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Journal of Dietary Supplements
ISSN: 1939-0211 (Print) 1939-022X (Online) Journal homepage: http://www.tandfonline.com/loi/ijds20
Functional Foods and Nutraceuticals as
Dietary Intervention in Chronic Diseases; Novel
Perspectives for Health Promotion and Disease
Prevention
Stephen Adeniyi Adefegha
To cite this article: Stephen Adeniyi Adefegha (2017): Functional Foods and Nutraceuticals as
Dietary Intervention in Chronic Diseases; Novel Perspectives for Health Promotion and Disease
Prevention, Journal of Dietary Supplements, DOI: 10.1080/19390211.2017.1401573
To link to this article: https://doi.org/10.1080/19390211.2017.1401573
Published online: 27 Dec 2017.
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JOURNAL OF DIETARY SUPPLEMENTS
https://doi.org/./..
REVIEWS
Functional Foods and Nutraceuticals as Dietary Intervention in
Chronic Diseases; Novel Perspectives for Health Promotion and
Disease Prevention
Stephen Adeniyi Adefegha, BSc, MSc, PhD
Functional Foods and Nutraceuticals Unit, Department of Biochemistry, School of Sciences, Federal University of
Technology, Akure, Ondo State, Nigeria
KEYWORDS
chronic diseases; disease
prevention; functional foods;
health promotion;
nutraceuticals
ABSTRACT
Functional foods describe the importance of foods in promoting health
and preventing diseases aside their primary role of providing the
body with the required amount of essential nutrients such as proteins,
carbohydrates, vitamins, fats, and oils needed for its healthy survival.
This review explains the interaction of functional food bioactive com-
pounds including polyphenols (phenolic acids [hydroxybenzoic acids
and hydroxycinnamic acids], flavonoids [flavonols, flavones, flavanols,
flavanones, isoflavones, proanthocyanidins], stilbenes, and lignans),
terpenoids, carotenoids, alkaloids, omega-3 and polyunsaturated fatty
acids, among others with critical enzymes (α- amylase, α- glucosidase,
angiotensin-I converting enzyme [ACE], acetylcholinesterase [AChE],
and arginase) linked to some degenerative diseases (type-2 diabetes,
cardiovascular diseases [hypertension], neurodegenerative diseases
[Alzheimer’s disease] and erectile dysfunction). Different functional
food bioactive compounds may synergistically/additively confer an
overwhelming protection against these degenerative diseases by mod-
ulating/altering the activities of these critical enzymes of physiological
importance.
Introduction
Nutrition, coined from the Latin word nutriremeaning “to nourish,” is defined as the sum of
all processes involved in how organisms obtain nutrients, metabolize them, and use them to
support all of life’s processes. It includes food intake, absorption, assimilation, biosynthesis,
catabolism, and excretion (Adams et al., 2006). Of great importance to nutrition is the balance
between the nutritional and antinutritional factors in food (Bora, 2014). The major nutrients
present in edible plants are carbohydrates (which could be in the between form of starch
and free sugars), proteins, fats and oils, minerals, vitamins, and organic acids. Antinutrients
include phytic acids or phytate, tannic acid/tannin, cyanide and trypsin inhibitors (Soetan
and Oyewole, 2009). Recent research has shown that antioxidant-rich diets protect humans
against degenerative diseases such as cancer, diabetes, cardiovascular and neurodegenerative
diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and amyotrophic
CONTACT StephenAdeniyi Adefegha saadefegha@futa.edu.ng Functional Foods andNutraceuticalsUnit, Department
of Biochemistry, School of Sciences, Federal University of Technology, P. M. B. , Akure, Ondo State, , Nigeria.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ijds.
©  Taylor & Francis Group, LLC
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2 S. A. ADEFEGHA
lateral sclerosis caused by free radicals (Uttara et al., 2009; Saikat and Chakraborty, 2011).
Free radicals are highly reactive chemical substances such as superoxide, hydroxyl radical,
singlet oxygen, and so on that are capable of attacking the healthy cells of the body, causing
them to lose their structure and function (Kumar, 2011). Antioxidants are capable of stabiliz-
ing, or deactivating, free radicals before they attack cells, chelating metal catalysts, activating
antioxidant enzymes, reducing α-tocopherol radicals, and inhibiting oxidases (Adefegha and
Oboh, 2013; Sisein, 2014). They are critical for maintaining optimal cellular and systemic
health and well-being, as they are believed to be the first line of defense against free radical
damage (Nagarajappa et al., 2015; Shukla et al., 2016).
