 18.3 ‑ ‑ ‑ Apricot, dried ‑ 17.6 ‑ ‑ ‑ Mangos, canned ‑ 13.1 ‑ ‑ ‑ Sweet patato, cooked ‑ 9.5 ‑ ‑ ‑ Carrots, cooked ‑ 8.0 ‑ ‑ ‑ Pumpkin, canned ‑ 6.9 ‑ ‑ ‑ Kale, cooked ‑ 6.2 ‑ ‑ ‑ Spinach, raw ‑ 5.6 ‑ 586.90 ‑ Spinach, cooked ‑ 5.2 ‑ 12.47 ‑ Winter butternut squash ‑ 4.6 ‑ ‑ ‑ Swiss chard, raw ‑ 3.9 ‑ ‑ ‑ Pepper, red, raw ‑ 2.4 ‑ ‑ ‑ Pepper, red, cooked ‑ 2.2 ‑ ‑ ‑ Cantaloupe, raw ‑ 1.6 ‑ ‑ ‑ Broccoli, cooked ‑ 1.3 ‑ ‑ ‑ Tomato paste ‑ 1.2 ‑ ‑ ‑ Tomato powder, drum or spray dried ‑ ‑ 112.63‑126.49 ‑ ‑ Sun‑dried tomato in oil ‑ ‑ 46.50 Pizza sauce, canned ‑ ‑ 12.71 ‑ ‑ Ketchup ‑ ‑ 9.90‑13.44 ‑ ‑ Tomato soup, condensed ‑ ‑ 7.99 ‑ ‑ Tomato sauce ‑ ‑ 6.20 ‑ ‑ Tomato paste ‑ ‑ 5.40‑150.00 ‑ ‑ Guawa, fresh ‑ ‑ 5.40 ‑ ‑ Tomato juice ‑ ‑ 5.00‑11.60 ‑ ‑ Tomatoes, cooked ‑ ‑ 3.70 ‑ ‑ Guawa, juice ‑ ‑ 3.34 ‑ ‑ ‑ continued on next page ©2010 Copyright Landes Bioscience. Not for Distribution. Carotenoid Content mg/100 g Wet Weight 80 Bio‑Farms for Nutraceuticals Table 2. Continued Food Source α‑Carotene β ‑Carotene Lycopene Lutein Zeaxanthin Grapefruit, raw pink ‑ ‑ 3.36 ‑ ‑ Watermelon, fresh ‑ ‑ 2.30‑7.20 ‑ ‑ Papaya, fresh ‑ ‑ 2.00‑5.30 ‑ ‑ Tomatoes, fresh ‑ ‑ 0.88‑4.20 ‑ ‑ Apricot, dried ‑ ‑ 0.86 ‑ ‑ Apricot, canned ‑ ‑ 0.06 ‑ ‑ Brussel sprout ‑ ‑ ‑ 61.0 ‑ Green collard ‑ ‑ ‑ 16.30 ‑ Beet, green ‑ ‑ ‑ 7.70 ‑ Green peas, cooked ‑ ‑ ‑ 1.69 ‑ Broad bean ‑ ‑ ‑ 50.6 ‑ Broccoli ‑ ‑ ‑ 161.40 ‑ Green cabbage ‑ ‑ ‑ 8.00 ‑ Lettuce ‑ ‑ ‑ 11.00 ‑ Parsley ‑ ‑ ‑ 581.20 ‑ Pea ‑ ‑ ‑ 163.30 ‑ Watercress ‑ ‑ ‑ 1.07 ‑ Orange ‑ ‑ ‑ 6.40 5.00 Peach ‑ ‑ ‑ 7.80 4.20 Tomato ‑ ‑ ‑ 7.80 ‑ cause modiication of macular pigments. For example, supplementation with lutein (30 mg per day over 140 days) resulted in increased serum level of lutein and corresponding increase in the concentration of lutein in the macula on the human eye.5,12 Carotenoids appear to be responsible for the potential health beneits such as reduction of the incidence of age‑related diseases of the eye, like cataract and age‑related macular degenera‑ tion disease (AMD), probably by their ability to quench active oxygen species. A study on men consuming high levels of lutein and zeaxanthin in a diet over eight years showed that those carotenoids lowered the risk of cataract by 19%. However, research with β‑carotene and cataract by US physicians over 12 years showed no beneit in healthy men, but the excess risk of cataract in smokers was attenuated by about one quarter.4 Another study showed that women with the highest intake of lutein and zeaxanthin had a 22% decreased risk of cataract compared to those in the lowest quintile.12 In a case‑control study, AMD patients and matched control subjects (who had eye prob‑ lems) were divided into ive groups and given various nutrients from foods. Carotenoids turned out to be the nutrient class with the strongest protective efect against AMD. People with the highest carotenoid intake showed a 43% lower risk of developing AMD compared to those with the lowest administration. It was found that lutein and zeaxanthin were responsible for this beneicial efect.12 ©2010 Copyright Landes Bioscience. Not for Distribution. Carotenoid Content mg/100 g Wet Weight 81 Dietary Phytochemicals and Human Health he healthful properties of plants might in part be due to their content of polyphenols. Plants produce phenolic compounds as secondary metabolites to interact with their environment. To be more precise, these compounds are responsible both for plant organoleptic qualities such as the colouring of leaves and fruits and for other physiological processes, including vasodilatatory, anti‑inlammatory, anti‑bacterial, anti‑viral, anti‑proliferative as well as attracting and repelling insects and protecting plants from herbivores. Fresh fruits, vegetables, leaves, nuts, seeds, lowers and barks are rich sources of these compounds which possess antioxidant activity via their ability to scavenge free radicals or bind pro‑oxidant metal ions by means of their OH groups. Also soya sprouts are a good source of phenolic compounds. hey have been used for centuries in many dishes in the Orient, but recently have also become popular in Western countries.19,20 Flavonoids Flavonoids represent the largest group of phenolic compounds and the most abundant species in the human diet. Over 6.000 diferent lavonoids have been identiied but, only a small number of them are important from a dietary point of view.21 According to their structure, lavonoids can be divided into six major subclasses: lavones, lavonols, lavanones, lavanols (catechins), antho‑ cyanidins and isolavones.8,22 Various studies have shown that the consumption of lavonoid‑rich foods may have positive efects on human health, even if their bioavailability is only partial. he absorbed portion of the amount which is ingested ranges from 0.2% to 0.9% for tea catechins to 20% for quercetin and isolavones. Moreover, the bioavailability of certain lavonoids difers markedly, depending on the food source. For instance, the absorption of quercetin from onions has been shown to be four‑fold higher than absorption from apples or tea.23,24 Comparing with other dietary antioxidant compounds such as tocopherols and vitamin C, the lavonoid concentration in blood plasma is very low. he concentration of lavonols, lavanols and lavanones ranges between 0.06‑0.07 µM. In the case of anthocyanidins it is lower than 0.15 µM. For α‑tocopherol and vitamin C the plasma concentration values are much higher and range between 30‑150 or 15‑40 µM, respectively.25 Although lavonoids are widespread in nature, their total daily intake is changeable. heir consumption mainly depends on food composition, food content as well as on dietary habits and preferences.26 Table 3 shows the dietary lavonoids intake resulting from various studies on lavones consumption in Europe, Asia and US. he estimated daily intake of lavonoids ranges from 3 mg in Finland, through 20 mg in Holland and USA up to 68 mg in Japan. Tea drinkers have a greater lavonoid intake estimated as 430 mg per day.23 Table 3. Flavones: apigenin, luteolin content in various products (data from ref. 26) Country Dietary Intake of Flavonoids* (mg/day) Major Dietary Sources of Flavonoids Danmark Finland Greece Italy Japan Netrerlands United States 26 3‑10; 0‑41 15 23‑34; 35 60‑68; 17 23; 33 20 Tea, onions, apples Fruit and vegetables; apples, onions Fruit and vegetables Red wine; fruit and vegetables Green tea Tea, onions, apples Onions, black tea *not total lavonoid intake, this values refer mostly to three lavonols (quercetin, myricetin and kae‑ mpferol) and two lavones (apigenin and luteolin). ©2010 Copyright Landes Bioscience. Not for Distribution. Phenolic Compounds 82 Bio‑Farms for Nutraceuticals Table 4. Flavonols: quercetin, myricetin, kaempferol content in various products (data from ref. 25) Product Vegetables Capers Dock leaves Fennel Hartwort leaves Red onions Kale Sweet potato leaves Chives Hot peppers Onions Broccoli raw Spinach Celery Broccoli cooked Cherry tomatoes Lettuce Fruits elderberries cranberries currants apples bilberries blueberries apricots grapes cherries plums blackberries Cereal Buckwheat Spices and herbs Dill weed Others Cocoa powder Green tea Black tea Red wine Flavonols Content (mg/100 g or mg/100 ml) 316 120 84,4 38,9 38,8 34,5 30,2 21,7 16,0–50,0 15,4 9,37 4,86 3,50 2,44 2,30–20,3 1,20–9,40 42,0 18,4 13,5 4,42 4,13 3,93 2,55 2,54 1,25 1,20 1,10 23,1 55,0 20,3 2,69 2,07 1,50 ©2010 Copyright Landes Bioscience. Not for Distribution. he most common lavonol in human diet is quercetin, which is present in various fruits and veg‑ etables, but the highest concentration of this molecule has been found in onion (284‑486 mg/kg). Onion is usually consumed in low quantities, but, on the other hand, tea and wine which contain lower amounts of quercetin, are consumed in high quantities in some countries.21 he richest dietary sources of lavonols in a human diet are shown in Table 4. Flavonoids possess a wide range of biological activities on humans. Most of those beneicial health efects are attributed to their antioxidant, free radical scavenging properties as well as metal 83 chelating abilities.27 he antioxidant properties of lavonoids depend on their chemical structure and on the number and arrangement of functional groups. he carbonyl group at C‑4 and the double bond between C‑2 and C‑3 are particularly important in this sense. Moreover, the presence of a catechol moiety controls the eiciency of the physical quenching of singlet oxygen (1O2) by lavonoids and the presence of a 3‑hydroxyl largely determines the eiciency in the reaction with 1O2. he antioxidant activity of lavonoids24 usually increases with the number of hydroxyl groups.24,28 he ability of lavonoids to inhibit low‑density lipoprotein (LDL) oxidation is thought to play an important role in the prevention of cardiovascular diseases. For example, high lavonoid intake has been related to a decreased incidence of myocardial infarction and a reduced risk of coronary heart disease (CHD).27 Several studies have shown that lavonoids might act as antiproliferative and anticarcinogenic agents. he inhibition of carcinogenesis, both in ‘in vitro’ and ‘in vivo’ experi‑ ments takes place by afecting the molecular events in the initiation, promotion and progression cellular phases.22 Moreover, some lavonoids have been reported to have anti‑inlammatory activi‑ ties, mainly related to their ability to inhibit the production of inlammatory mediators such as prostaglandins, leukotrienes and nitric oxide. Flavonoids also possess antiallergic, antidiabetic, antineoplastic, antiviral, antibacterial, hepato‑ and gastro‑protective activities.24,29 Phenolic Acids Most plant phenolic acids such as gallic acid, vanillic acid, procatechuic acid and syringic acid are derived from hydroxybenzoic acid. Others, such as p‑coumaric acid, cafeic acid and ferulic acid, are derived from hydroxycinnamic acids.19 Cafeic and chlorogenic acids occur in fruits, soybeans and cofee beans. Ferulic acid is present in fruits, soybean and rice. Gallic acid occurs in big amounts in guava and Geraniaceae species.30 Various studies suggest the anticancer properties of phenolic acids. According to these studies the carcinogenesis is avoided through several mechanisms: the inhibition of carcinogen uptake, the inhibition of carcinogen activation, the deactivation or organism detoxiication in presence of carcinogenic species. Phenolic acids also afect apoptosis in tumour cells, prevent the carcinogen binding to DNA and enhance the level or idelity of DNA repair. Besides, phenolic acids have good antioxidant properties due to their chemical structure.19 Catechins Catechins are a class of compounds derived from the di‑ or tri‑hydroxyl group substitution and the meta‑5,7‑dihydroxy group substitution in the B and A rings of lavanols, respectively. hey are responsible for the bitterness and the astringency of food. Substantial quantities of these compounds are present in diferent blends of tea. he (−)‑epigallocatechin‑3‑gallate (EGCG), (−)‑epigallocatechin (EGC), (−)‑epicatechin‑3‑gallate (ECG), (−)‑epicatechin (EC), (+)‑gal‑ locatechin (GC) and (+)‑catechin (C) are the major catechins present in green tea. Besides their presence in green and black teas, catechins are present in large quantities in fruits such as berries, grapes, spotted knapweed, shea, cocoa, carob and grape seeds.31 Table 5 shows some of the richest sources of catechins in the human diet. Green tea catechins are natural chemopreventive agents recognized as potent inhibitors of the nuclear transcription factor kappa‑light‑chain‑enhancer of activated B‑cells (NF‑κB) which plays an important role in regulating the immune response to infection. he incorrect regulation of NF‑κB has been linked to cancer, inlammatory and autoimmune diseases, septic shock, viral infection and improper immune development. Catechins may block one or more steps in the NF‑κB signalling pathway such as the activation of NF‑κB signalling cascade, the translocation of NF‑κB into the nucleus, the DNA binding of the dimers, or the interactions with the basal transcriptional machinery. Moreover, they suppress the enzyme Cyclooxygenase‑2 (COX‑2) which is responsible for the formation of prostanoids, engaged in inlammation. he epigallocatechin‑3‑gallate, epigal‑ locatechin, epicatechin‑3‑gallate and thealavins from black tea, also inhibited COX‑dependent arachidonic acid metabolism in human colon mucosa and colon tumours. In addition, catechins inhibit DNA methylation, which is observed in a wide variety of cancers.31 Catechin and epi‑ catechin have also been shown to be prooxidants as they induced oxidative damage to DNA in ©2010 Copyright Landes Bioscience. Not for Distribution. Dietary Phytochemicals and Human Health 84 Bio‑Farms for Nutraceuticals Table 5. Catechins: (‑)‑epicatechin, (‑)‑epigallocatechin gallate content in various products (data from ref. 25) Fruits Blackberries Grapes Cherries Apricots Raspberries Apples Plums Cranberries Raisins Pears Nectarines Peaches Blueberries Others Green tea Dark chocolate Black tea Milk chocolate Red wine Catechins Content (mg/100 g or mg/100 ml) 18.7 17.6 11.7 11.0 9.23 9,0 6.19 4.20 3.68 3.43 2.75 2.30 1.11 132 53,5 33,0 13,4 12,0 a human leukemia cell line by generating H2O2 during redox reactions. Epigallocatechin, the major form of catechins, besides antioxidant activity also exerts an immunomodulatory function and antimicrobial activity against some pathogens as well. Epigallocatechin gallate and epigal‑ locatechin have been reported to inhibit cell‑mediated oxidation of low‑density lipoprotein in a concentration of 0‑400 µM.19 Green tea extracts, gallocatechin gallate, gallocatechin, (−)‑epigallocatechin‑3‑gallate, cat‑ echin‑3 gallate and catechin at 100 µM concentration have been shown to inhibit antiapoptotic Bcl‑2 proteins. Polyphenols present in green tea were also reported to induce apoptosis through accumulation of Apoptotic Protease Activating Factor 1 protein which is a precursor of apoptosis. Efects of catechins on DNA and gene expression may also contribute to their anticarcinogenic properties.19 Catechins are poorly absorbed from the human body and undergo a substantial biotransforma‑ tion to species that include glucuronides, sulfates and methylated compounds.30 In blood serum, the concentration of catechin ingested in the form of tea, ranges between 0.2% and 2% with maximum concentrations achieved 1.4‑2.4 h ater consumption. A study performed on humans has shown that the consumption of eight cups of black tea a day caused a rise of catechins in serum from 0.08 to 0.2 µM.19 Some epidemiological experiments have demonstrated that green tea can be efective for the chemoprevention of prostate cancer since the incidence of prostate cancer is lower in Japanese and Chinese populations32—the major consumers of green tea. Moreover, green tea ointment and capsules have been shown to be efective for treating cervical lesions, suggesting that green tea extracts can be a potential therapy regimen for patients with HPV (Human Papilloma Virus). Epigallocatechin gallate is also interesting because of its sunscreen protective activity against UVB signal transduction.30 ©2010 Copyright Landes Bioscience. Not for Distribution. Product Dietary Phytochemicals and Human Health 85 Stilbenes are organic compounds containing the functional group 1,2‑diphenylethylene.19 Stilbene itself exists as two possible isomers. he irst is trans‑1,2‑diphenylethylene, called (E)‑stilbene or trans‑stilbene. he second is cis‑1,2‑diphenylethylene, called (Z)‑stilbene or cis‑stilbene. Many stilbene derivatives, such as the hydroxylated compounds, are present naturally in plants. he most representative of the latter is resveratrol (3,5,4‑trihydroxystilbene), that exists in the form of cis‑ and trans‑ isomers. In fruits it is present in several complex and substituted forms. Trans‑resveratrol is a natural component of grapes Vitis vinifera L. Especially grapes’ skin and the leaf epidermis are rich sources of this compound. Resveratrol is not unique to Vitis species but is also present in at least 72 other plant species, distributed in 12 families and 31 genera, e.g., Veratrum, Arachis, Morus, Vaccinium and Trifolium—some which for instance, mulberries and peanuts are constituents of the human diet.32 Resveratrol was irst found by Michio Takaoka in 1940 as a component of the roots of white hellebore (Veratrum grandilorum (Maxim. ex Baker) Loes. (Liliaceae)) and identiied by Nonomura et al later (in 1963) in the dried roots of Japanese knotweed Polygonum cuspidatum Sieb. et Zucc. (Polygonaceae). In Japanese and Chinese traditional medicine, it is used for the treatment of dermatitis, gonorrhea favus, hyperlipemia, favus, athlete’s foot and arteriosclerosis, as well as in allergic and inlammatory diseases and other pathologies. In 1976, trans‑resveratrol was detected in grapevines by Langcake and Pryce. It is synthesised by leaf tissues in response to fungal infection by Botrytis cinerea, or ater exposure to ultraviolet light. In 1992, the presence of resveratrol was reported in red wines. A number of epidemiological studies suggested that the moderate consump‑ tion of red wine by French and other Mediterranean populations was connected with the reduced incidence of cardiovascular diseases, despite high‑fat diet, little exercise and widespread smoking. Resveratrol may protect against coronary heart disease by way of its signiicant antioxidant activ‑ ity, modulation of lipoprotein metabolism, vasodilatory and platelet antiaggregatory properties.32 In its antioxidant activity a key role is played by the number and position of the hydroxyl groups in the molecule.33 Resveratrol is absorbed and transferred across the small intestine as a glucuronide, probably cleaved back to the bioactive aglycone form—resveratrol—by