Pollution, cigarette smoke, stress, illness, and even exercise can increase free radical expo-
sure; hence, the need for antioxidants becomesmore critical (Rakesh et al., 2010; Shukla et al.,
2016). Regular consumption of foods that are naturally high in antioxidants such as fruits,
vegetables, whole grains, nuts and seeds, legumes, and herbal seasonings help improve body
antioxidant status thereby fighting against degenerative diseases (Adefegha and Oboh, 2013).
Thus, there is a need to shift from the nutritional aspect of food to functional foods, nutraceu-
ticals, and dietary supplements as forms of dietary remedy in various human pathologies
(Olaiya et al., 2016). Research has shown that some of these foods, as part of an overall
healthful diet, can delay the onset of many age-related diseases as a result of high levels of
antioxidants and other phytonutrients. Phytonutrients, otherwise known as phytochemicals,
are compounds found in plants. They play a crucial role in protecting plants from predators
and keeping the plant healthy.
Phytonutrients such as vitamins, minerals, carotenoids, and polyphenols are present in
different forms of foods, and studies have shown that they could exert antioxidant proper-
ties (Adefegha and Oboh, 2013; Scalbert et al., 2005). Some of these antioxidants are natural
colorants, characterized by their distinctive colors, such as the deep red color of cherries, the
red color in tomatoes, the orange color in carrots, and the yellow color of corn, mangos, and
saffron. Other well-known antioxidants include vitamins A, C, and E, beta carotene, and sele-
nium. Sources of vitamin C include citrus fruits and their juices, berries, dark green vegeta-
bles (spinach, asparagus, green peppers, brussels sprouts, broccoli, watercress, other greens),
spices, red and yellow peppers, tomatoes and tomato juice, pineapple, cantaloupe, mango,
papaya, and guava (Yang et al., 2004; Adom et al., 2005; Liu et al., 2005; Adefegha and Oboh,
2011, 2012a, 2012b, 2013). Sources of vitamin E include vegetable oils such as olive, soybean,
corn, cottonseed, and safflower, nuts and nut butters, seeds, whole grains, wheat, wheat germ,
brown rice, oatmeal, soybeans, sweet potatoes, legumes (beans, lentils, split peas), and dark
leafy green vegetables. Brazil nuts, brewer’s yeast, oatmeal, brown rice, chicken, eggs, dairy
products, garlic, molasses, onions, salmon, seafood, tuna, wheat germ, whole grains, andmost
vegetables are good sources of selenium (Suvetha and Shankar, 2014). ß-carotene is available
in a variety of dark orange, red, yellow, and green vegetables and fruits such as broccoli, kale,
spinach, sweet potatoes, apples, carrots, red and yellow peppers, apricots, cantaloupes, and
mangoes (Sun et al., 2002; Underwood,2000; Tang et al., 2012; Adom et al., 2005). Antioxi-
dants protect by donating an electron of their own, thereby neutralizing free radicals, and help
prevent cumulative damage to body cells and tissues (Singh et al., 2013; Alia et al., 2003).Much
of the total antioxidant activity of fruits and vegetables depends on their vitamin C content as
well as their phenolic content (Podsedek, 2007; Beh et al., 2012). Phenols and flavonoids pro-
tect body cells against the damage caused by oxygen that is released as a by-product of energy
metabolism (antioxidation) (Stratil et al., 2008). Natural polyphenols can remove free radi-
cals, chelate metal catalysts, activate antioxidant enzymes, reduce α-tocopherol radicals, and
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JOURNAL OF DIETARY SUPPLEMENTS 3
Figure . Some foods that display health-promoting and disease-preventing effects and their nutritional
roles (functional foods).
inhibit oxidases; they exert their beneficial health effects by their antioxidant activity (Khun-
drakpam and Sivakami, 2016; Adetuyi and Ibrahim, 2014; Adefegha and Oboh, 2013). Plant-
derived foods contain natural antioxidants that can scavenge free radicals (Rakesh et al., 2010;
Lobo et al., 2010; Mahantesh et al., 2012).