the β‑glucuronidases found in a variety of organs and body luids, such as macrophages, blood cells, liver, lung and serum.19 A bio‑ availability study conducted on human healthy subjects, consuming 25 mg of pure trans‑resveratrol in three diferent matrices (white wine with 11.5% ethanol, grape juice and vegetable juice/ homogenate), showed that the concentration of free (1.7 to 1.9% of total polyphenol levels) and conjugated polyphenols in serum were similar for all three sources and reached a maximum con‑ centration ater 30 minutes from the ingestion decreasing to the base level within 4 hours. Also urinary 24‑h excretion ater oral consumption did not show any matrix efect and accounted for 16.5% of the dose administered.33 So far, little is known about pharmacological activity of the cis‑ form. he cis isomer has not been detected in grapes but is present in wines, being probably produced from trans‑resveratrol by yeast isomerases during fermentation, or released from viniferins, or from resveratrol glucosides.32 Resveratrol glycosides, present in grape juice have shown lower bioavailability than the aglycone form, the cumulative excretion of resveratrol being only 5 vs 50% of the administered dose.33 he anti‑initiation activity of resveratrol might be related to its antioxidant and anti‑mutagenic efects.19 Both cis‑ and trans‑isomers exhibit typical antioxidant activity, i.e., they block extra‑ and intracellular production of reactive oxygen species, through the inhibition of both NAD(P)H oxi‑ dase activity and nitric oxide production. In addition, resveratrol inhibits lipid peroxidation.32 Resveratrol and its dimer vineferin, have been reported to inhibit the activities of cytochromes involved in bioactivation or deactivation of numerous carcinogens. he ability to induce apoptosis might also contribute to anticancer efects ascribed to resveratrol. Another possible explanation for the anticancer efects of resveratrol is the regulation of production or activation of speciic enzymes. Moreover, resveratrol has been shown also to have estrogenic activity and immunosup‑ pressive and immunoenhancing properties.19 ©2010 Copyright Landes Bioscience. Not for Distribution. Stilbenes 86 Bio‑Farms for Nutraceuticals Curcumin (diferuloylmethane) is a yellow pigment of the rhizome of turmeric (Curcuma longa L.) widely used as a spice in food. his phenolic compound shows antioxidant, anti‑inlammatory and chemopreventive activity. he anticancer potential comes from its ability to suppress prolifera‑ tion of a wide variety of tumour cells, to regulate transcription factors, chemokines, cell surface adhesion molecules, growth factor receptors and kinases. he daily oral dose of 3.6 g is recom‑ mended in the prevention or treatment of cancer.30 Curcumin as well as various other curcuminoids mediate their therapeutic efects by regulating the transcription factor NF‑κB and NF‑κB regulated gene products COX‑2, cy‑ clin D1 gene, adhesion molecules, matrix metalloproteinase endopeptidases, inducible nitric oxide synthase, B‑cell lymphoma 2, B‑cell lymphoma‑extra large and tumour necrosis factors. Moreover, they could suppress the activator protein 1 transcription factor activation process and the activation of Antiapoptotic Kinase protein which plays an important role in various mammalian cancers.31 Curcumin and resveratrol are also known to modulate the activity of the tumor protein 53 which is a tumour‑suppressor and transcription factor. Tumor protein 53 is a critical regulator in many cellular processes including cell signal transduction, cellular response to DNA‑damage, genomic stability, cell cycle control and apoptosis. he protein activates the transcription of genes, which induce the apoptotic process, inhibiting the growth of cells with damaged DNA or cancer cells. Curcumin, resveratrol, quercetin and green tea polyphenols also target the chemokines which are directly involved in the migration of leukocytes activating the inlammatory responses and participate in the regulation of tumour growth.31 Finally curcumin is able to modulate the mitogen‑activated protein kinases signalling pathway contributing, in this way, to the inhibition of inlammation and has a direct action on liver injury and liver detoxiication enzyme system.31,33 Phytoestrogens Phytoestrogens are natural estrogen‑like substances found in numerous plants especially of the Leguminosae family, but also in some vegetables, fruits and berries. Four diferent families of phenolic compounds are considered as phytoestrogens and include isolavonoids, stilbenes, lignans and coumestans. hese compounds are structurally similar to estradiol and thanks to this similarity they exhibit estrogenic activity due to the presence of two hydroxyl groups that provide the correct geometry to bind estrogen receptors.16,34 Human cells have two types of estrogen receptors: ERα and ERβ. Phytoestrogens bind mainly to the ERβ, whereas mammalian estradiol has a higher binding ainity for ERα.16 he estrogenic activity of these compounds was irst discovered in the 1940s, when they were seen as the cause of infertility and miscarriage problems of Australian sheep feeding on clover leaves. Clover leaves contain large amounts of the two isolavones biochanin A and formononetin that afect the estrogen‑mediated response by activating the aryl hydrocarbon receptor involved in the reproductive physiology in multiple ways (AhR).35 Moreover, dietary phytoestrogens could play an important role in the prevention of breast cancer and prostate cancer. hey may also afect bone density, cardiovascular health, cognitive ability and diminish the symptoms of the menopause.23,35 Isolavones Isolavones are diphenolic secondary metabolites synthesised from the products of the shikimic acid and malonyl pathways by the fusion of a phenylpropanoid with three malonyl coenzyme A residues. In nature as well as in processed food, only a small fraction appears as glucoside‑free (aglycones). Most compounds exist primarily as glycosides with 1‑4 sugar substitutions, which may occur also in acetylated or malonylated form. However, the glycosides are readily hydrolysed in the intestine to their aglycones, which are easily transported across intestinal epithelial cells.36,37 ©2010 Copyright Landes Bioscience. Not for Distribution. Curcumin 87 Dietary Phytochemicals and Human Health Table 6. Isolavones content in selected vegetable and food (data from ref. 40) Food Daidzein Genistein Glycetin Isolavones Total Roasted soybeans Textured vegetable protein Green soybean Soylour Tempeh Tofu Tofu yoghurt Soynoodle (dry) 56,3 47,3 54,6 22,6 27,3 14,6 5,7 0,9 86,9 70,7 72,9 81,0 32,0 16,2 9,4 3,7 19,3 20,2 7,9 8,8 3,2 2,9 1,2 3,9 162,5 138,2 135,4 112,4 62,5 33,7 16,4 8,5 Isolavones are found in a variety of vegetables and fruits. Table 6 shows some of the richest dietary sources of selected isolavones. hese compounds are found at high amounts in some plants of the subfamily Papilionoideae of the Leguminosae, which includes soybean. heir content in soybean ranges from 0.14 to 1.53 mg/g and in soy lour from 1.3 to 1.98 mg/g.36,38 Some Trifolium species may contain even up to 10 mg/g of isolavones in aerial parts.39 Unlike string beans or snap peas, soybeans cannot be eaten as raw plant material, because they contain trypsin inhibitors, which can disrupt digestion activities in the stomach, leading to cramping and associated discomfort. For this reason, soybean seeds are usually consumed as fermented products.36,38 Numerous epidemiological studies have demonstrated an association between the consumption of soybean and the reduction of risk for breast and prostate cancers, cardiovascular diseases and atherosclerosis probably connected with the availability of isolavonoids.36,37 Isolavones possess numerous biological activities. hey play an important role in the prevention of endometrial, breast and prostate cancer, reduce risk for cardiovascular disease and afect the health problems associated with menopause and osteoporosis. Some studies also report that isolavones might support cognitive functions.35,36 In Western diets, the consumption of these compounds is very low, while it is very high in Asian diets. Asian people have a daily intake of lavonoids ranging from 20 to 100 times more than the European intake.36,37 Several studies demonstrate that isolavones also exhibit hormonal activity as they stimulate the synthesis of the sex hormone binding globulin.41 here are correlations between high isolavone consumption diet and the reduced incidence of breast and prostate cancer in humans. In Asian countries, these types of cancer are considerably lower, while an increased risk appears for Asian immigrants living in the US probably due to the change in their dietary habits.35,42 Some studies have also revealed that Japanese women in their homeland have a high number of in situ tumours but with fewer nodal metastases. Tumors presenting metastases have less nodal spread than women with breast cancer in the US or Great Britain.41 Several studies have covered the relation between soy and isolavones intake and prostate cancer risk, the incidence of which is lower in Asians, Africans and native Americans with compareed to western countries. A study performed on Japanese men living in Hawaii has shown a decreased risk of prostate cancer in those consuming rice and tofu. A similar efect has been reported for a group of Seventh Day Adventist men consuming beans, lentils and peas, tomatoes, as well as dried fruits. In a similar vein, Japanese immigrating to North America at a younger age have reported an increase in the incidence of prostate cancer.41 ©2010 Copyright Landes Bioscience. Not for Distribution. Concentration (mg/100 g) Bio‑Farms for Nutraceuticals here are been also some studies investigating the inluence of an isolavone supplemented diet on other types of cancer such as gastric, colon and endometrial. Soy consumption seems signiicantly protective against stomach cancer, but there is also some evidence that fermented soy foods can increase the risk of this cancer. his efect has been explained by hypothesizing the presence of a high concentration of N‑nitroso salts and other unidentiied compounds in fermented foods. Moreover, studies assessing the relationship between soy intake and the risk of colon and rectal cancers, have generally not been supportive of a protective efect: while, on the one hand, it has been reported that a rich‑soy diet efectively reduces the risk of en‑ dometrial cancer in the multiethnic population of Hawaii and in Chinese women,43 on the other hand it has been reported that miso, a traditional food made with soy, signiicantly increases the risk of rectal cancer.44,45 Isolavones also possess estrogenic activity, thus, they deeply inluence women’s emotional state and health. In particular they play an important role in maintaining bone density,37 lipoprotein metabolism and regulate serum cholesterol level which is one of the main risk factors for the development of cardiovascular diseases.42 Menopausal disorders such as osteoporosis, hot lushes and mood swings caused by the lowering of estrogenic hormones are usually treated with synthetic estrogens (hormone replacement therapy). Phytoestrogen compounds used to treat women with climacteric syndrome should contain 40 to 100 mg of isolavones consisting of variable combinations of diferent aglycons (i.e., genistein, daidzein, glycitein, formononetin and biochanin A): this daily dose is toxicologically safe and consistent with the dietary content of isolavones in Asian countries.42 Since it is commonly known that Asian women have considerably fewer menopausal symptoms than Western women, it has been hypothesised that this diference is due to their high intake of phytoestrogen, particularly isolavones. his medical study relates to the eicacy of isolavone‑rich soy or isolavone supple‑ ments as a possible dietary alternative to hormone replacement therapy.44,46 he beneicial efects of isolavones on cholesterol level and bone density have been reported in various studies demonstrating their inluence on the improvement of vascular reactivity,37 the reduction of platelet activation and aggregation as well as on the induction of vasodilation through the stimulation of the endothelial enzyme nitric oxide synthase 3.42 With regard to the beneicial efects in the prevention of osteoporosis, studies demonstrate that isolavones increase the synthesis of vitamin D in a number of nonrenal cell types thus contributing to bone mineral density.35‑37 However, contrary or uncertain efects have also been reported.37 A few studies have also examined the efect of phytoestrogens on the improvement of cognitive function, even if there is no clear evidence to support this thesis. In this study, a group of male and female students were assigned both a high (100 mg per day) and low (0.5 mg per day) isolavones diet. he results showed that students on the high isolavone diet group showed signiicant im‑ provement in short and long‑term memory and mental lexibility.35 Finally, isolavones may have a protective efect on skin health, improving skin elasticity by increasing local blood low. In addition, the antioxidant and anti‑inlammatory properties of phytoestrogens may alleviate the carcinogenic efect of various exogenous noxious agents such as ionizing radiation or chemical compounds.42 Lignans Lignans constitute a class of phytoestrogens derived from phenylalanine by dimerization of substituted cinnamic alcohols to a dibenzylbutane skeleton. he cyclisation or modiication of dimers results in a large variety of chemical structures in which diferent sub‑groups can be identi‑ ied such as furofuran, furan, dibenzylbutane, dibenzylbutyrolactone, aryltetralin, arylnaphthalene, dibenzocyclooctadiene and dibenzylbutyrolactol.43,47 Lignans are widespread in many plant families: in particular, they are synthesised and ac‑ cumulated in the heartwood region of trees as a metabolic event in its formation and protection against fungi causing rotting.43,47 ©2010 Copyright Landes Bioscience. Not for Distribution. 88 89 In mammals, lignans are metabolized by the gut lora producing the so‑called ‘mammalian lignans’: enterodiol and enterolactone. hese compounds difer from their precursors by the pres‑ ence of some hydroxyl groups replacing methyl groups on the aromatic rings.35,48 Enterodiol and enterolactone exert estrogenic and/or anti‑estrogenic activity by regulating the unconjugated/ conjugated sex hormones levels, high values of which are considered a risk factor for breast and prostate cancers.35 Lignans exhibit also antioxidant activity and prevent colon and thyroid cancers.49 In the treat‑ ment of cancer an important role is played by the semisynthetic derivatives of podophyllotoxin (PTOX) which is a non‑alkaloid toxin in the lignan family. his molecule is an active antiwart agent as well as the pharmacological precursor for the important anti‑cancer drug etoposide.43 he chemical synthesis of PTOX is not a cheap process and thus it is highly desirable to develop alternative sources for this compound. One solution is the extraction from plant roots and rhizomes such as Podophyllum peltatum propagated under in vitro conditions, cell suspension cultures of Linum album or other species within the Linum genus.43 Polyunsatured Fatty Acids Polyunsaturated fatty acids (PUFAs) are carboxylic acids of 20 and 22‑carbon chains having various double bonds. he most important for human diet are Omega‑3 and Omega‑6 in which the irst double bond is located at the positions 3 and 6, respectively. he most well‑known among the Omega‑6 PUFAs are the linoleic and arachidonic acids. he most well‑known Omega‑3’s are α‑linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. he human body cannot synthesize PUFAs but can convert linoleic acid to arachidonic acid and ALA to EPA.50 hus, only the precursors need be provided in the diet. Good sources of omega‑3 PUFAs are dark leshed ishes such as herrings, mackerels, sardines and salmons, marine foods and ish oil supple‑ ments;50‑53 α‑linolenic acid is present also in leafy green vegetables, purslane, walnuts and perilla seed, pumpkin seed, laxseed and rapeseed oils, soybean and canola oils.50,51,54 However, excessive consumption of ish should be avoided especially by women of childbearing‑age since they contain a high amount of mercury, causing an improper foetus development.55 Omega‑6 PUFAs, rather, are contained in most vegetable oils,54 cereals, eggs, animal fat, whole grain breads, sunlower and corn oils.50,52,54 he conversion of ALA to EPA and EPA to DHA by a human organism is low, ranging from 0.2% to 15%. his applies to ALA even when is fed at a high level. However, high intakes of ALA have been reported to result in signiicant increases in very long chain omega‑3 fatty acids in vari‑ ous body compartments.51 An optimal balance between Omega‑3 and Omega‑6 fatty acids is extremely important for human body, since they contribute to the maintenance of the whole hormone balance.50 Moreover, EPA and DHA consumption has also been connected with reduction of the risk of cardiovascular diseases.52,53 he cardioprotective efect includes anti‑arhythmic, anti‑thrombotic and anti‑inlammatory activities, lowering blood pressure, endothelial function improvement and the slowing down of atherosclerotic plaque growth.51 PUFAs afect also cell membranes luidity and the behavior of enzymes and receptors bound to membranes. Furthermore, they have antibiotic‑like properties. α‑linolenic acid, for example, rapidly kills Staphylococcus aureus and suppresses proinlammatory cytokines such as interleukins and tumour necrosis factor.50 An important role is played by Omega‑3 also in the development and activity of the central nervous system and the improvement of cognitive development and memory‑related