Functional food bioactive compounds
Plant foods such as vegetables, fruits, cereals, spices, and legumes (Figure 1) have been
reported to play crucial roles in the protection against and prevention of various chronic
diseases such as diabetes, obesity, cancer, erectile dysfunction, cardiovascular diseases, and
Alzheimer’s disease by modulating several metabolic processes (Oboh and Akindahunsi,
2004; Oboh, 2005; Adefegha and Oboh, 2012a, 2012b, 2013; Mythri and Bharath, 2012;
Kennedy, 2014; Adefegha et al., 2014, 2016a, 2016b, 2016c; Adefegha et al., 2017a, 2017b;
Adefegha et al., 2017c; Gupta and Prakash, 2015).
Functional food bioactive compounds are extranutritional constituents that occur nat-
urally in plants and can exert biological effect (Ghanbari et al., 2012; Lobo et al., 2010).
The intake of natural dietary bioactive compounds is associated with low incidence of these
chronic diseases (Lima et al., 2014; Zhang et al., 2015). Epidemiological, clinical, and bio-
chemical studies have revealed that these bioactive compounds through differentmechanisms
have various activities in the human body such as antioxidant, antidiabetic, antihypertensive,
anti-Alzhemic, Antiproliferative, and antimicrobial activities (Gupta and Prakash, 2015; Chu
et al., 2002; Sun et al., 2002; Oboh et al., 2013, 2015a; Adefegha et al., 2015a, 2016d). These
unique properties have been linked to some bioactive food components/compounds that can
promote health and prevent diseases (Liu, 2003; Hasler, 1998).
The biological effects of these chemicals present in food and food-related products may
be associated with their affinity for certain proteins, via inhibition or modulation of some
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4 S. A. ADEFEGHA
Figure . Functional food bioactive components/compounds.
enzymes, and their antioxidant activity (Pandey and Rizvi, 2009; Pang et al., 2012). More-
over, the antioxidant activities of bioactive compounds from plant foods have been widely
studied because of their negative correlation with oxidative stress–mediated diseases (Gupta
and Prakash, 2015; Cencic and Chingwaru, 2010). As shown in Figure 2, more than 8,000
bioactive compounds, including polyphenols, terpenoids, carotenoids, alkaloids, omega-3,
and polyunsaturated fatty acids, have been identified in plants, and there are many yet to be
discovered (Saxena et al., 2013; Rao, 2003).
Phenolic compounds
Phenolic compounds are chemical compounds produced by plants (Scalbert et al., 2005).
Structurally, phenolic compounds possess one or more aromatic rings with one or more
hydroxyl groups (Ohri and Pannu, 2010). Examples of these compounds are phenolic acids,
flavonoids, anthocyanins, stilbenes, coumarins, and tannins (Cai et al., 2004). Phenolic
compounds are the products of secondary metabolism in plants (Mazid et al., 2011). They
provide essential functions in the reproduction and growth of the plants, protect them
against pathogens, parasites, predators, and UV irradiation, and contribute to their color
(Liu, 2013). Furthermore, phenolic compounds bestow flavor and various beneficial health
effects (Setyopratomo, 2014; Ayseli and Ayseli, 2016). In addition to their roles in plants,
phenolic compounds in our diet may provide additional health benefits associated with
reduced risk of developing chronic diseases (Liu, 2013; Robbins, 2003). Phenolic compounds
play a major role as antioxidants with a high capacity to scavenge free radicals, which is
dependent on their structure (Bendary et al., 2013; Rice-Evans et al., 1997). The total phenol
content of some tropical vegetables, fruits, legumes, spices, teas, pepper, roselle, and cocoa
determined in our laboratory have been reported (Oboh andAkindahunsi, 2004; Oboh, 2005;
Oboh et al., 2008, 2010a, 2010b, 2010c, 2012b; Adefegha and Oboh, 2011, 2012a, 2012b,
2013; Adefegha et al., 2014; Adefegha et al., 2015b; Adefegha et al., 2016a, 2016b, 2016c).