learning.54,56 Docosahexaenoic acid, especially, is involved in the growth and function of nervous tissue afect‑ ing both the neurogenesis and the neurotransmission. his accounts for considering DHA as an essential supplement in the diet of preschool and young infants: their organism is not able to produce DHA at the rate required by the rapid growth of their brain, thus, it must provided by appropriate dietary supplements.53 ©2010 Copyright Landes Bioscience. Not for Distribution. Dietary Phytochemicals and Human Health Bio‑Farms for Nutraceuticals In Western diets, the ratio of omega‑6 to omega‑3 PUFAs ranges from 15‑16:1 while recent dietary data suggests the healthy range of 1‑4:1.50 he recommended daily amount of EPA and DHA for adults is at least 220 mg. Two or three servings of fatty ish per week (about 1250 mg EPA and DHA per day) are regarded as protection from psychiatric and neurological disorders. he same amount of EPA and DHA is provided in form of 3000 to 4000 mg standardised ish oils ingested per day. In the case of ALA, the adequate daily intake for adults should be roughly 2220 mg per day. Regarding laxseed oil, doses up to 3000 mg per day are recommended to prevent neurodegenerative disorders and doses up to 6000 mg per day may be recommended to treat these conditions. If it is taken in the form of laxseeds, the recommended dose is 1 tablespoon two to three times per day or 2 to 4 tablespoons once per day and seeds should be ground before eating and taken with lots of water. Decoction of laxseeds can be ingested too. 100 g of raw laxseed provides 22800 mg of ALA.54 Conjugated Linoleic Acids Conjugated Linoleic Acids (CLA) are a mixture of positional and geometrical isomers of linoleic acid discovered accidentally in grilled beef.16,57 At least 28 structures are known for these compounds mainly contained in ruminant meats (beef, lamb) and dairy products and in lower amounts in nonruminant meat.57‑59 Table 7 present some of the richest dietary sources of CLA. he diferent content of CLA in foods is mainly due to the type of feeding and the quality of feedstuf chosen for animals. For instance, it has been proven that modern agricultural feeding practice limits CLA content in animal tissues and their products.61 In the laboratory, CLA can be produced from pure linoleic acid, sunlower oil or corn oil heated in the presence of alkali. As an alternative, the isomerisation of linoleic acid induced by the bacteria Lactobacillus plantarum can be used.58,59 Conjugated Linoleic Acids have been linked to a multitude of health beneits which range from anticarcinogenic, antitherogenic, antiadipogenic and antidiabetogenic activity to the prevention of heart diseases, improvement of the immune system, treatment of obesity and the increase of lean body mass.57,59 Mostly, these results have been obtained from studies using mixtures of CLA isomers. Indeed, the diferent isomers show diferent activities and mechanism of action on speciic tissues and organs and the major efects can be attributed to the two species cis‑9, trans‑11 and trans‑10, cis‑12 conjugated linoleic acid.57,62,63 he evidence of CLA efects on the balance of lean and fat body mass has been obtained by studies performed on diferent rodents (mice, rats) and pigs and on overweighed humans fed with various isomers of CLA in variable dosages. In the former, a lowering of fat body mass together with an increase of lean body mass has been observed in CLA‑treated animals compared to nontreated ones.62‑64 In the latter, contrasting results have been obtained: some sustaining a reduction in body fat mass, during the irst 6 months of treatment, others reporting no efect on fat mass, fat‑free mass, percent body fat, body weight or blood lipids.63,64 he antiatherogenic efect has been shown, studying the inluence on thromboxane production, platelet aggregation and cholesterol level in the blood plasma of rabbits and hamsters. In the irst case, the results have suggested that a diet with 0,5 g of CLA per day causes a reduction of 12% in the atherosclerotic lesions of the aortic surface. In the second case, hamsters fed with 20% butterfat for 12 weeks, have shown a signiicant lowering in the aortic lipid deposition.57‑59 Similar studies performed on humans with a 0.7% CLA supplementation per day, have dem‑ onstrated a decrease in the level of total cholesterol, triglycerides as well as HDL cholesterol in serum. However, opposite results have been also obtained reporting no changes in plasma lipid and lipoprotein concentrations ater the consumption of 3.9 g of CLA per day.57 Among the beneicial efects of CLA is also the action on the immune system: researchers have observed that these compounds in addition to decreasing the production of inlammatory media‑ tors like prostaglandins, show an inhibitor efect on proinlammatory cytokines in animal and human cell lines, decrease the regulation of hypersensitivity reactions caused by the body immune response to allergens and inhibit hepatoma, colorectal, breast, prostate and lung carcinogenesis at ©2010 Copyright Landes Bioscience. Not for Distribution. 90 91 Dietary Phytochemicals and Human Health Table 7. The concentration of conjugated linoleic acids (CLA) in various products (data modiied from refs. 60,62,64) Dairy products Condensed milk Butter fat Homogenized milk Cultured buttermilk Plain yoghurt Butter Sour cream Low‑fat yogurt 2% milk Ice cream Cheeses Ricotta Swiss Edamer Mozzarella Cottage Brie Cheddar sharp Cheddar medium Parmesan Meat Lamb Fresh ground beef Veal Fresh ground turkey Pork Chicken Egg yolk Salmon Vegetable oils Saflower oil Sunlower oil Peanut Olive CLA (mg/g fat) 7,0 6,1 5,5 5,4 4,8 4,7 4,6 4,4 4,1 3,6 5,6 5,4 5,3 4,9 4,8 4,7 4,5 4,0 4,0 5,8 4,3 2,7 2,6 0,6 0,9 0,6 0,3 0,7 0,4 0,2 0,0 various levels: initiation, promotion and progression. In addition, the intake of cis‑9, trans‑11 and trans‑10, cis‑12 isomers should inluence the immune function decreasing the T‑cell lymphocyte activation. However, no efects on immune system ater inluenza vaccination have been displayed in some young healthy women and no alteration in prostaglandin production and lymphocyte proliferation have been noticed in stimulated peripheral blood mononuclear cells.57,63 Finally, CLA might afect bone metabolism as some studies demonstrate that: (1) human intestinal cells treated with CLA are able to mobilise higher amounts of Calcium;57 (2) supple‑ mented‑CLA chicks show a higher dry and fat‑free bone ash comparing to control fed chicks;61 (3) male Wistar rats on CLA diet, show an enhancement in Calcium absorption even if measurable efects on bone mass cannot be observed.57 ©2010 Copyright Landes Bioscience. Not for Distribution. Product 92 Bio‑Farms for Nutraceuticals Tocopherols and Tocotrienols Tocopherols and tocotrienols belong to the family of vitamin E which was discovered in 1922 by Evans and Bishop as an essential factor for the reproduction in rats. he family consists of eight lipid‑soluble molecules composed of a chromonal ring with a side chain. In tocopherols, the ring has a 15‑carbon side chain at the C‑2 position; tocotrienols are structurally similar except for the presence of three trans double bonds in the hydrocarbon tail.65,66 Tocopherols are generally present in nuts (almonds) and common vegetable oils (wheat germ, sunlower). Tocotrienols are present in cereal grains (oat, barley and rye) and some vegetable oils (palm oil and rice bran oil)66‑68 (Table 8). Both tocopherols and tocotrienols are synthesised in photosynthetic organisms including bac‑ teria, algae, plants and fungi. Vitamin E was chemically synthesised for the irst time in 1938.67 he overall intake of vitamin E derivatives largely depends on the dietary preferences in difer‑ ent countries. For instance, the daily intake in European and US countries ranges from 6.4 mg to 12.6 mg. he daily recommended dose according to diferent Medicine and Nutrition institutes should vary from 12 to 15 mg per day to the upper limit of 1000 mg per day. his amount has been raised to 1073 mg in some clinical trials, with no negative efects observed on the patients.10,66,70 Most of the scientiic literature on vitamin E and its derivatives concerns the tocopherols. Vitamin E as well as tocotrienol and tocopherol homologues possess antioxidant activity, protect against cardiovascular disease, atherosclerosis and certain types of cancer. Moreover, they reveal Table 8. Composition and amounts of vitamin E in dietary vegetable oils (data from ref. 69) Vegetable Oil Tocopherols (%) Vitamin E Total (mg/Tb) α β γ δ α Tocotrienols (%) β γ Wheat germ 33 45 27 10 10 1 7 0 Palm 12 21 0 32 0 15 3 29 Soybean 11 8 0 64 28 0 0 0 Cottonseed 10 53 0 47 0 0 0 0 Corn 10 20 6 74 0 0 0 0 Canola 8 38 0 60 2 0 0 0 Saflower 7 69 0 31 0 0 0 0 Sunlower 7 89 0 9 2 0 0 0 Peanut 5 45 0 50 5 0 0 0 Olive oil 1 100 0 0 0 0 0 0 Coconut 0,5 26 0 0 14 12 3 45 Kilocalorie consideration: Tablespoon oil = 126 kilocalories (1 Tablespoon oil = 14 g; fat has 9 kilocalories/g). ©2010 Copyright Landes Bioscience. Not for Distribution. Positive efects have also been noticed in postmenopausal women consuming higher amounts of CLA in their diet; an improvement of bone mineral density was observed.57 Some studies also indicate that CLA might possess an antidiabetic efect. A lowering of glucose level, plasma insulin and free fatty acids was observed in obese and diabetic rats ater the supplementation of their diet with 1.5% of CLA isomers.58,59 Increased insulin sensitivity ater administering trans‑10, cis‑12 isomer was also noted.63 However, caution is of the utmost since another study reports no changes in plasma glucose or insulin levels in cows fed with 10 g per day of CLA isomers.64 93 beneicial efects in neurodegenerative diseases such as Alzheimer’s or Parkinson’s. Vitamin E also shows beneicial efects as anti‑tumourigenic, photoprotective and skin barrier stabilizer that accounts for its wide use in cosmetic and skin care products.65,66,70,71 α‑tocopherol exerts its antioxidant activity by both scavenging those radicals which are re‑ sponsible for the propagation of lipid peroxidation chain reaction and decreasing the assembly of active Nicotinamide Adenine Dinucleotide Phosphate‑oxidase responsible for the reactive oxygen species production, which is involved in lipid peroxidation.72 Some epidemiological studies support also the health beneits of tocopherols and tocotrienols in cardiovascular disease prevention and cholesterol lowering. In particular, an inverse association between vitamin E intake and the risk of cardiovascular disease has been demonstrated and the inhibition of the hepatic enzyme 3‑hydroxy‑3‑methylglutaryl‑coenzyme A, responsible for choles‑ terol synthesis, has been observed even in presence of micromolar amounts of tocotrienol.65,68 With regard to tocopherols’ anti‑tumourigenic activity, some studies report a protective ef‑ fect of α‑tocopherol and γ ‑tocopherol against prostate cancer and of γ ‑tocopherol against colon cancer. In the irst case, the therapeutic efect seems to pertain to the γ‑tocopherol form, while no protective efects are ascribed to α‑tocopherol.73 Limonene Limonene is a hydrocarbon classiied as a cyclic monoterpene. he molecular skeleton of monoterpenes consists of two isoprene units but oxygen‑containing compounds such as alco‑ hols, aldehydes or ketones (terpenoids) are also found. hese compounds are very widespread in the essential oils of many plants and show chemoattractant or chemorepellent activity as well as providing plants with their distinctive fragrance.20 Limonene is particularly abundant in citrus fruits such as lemon, sweet orange, grapefruit and the mandarin C. clementina.31,74‑76 Some analyses on the volatile components emitted by citrus have shown that the highest level of limonene condenses in the gynaecium (62.5%), stamens (22.9%) and petals (3.1%), while no production of limonene has been found in the pollen. Moreover, young leaves contain more limonene (65.3%) than the old ones (30.1%).77,78 A considerable amount is present also in celery (Apium graveolen), cardamom, caraway, dill, peppermint and mopanes;31,74 in the latter, limonene and α‑pinene are presumably responsible for the strong turpentine odor of the pods.79 On the basis of its properties, limonene is applied as a lavouring agent for fruit juices, sot drinks, baked goods and dairy products as well as for cosmetics and cleaning products.74 However, limonene is also known to medicine for its chemotherapeutic activity and minimal toxicity in preclinical studies: the D‑limonene isomer signiicantly increases tumour latency and reduces tumour multiplicity by regulating the signal transduction and cell growth;74,75 moreover it improves bile low, the immune system, the metabolism of cholesterol and can help to dissolve gallstones.80 Allicin and Diallyl Disulide Allicin belong to the group of thiosulinate compounds, appearing in high amounts in garlic extracts. he species γ‑glutamylcysteine present in raw garlic and onion is the precursor of various sulfur‑containing sulfoxides which are responsible for the characteristic odor and lavor of garlic and onion.81 hiosulinates‑ including allicin‑ are volatile, unstable compounds which rapidly transform into other types of organosulfur compounds.82 For instance, allicin is easily converted to allin by the enzyme alliinase released from vacuoles when garlic tissues are destroyed by cutting, crushing or chewing; ater keeping allicin at 20˚C for 20 h, it rapidly decomposes to diallyl disulide, diallyl sulide, diallyl trisulide and sulfur dioxide.81‑83 Moreover, it can be easily denatured by boiling.84 he stable forms of allicin and of other highly reactive thiosulinates are responsible for most of the health beneits attributed to onion and garlic. For many years garlic has been used as a spice and as a medicinal plant against headache, bites, intestinal worms, tumours and antiseptic remedy ©2010 Copyright Landes Bioscience. Not for Distribution. Dietary Phytochemicals and Human Health Bio‑Farms for Nutraceuticals for wounds and ulcers. In China, onion and garlic tea have been recommended at length for fever, cholera and dysentery.81 Other properties of garlic and onion include antimicrobial, antioxidant, antimutagenic, antia‑ sthmatic, immunomodulatory and prebiotic.81,84,85 Garlic inhibits the growth of both gram‑positive and gram‑negative bacteria; onion is efective against gram‑positive ones.81 In ‘in vitro’ conditions, fresh garlic extract (even applied at 128 times dilution) inhibits the growth of a broad spectrum of bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas, Proteus, Salmonella, Micrococcus, Bacillus subtilis, Mycobacterium and Clostridium.84 Organo‑sulfur compounds are protective agents in cardiovascular diseases, as they reduce serum cholesterol and triacylglycerol levels, show hypolipidemic, anti‑hypertensive, anti‑diabetic and antithrombotic activity as well as antioxidant properties preventing atherosclerosis.81,84,85 Diallyl sulide and diallyl disulide protect the stomach against Helicobacter pylori infection, causing dyspepsia, gastric and duodenal ulcer and probably gastric cancer.84 Furthermore, an antiviral efect (against herpes simplex types 1 and 2 viruses, inluenza A virus, inluenza B virus, human cytomegalovirus, vesicular stomatitis virus, rhinovirus, human immunodeiciency virus, pneumonia virus and rotavirus81) has been observed, as well as insecticide and protective efects against parasites, fungi and yeasts. Protozoan parasites include: Opalina ranarum, Opalina dimid‑ icita, Balantidium entozoon, Entamoeba histolytica, Tripanosoma brucei, Leishmania, Leptomonas colosoma, Crithidia fasciculata, Giardia lamblia, Giardia intestinalis, Cryptosporidium baileyi, Tetratrichomonas gallinarum and Trichomonas vaginalis.81,86 Fungi and yeasts include: Candida, Trichophyton, Torulopsis, Rhodotorula, Cryptococcus, Aspergillus and Trichosporon.81 Anticarcinogenic beneits are mainly concerned with oesophagus, stomach, colon, bladder, prostate, liver, lungs, mammas, brain and skin sarcomas and carcinomas, as sulfur compounds inluence DNA repair, acting as antimutagenic agents, stimulate T‑cell proliferation and mac‑ rophages cytotoxicities on tumour cell lines and stimulate the activity of detoxifying enzymes.81,83,85 Sometimes, the supplementation of raw‑garlic extracts leads to allergic reactions such as contact dermatitis, bronchial asthma and chemical burns on the skin. hese drawbacks can be overcome using diferent pharmaceutical products retaining garlic’s health beneits. An example is given by aged garlic extracts, for which additional therapeutic efects have been found: they possess hepatoprotective, neuroprotective and antioxidative activities probably linked to the formation of new compounds during the long‑term extraction. Additionally, no severe toxic side efects were observed even in cases of high ingestion dosages.81,82 Glucosinolates Glucosinolates are nitrogen‑sulfur containing compounds87 occurring in high concentration in all cruciferous vegetables such as cabbages, broccoli, caulilowers, Brussels sprouts, radishes, turnips, cress and in some relishes and oilseeds.10 At least 120 compounds are known, sharing a common chemical structure made of a sulfonated moiety, a β‑D‑thioglucose group and a variable side chain derived from one amino acid. Depending on the type of amino acid precursor, glu‑ cosinolates can be classiied into three chemical groups: aliphatic (those derived from Ala, Leu, Ile, Met, or Val), aromatic (those derived from Phe or Tyr) and indolic (those derived from Trp).87,88 Upon plant damage, (e.g., by cutting, crushing, or chewing) glucosinolates are hydrolysed by the enzyme thioglucoside glucohydrolase and degraded into a variety of products. Some of them, like isothiocyanates and indolic compounds seem to be responsible for the majority of glucosinolates’ beneicial efects.16,87 he decrease of risk of lung, stomach, colon and rectum carcinomas are some of the proper‑ ties ascribed to these molecules.16,88 Some compounds are identiied as potent cancer prevention agents due both to their ability to improve the activity of detoxiication enzymes, such as quinone reductase, glutathione‑S‑transferase and glucuronosyl transferases and due to their property of preventing tumour growth by blocking cell cycle and promoting apoptosis. Moreover, some compounds exhibit potential for treating gastritis and stomach cancer caused by Helicobacter pylori by reducing the number of precancerous lesions.87 Despite this, no absolute certainty exists ©2010 Copyright Landes Bioscience. Not for Distribution. 