Previous studies have established that phenolic acids and flavonoids are the most abundant
phenolic compounds found in plants and plant-based foods (Sun et al., 2002; Chu et al., 2002;
Liu, 2004).
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JOURNAL OF DIETARY SUPPLEMENTS 5
Phenolic acids
Phenolic acids are phenolic compounds that have carboxylic acids (Saxena et al., 2012). They
are widely distributed in plants and account for about one-third of polyphenolic compounds
(Saxena et al., 2012). These bioactive compounds are characterized by their hydroxycinnamic
and hydroxybenzoic acid structures, making them compounds of great interest in biological,
clinical, medical, and chemical research (Singh et al., 2016; Ignat et al., 2011). The functions
of phenolic acid in plants are not fully understood. However, some studies have shown that
these compounds participate in nutrient uptake, protein synthesis, enzyme activity, and pho-
tosynthesis (Nour et al., 2013). Furthermore, phenolic acids have been shown to play a major
role in food quality, improving taste, color, and nutritional and antioxidant properties of foods
(Gharras, 2009). Most common forms of phenolic acids are gallic acid, chlorogenic acid, caf-
feic acid, p-coumaric acid, vanillic acid, ferullic acid, and protocatechuic acid (Robbins, 2003;
Tumbas et al., 2004; Wen et al., 2005). The concentrations of phenolic acids vary from one
plant to another as well as in different plant parts. Levels of these compounds also vary in
different stages of maturation and could be affected by growing conditions such as tempera-
ture (Yousfi et al., 2006; Ribera et al., 2010; Zheng and Wang, 2001). Many scientific reports
have revealed that phenolic acids are present in fruits, vegetables, spices, grains, coffees, teas,
and other plant-based foods (Carlsen et al., 2010; Habauzit andMorand, 2012). Their ubiqui-
tous presence in plant-based foodsmakes it possible for daily human consumption (Mendoza
et al., 2011). Clifford (1999) reported an estimate of about 25 mg/g per day of phenolic acids
consumed by humans depending on the diet taken. The metabolic fates and bioavailability of
these compounds have not been widely established. However, the fates of caffeic, ferulic, and
chlorogenic acids have been explored (Zhao and Moghadasian, 2010). The bioavailability of
these compounds in the bodywill determine their bioactivity (Habauzit and Morand, 2012).
Phenolic acids possess antioxidant activity due to the hydroxylated aromatic rings, which are
capable of donating hydrogen atoms and quenching singlet oxygen (Habauzit and Morand,
2012;Oboh et al., 2015a). Furthermore,Maggi-Capyeron et al. (2001) have reported that some
phenolic acids are capable of inhibiting transcriptional activity of AP-1, which is an activator
protein that has been linked to the control of inflammation, cell differentiation, and prolifer-
ation. Specifically, caffeic acid has been discovered to be a selective blocker of the biosynthe-
sis of leukotrienes, components involved in immunoregulation diseases, asthma, and allergic
reactions (Koshihara et al., 1984). Caffeic acid might possess antitumor activity against colon
cancer (Rao et al., 1993; Olthof et al., 2001). Caffeic acid derivatives such as dicaffeoylquinic
and dicaffeolytartaric acids have been shown to be strong inhibitors of human immunodefi-
ciency virus type 1 (HIV-1) integrase (Stojakowska et al., 2012; McDougall et al., 1998).
Flavonoids
Flavonoids are one of the largest groups of phenolic compounds in fruits, vegetables, and
other plant-based foods (Liu, 2013). They are secondary metabolites that are synthesized in
plants via the phenylpropanoid pathway (Weston and Mathesius, 2013; Schijlen et al., 2004).
Secondary metabolites have no apparent involvement in basal cellular processes such as pho-
tosynthesis, respiration, or protein and nucleic acid synthesis, processes that are the domain
of the primary metabolites (Boerjan et al., 2003; Besseau et al., 2007). Hence, the secondary
metabolites appear at first glance to be dispensable to the immediate survival of the organ-
ism. Phenylpropanoids are a diverse group of compounds derived from the carbon skeleton
of phenylalanine that are involved in plant defense, structural support, and survival (Vogt,
2010). The phenylpropanoid pathway is required for the biosynthesis of lignin and serves as a
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6 S. A. ADEFEGHA
starting point for producing many other important compounds, such as the flavonoids,
coumarins and lignans (Boerjan et al., 2003; Besseau et al., 2007; Vogt, 2010).