94 Dietary Phytochemicals and Human Health 95 about the healthy properties of glucosinolates since an inverse relation has been found between the concentration of isothiocyanate metabolites in the urine of a group of Chinese men and the incidence of lung cancer.88 Capsaicinoids are nitrogen‑containing plant secondary metabolites homologous with branched‑ or straight‑chain alkylvanillylamides. hey are found mainly in the Capsicum fam‑ ily, with the highest concentration present in chilli peppers. Capsacinoids are responsible for peppers’ typical pungency which depends on the type of pepper and its geographical origin. his family of molecules include various compounds such as capsaicin, nordihydrocapsaicin, homocapsaicin, nonivamide and homodihydrocapsaicin.16,89,90 In addition to their lavouring property which makes them particularly useful as food addi‑ tives, capsaicinoids reveal interesting pharmacological actions. For instance, capsaicin acts on the peripheral part of the sensory nervous system reducing the painful states caused by rheumatoid arthritis, postherpetic neuralgia, postmastectomy pain syndrome and diabetic neuropathy.90,91 Moreover, it demonstrates a chemoprotective efect due to the modulation of the metabolism of carcinogens and/or mutagens interacting with DNA: the action mechanism shown by capsaicin is the suppression of the carcinogen binding to DNA that has been observed in the case of many polycyclic aromatic hydrocarbons.16,90,91 However, opposite results have also been reported dem‑ onstrating that capsaicin induces gastric cancer in rats and could increase the risk factor for gastric cancer also in people consuming chilli.16,90 Conclusion Living plants produce a series of secondary metabolites which appear to be important in numerous ields: toxicology, environment, pharmacology, cosmetics, medicine, food chemistry, etc. An important role played by these compounds is their beneicial efect on human health and their ability to prevent diseases. In Western Europe, the aging of population has been and currently is a driving force for the study of new phytochemical products, able to ight age‑related conditions and prevent dseases such as high blood cholesterol level, high blood pressure, arthritis, obesity and cancer. In fact, only a few plants have been the subject of detailed investigations but more than 1000 species have been claimed to ofer special beneits.92 In 2002 the market for functional food in Europe exceeded 2 billion US$ (33 billion US$ in USA), representing less than 1% of the European food market,93 but it is expected to reach 5% in the near future. However, in many cases no certainty exists about the real efects of dietary phytochemicals and more epidemiological surveys and clinical studies should be performed. Moreover, in various cases contrary efects are reported. Probably the main reason for this discrepancy is that many clinically tested “products” are, in fact, multicomponent mixtures since it is frequently very diicult to isolate only one component to study its biological efect. For this reason, standardised analytical procedures are needed and ‘in vitro’ and ‘in vivo’ models for fast screening of biological activity of minute amounts of phytochemicals need to be developed. Furthermore, the bioavailability and the concentration of diferent phytochemicals at the action sites needs to be better understood to ofer improved methods to design functional foods: this could become particularly important when combining phytochemicals to avoid improper combinations that might cause lower absorbance or even nullify the efect of one or all the supplements.92 Finally, advances in biotechnology should be better exploited, even though genetically modiied organisms are hardly accepted in European markets. he reason is that, indeed, biotech‑ nology ofers massive opportunities to produce the desired metabolites, modifying the genoma in such a way that their biosynthesis is improved and the processes of extraction and isolation become easier. ©2010 Copyright Landes Bioscience. Not for Distribution. Capsacinoids 96 Bio‑Farms for Nutraceuticals Acknowledgements We are grateful to European Community for support (EU N. FOOD‑CT‑2005‑023044). Fai‑MoMa was inanced by ASI for Nutraceuticals in support to astronauts in space. 1. Jones WHS ed. Hippocrates. Nutriment 1923; 351. 2. Funk C, he etiology of deiciency diseases. State Medicine 1912; 20:341‑368. 3. Bidlack WR, Wang W. Designing functional food to enhance health. z Bidlack WR, Omaye ST, Meskin MS et al eds, Phytochemicals As Bioactive Agents. Lancaster: Technomic Publishing Co., Inc, 2000:241‑270. 4. Fraser PD, Bramley PM. he biosynthesis and nutritional uses of carotenoids. Progress in Lipid Research 2004; 43:228‑265. 5. Stahl W, Sies H. Bioactivity and protective efects of natural carotenoids. Biochimica et Biophysica Acta 2005; 1740:101‑107. 6. Delgado‑Vargas F, Jiménez AR, Paredes‑López O. Natural pigments: carotenoids, anthocyanins and betalains‑characteristics, biosynthesis, processing and stability. Crit Rev Food Sci Nutr 2000; 40(3):173‑289. 7. Rao AV, Rao LG. Carotenoids and human health. Invited review. Pharmacological Research 2007; 55:207‑216. 8. Tapiero H, Tew KD, Nguyen BG et al. Polyphenols: do they play a role in the prevention of human pathologies? Biomed Pharmacother 2002; 56:200‑207. 9. Schieber A, Carle R. Occurrence of carotenoid cis‑isomers in food: technological, analytical and nutri‑ tional implications. Trends Food Sci Technol 2005; 16:416‑422. 10. Stahl W, van den Berg H, Arthur J et al. Bioability and metabolism. Mol Aspects Med 2002; 23:39‑100. 11. Rock CL. Carotenoids: biology and treatment. Phannncol her 1997; 75(3):185‑197. 12. Krinsky NI, Johnson EJ. Carotenoid actions and their relation to health and disease. Mol Aspects Med 2005; 26:459‑516. 13. Roldán JM, Luque de Castro MD. Lycopene: the need for better methods for characterization and determination. Trends Analyt Chem 2007; 26(2):163‑170. 14. Tapiero H, Townsend DM, Tew KD. he role of carotenoids in the prevention of human pathologies. Biomed Pharmacother 2004; 58:100‑110. 15. Palace VP, Khaper N, Qin Q et al. Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease. Free Radic Biol Med 1999; 26(5/6):746‑761. 16. Eskin NAM, Tamir S. Dictionary of Nutraceuticals and Functional Foods, Taylor and Francis Group, Boca Raton, London, New York 2006; 1‑507. 17. Omoni AO, Aluko RE. he anticarcinogenic and anti‑atherogenic efects of lycopene: a review. Trends Food Sci Technol 2005; 16:344‑350. 18. Astorg P. Food carotenoids and cancer prevention: an overview of current research. Trends Food Sci Technol 1997; 8:406‑413. 19. Nichenametla SN, Taruscio TG, Barney DL et al. A review of the efects and mechanisms of polyphe‑ nolics in cancer. Crit Rev Food Sci Nutr 2006; 46:161‑183. 20. Bachioca M, Biagioti E, Ninfali P. Nutritional and technological reasons for evaluating the antioxidant capacity of vegetable products. Ital J Food Sci 2006; 2(18):209‑217. 21. Erlund I. Review of the lavonoids quercetin, hesperetin and naringenin. Dietary sources, bioactivities, bioavailability and epidemiology. Nutrition Research 2004; 24:851‑874. 22. Lin JK, Weng MS. Flavonoids as Nutraceuticals. In: Grotewold E. ed. he Science of Flavonoids. New York:Springer, 2006:213‑238. 23. Le Marchand L. Cancer preventive efects of lavonoids—a review. Biomed Pharmacother 2002; 56:296‑301. 24. Yao LH, Jiang YM, Shi J et al. Flavonoids in food and their health beneits. Plant Foods Hum Nutr 2004; 59:113‑122. 25. Lotito SB, Frei B. Consumption of lavonoid‑rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic Biol Med 2006; 41:1727‑1746. 26. Aherne SA, O’Brien NM. Dietary lavonols: chemistry, food content and metabolism. Nutrition 2002; 18:75‑81. 27. Heim KE, Tagliaferro AR , Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure‑activity relationships. J Nutr Biochem 2002; 13:572‑584. 28. Harborne JB, Williams CA. Advances in lavonoid research since 1992. Phytochemistry 2000; 55:481‑504. 29. Di Carlo G, Mascolo N, Izzo AA et al. Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sciences 1999; 65(4):337‑353. ©2010 Copyright Landes Bioscience. Not for Distribution. References 97 30. Russo M, Tedesco I, Iacomino G et al. Dietary phytochemicals in chemoprevention of cancer. Curr Med Chem—Immun, Endoc and Metab Agents 2005; 5:61‑72. 31. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancers. Biochem Pharmacol 2006; 71:1397‑1421. 32. Orallo F. Comparative studies of the antioxidant efects of cis‑ and trans‑resveratrol. Curr Med Chem 2006; 13:87‑98. 33. Vitaglione P, Morisco F, Caporaso N et al. Dietary antioxidant compoundsand liver health. Crit Rev Food Sci Nutr 2004; 44:575‑586. 34. Martin JHJ, Crotty S, Warren P et al. Does an apple a day keep the doctor away because a phytoestrogen a day keeps the virus at bay? A review of the antiviral properties of phytoestrogens. Phytochemistry 2007; 68:266‑274. 35. Cornwell T, Cohick W, Raskin I. Dietary phytoestrogens and health. Phytochemistry 2004; 65:995‑1016. 36. McCue P, Shetty K. Potential health beneits of soybean isolavonoids and related phenolic anti‑ oxidants. In: Shetty K, Paliyath G, Pometto AL, Levin RE, eds. Functional Foods and Biotechnology. London:Taylor and Francis Group, 2007:133‑150. 37. Brouns F. Soya isolavones: a new and promising ingredient for the health foods sector. Food Res Int 2002; 35:187‑193. 38. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: lavonoids and isolavonoids. Pharmacology and herapeutics 2001; 90:157‑177. 39. Oleszek W, Stochmal A, Janda B. Concentration of isolavones and other phenolics in the aerial parts of Trifolium species. J Agric Food Chem 2007; 55:8095‑8100. 40. Knight DC, Eden JA. A review of the clinical efects of phytoestrogens. Obstet Gynecol 1996; 87(5/2):897‑904. 41. Davis SR, Murkies AL, Wilcox G. Phytoestrogens in clinical practice. Integr Med 1998; 1(1):27‑34. 42. Tempfer CB, Bentz EK, Leodolter S et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril 2007; 87(6):1243‑1249. 43. Fuss E. Lignans in plant cell and organ cultures: an overview. Phytochemistry Reviews 2003; 2:307‑320. 44. Duncan AM, Phipps WR, Kurzer MS. Phytoestrogens. Best Pract Res Clin Endocrinol Metab 2003; 17(2):253‑271. 45. Lof M, Weiderpass E. Epidemiologic evidence suggests that dietary phytoestrogen intake is associated with reduced risk of breast, endometrial and prostate cancers. Nutr Res 2006; 26:609‑619. 46. Beck V, Rohr U, Jungbauer A. Phytoestrogens derived from red clover: an alternative to estrogen replace‑ ment therapy? J Steroid Biochem Mol Biol 2005; 94:499‑518. 47. Suzuki S, Umezawa T. Biosynthesis of lignans and norlignans. J Wood Sci 2007; 53:273‑284. 48. Meagher LP, Beecher GR. Assessment of data on the lignan content of foods. J Food Compost Anal 2000; 13:935‑947. 49. Niemeyer HB, Metzler M. Diferences in the antioxidant activity of plant and mammalian lignans. J Food Eng 2003; 56:255‑256. 50. El‑Badry AM, Graf R, Clavien PA. Omega 3—Omega 6: what is right for the liver? J Hepatol 2007; 47:718‑725. 51. Balk EM, Lichtenstein AH, Chung M et al. Efects of omega‑3 fatty acids on serum markers of cardio‑ vascular disease risk: a systematic review. Atherosclerosis 2006; 189:19‑30. 52. Kinney AJ. Metabolic engineering in plants for human health and nutrition. Curr Opin Biotechnol 2006; 17:130‑138. 53. Sijtsma L, de Swaaf ME. Biotechnological production and applications of omega‑3 polyunsatureted fatty acid docosahexaenoic acid. Appl Microbiol Biotechnol 2004; 64:146‑153. 54. Mazza M, Pomponi M, Janiri L et al. Omega‑3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:12‑26. 55. Domingo JL. Omega‑3 fatty acids and the beneits of ish consumption: is all that glitters gold? Environ Int 2007; 33:993‑998. 56. Beltz BS, Tlusty MF, Benton JL et al. Omega‑3 fatty acids upregulate adult neurogenesis. Neurosci Lett 2007; 415:154‑158. 57. Bhattacharya A, Banu J, Rahman M et al. Biological efects of conjugated linoleic acids in health and disease. J Nutr Biochem 2006; 17:789‑810. 58. Nagao K, Yanagita T. Conjugated fatty acids in food and their health beneits. J Biosci Bioeng 2005; 100(2):152‑157. 59. Whigham LD, Cook ME, Atkinson RL. Conjugated linoleic acid: implications for human health. Pharmacol Res 2000; 42(6):503‑510. 60. Sieber R, Collomb M, Aeschlimann A et al. Impact of microbial cultures on conjugated linoleic acid in dairy products—a review. Int Dairy J 2004; 14:1‑15. ©2010 Copyright Landes Bioscience. Not for Distribution. Dietary Phytochemicals and Human Health Bio‑Farms for Nutraceuticals 61. Cook ME, Pariza M. The role of conjugated linoleic acid (CLA) in health. Int Dairy J 1998; 8:459‑462. 62. Rainer L, Heiss CJ. Conjugated linoleic acid: health implications and efects on body composition. J Am Diet Assoc 2004; 104(6):963‑968. 63. Collomb M, Schmid A, Sieber R et al. Conjugated linoleic acids in milk fat: variation and physiological efects. Int Dairy J 2006; 16:1347‑1361. 64. Evans ME, Brown JM, McIntosh MK. Isomer‑speciic efects of conjugated linoleic acid (CLA) on adiposity and lipid metabolism. J Nutr Biochem 2002; 13:508‑516. 65. Sen CK, Khanna S, Roy S. Tocotrienols: vitamin E beyond tocopherols. Life Sci 2006; 78:2088‑2098. 66. Zingg JM. Vitamin E: an overview of major research directions. Mol Aspects Med 2007; 28 (5‑6):400‑422. 67. Saldeen K, Saldeen T. Importance of tocopherols beyond α‑tocopherol: evidence from animal and hu‑ man studies. Nutr Res 2005; 25:877‑889. 68. heriault A, Chao JT, Wang Q et al. Tocotrienol: a review of its therapeutic potential. Clin Biochem 1999; 32(5):309‑319. 69. Kline K, Lawson KA, Yu W et al. Vitamin E and breast cancer prevention: current status and future potential. J Mammary Gland Biol Neoplasia 2003; 8(1):91‑102. 70. Tucker JM, Townsend DM. Alpha‑tocopherol: roles in prevention and therapy of human disease. Biomed Pharmacother 2005; 59:380‑387. 71. Reiter E, Jiang Q, Christen S. Anti‑inlammatory properties of α‑ and γ‑tocopherol. Mol Aspects Med 2007; 28(5‑6):668‑691. 72. Lapointe A, Couillard C, Lemieux S. Efects of dietary factors on oxidation of low‑density lipoprotein particles. J Nutr Biochem 2006; 17:645‑658. 73. Azzi A, Gysin R, Kempná P et al. he role of α‑tocopherol in preventing disease: from epidemiology to molecular events. Mol Aspects Med 2003; 24:325‑336. 74. Crowell PL. Monoterpenes in breast cancer chemoprevention. Breast Cancer Res Treat 1997; 46:191‑197. 75. Vigushin DM, Poon GK, Boddy A et al. Phase I and pharmacokinetic study of D‑limonene in patients with advanced cancer. Cancer Chemother Pharmacol 1998; 42:111‑117. 76. Merle H, Moro M, Amparo Blázquez M et al. Taxonomical contribution of essential oils in mandarins cultivars. Biochem Syst Ecol 2004; 32:491‑497. 77. Flamini G, Tebano M, Cioni PL. Volatiles emission patterns of diferent plant organs and pollen of citrus limon. Anal Chim Acta 2007; 589:120‑124. 78. Tirillini B, Pellegrino R, Pagiotti R et al. Volatile compounds in diferent cultivars of Apium graveolens L. Ital J Food Sci. 2004; 4(16):477‑482. 79. Ferreira D, Marais JPJ, Slade D. Phytochemistry of the mopane, colophospermum mopane. Phytochem‑ istry 2003; 64:31‑51. 80. Friedman MI, Preti G, Deems RO et al. Limonene in expired lung air of patients with liver disease. Dig Dis Sci 1994; 39(8):1672‑1676. 81. Corzo‑Martínez M, Corzo N, Villamiel M. Biological properties of onions and garlic. Trends Food Sci Technol 2007; 18:609‑625. 82. Amagase H. Clarifying the real bioactive constituents of garlic. J Nutr 2006; 136:716S‑725S. 83. Wu CC, Chung JG, Tsai SJ et al. Diferential efects of allyl sulides from garlic essential oil on cell cycle regulation in human liver tumor cells. Food Chem Toxicol 2004; 42:1937‑1947. 84. Sato T, Miyata G. he Nutraceutical Beneit, part IV, Garlic Nutrition 2000; 16(9):787‑788. 85. Jakubowski H. On the Health Beneits of Allium sp. Nutrition 2003; 19(2):167‑168. 86. Anthony JP, Fyfe L, Smith H. Plant active components—a resource for antiparasitic agents? Trends Parasitol 2005; 21(10):299‑322. 87. Halkier BA, Gershenzon J. Biology and biochemistry of glucosinolates. Annu Rev Plant Biol 2006; 57:303‑333. 88. Johnson IT. Glucosinolates in the human diet. Bioavailability and implication for health. Phytochemistry Reviews 2002; 1:183‑188. 89. Surh YJ, Ahn SH, Kim KCh et al. Metabolism of capsaicinoids: evidence for aliphatic hydroxylation and its pharmacological implications. Life Sci 1995; 56(16):305‑311. 90. Surh YJ, Lee SS. Capsaicin in hot chili pepper: carcinogen, cocarcinogen or anticarcinogen? Fd Chem Toxic 1996; 34(3):313‑316. 91. Surh YJ, Lee SS. Capsaicin, a double‑edged sword: toxicity, metabolism and chemopreventive potential. Life Sci 1995; 56(22):1845‑1855. 92. Andlauer W, Fürst P. Nutraceuticals: a piece of history, present status and outlook. Food Res Int 2002; 35(2‑3):171‑176. 93. Menrad K. Market and marketing of functional food in Europe. J Food Eng 2002; 56:181‑188. ©2010 Copyright Landes Bioscience. Not for Distribution. 98

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