Structurally, flavonoids have the polyphenolic structure with the basic C6-C3-C6 struc-
tural skeleton, consisting of two aromatic C6 rings (A and B) and a heterocyclic ring (C) that
contains one oxygen atom (Hanrahan et al., 2011; Ghasemzadeh and Ghasemzadeh, 2011;
Habauzit and Morand, 2012). It has been estimated that up to about 6,000 flavonoids have
been identified and isolated, with the majority in plants (Tolonen et al., 2002; Austin and
Noel, 2003).
There are six major groups of flavonoids that have been classified by the generic struc-
ture of their heterocyclic ring C (Temidayo, 2013; Matias et al., 2016). Flavonols (which
are mainly quercetin, kaempferol, myricetin, and galangin), flavones (luteolin, apigenin, and
chrysin), flavanols (catechin, epicatechin, epigallocatechin [EGC], epicatechin gallate [ECG],
and EGC gallate [EGCG]), flavanones (naringenin, hesperitin, and eriodictyol), anthocyani-
dins (cyanidin, malvidin, peonidin, pelargonidin, and delphinidin), and isoflavonoids (genis-
tein, daidzein, glycitein, and formononetin) are common dietary flavonoids found in plant
foods (Liu, 2013; Habauzit andMorand, 2012). In nature, flavonoids are generally in the form
of conjugated glycosides or in esterified forms, but they can also occur in the form of agly-
cones (Chu et al., 2002; Sun et al., 2002; Adefegha and Oboh, 2013), which could be due to
effects of food processing (Liu, 2002). The aglycone forms of flavonoids are readily absorbed
along the gastrointestinal tract (GIT), while the glycosidesmay escape the GIT and exert their
bioavailability in the colon (Chu et al., 2002; Sun et al., 2002). There are many different gly-
cosides of flavonoids in nature because over 80 different sugars have been identified bound to
flavonoids (Hollman andArts, 2000; Liu, 2002). Red and blue colors in some fruits, vegetables,
and whole grains are rich in anthocyanidins (Liu, 2004b). Oranges and orange juice are good
sources of hesperetin and naringenin (Habauzit and Morand, 2012). The major flavonoids
in apples are quercetin, epicatechin, and cyanidin (Parker et al., 2007). There is an apprecia-
ble amount of rutin and quercetin in avocadoes, tomatoes, pineapples, guavas, African star
apples, watermelons, cashews, and soursop (Oboh et al., 2015b). There are also high levels
of luteolin in carrots, pineapples, guavas, and oranges (Silva Dias, 2014; Arabbi et al., 2004).
Dietary intake of all flavonoids has been estimated at about 100–650 mg/d (Hollman and
Katan, 1999). Hertog et al. (1993) reported the total average intake of flavonols (quercetin,
myricetin, and kaempferol) and flavones (luteolin and apigenin) was estimated at 23 mg/dl,
of which quercetin contributed about 70%, kaempferol 17%, myricetin 6%, luteolin 4%, and
apigenin 3%. Flavonoids from tea, cocoa, chocolate, fruits, vegetables, and wine have been
reported to be strong antioxidant compounds that help reduce the incidence of chronic dis-
eases such as stroke, heart failure, diabetes, and cancer (Ding et al., 2006; Erdman et al., 2007).
The antioxidant properties of flavonoids have been associated with their ability to scavenge
free radicals and inhibit the production of protein oxidation and lipid peroxidation products
(Nijveldt et al., 2001). The anticancer effects of flavonoids have been well studied (Kahali,
2014).
Alkaloids
Alkaloids are biologically active secondary metabolites that can be found in plants, animals,
and microorganisms (Demirgan et al., 2016). These compounds consist of a basic nitrogen
atom that may or may not be part of a heterocyclic ring (Dewick, 2002). They are produced
in plants via the amino acid biosynthetic pathway or transamination reaction processes, and
they are classified according to the amino acid that yields the nitrogen atom as well as the
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JOURNAL OF DIETARY SUPPLEMENTS 7
part of its skeleton for the synthesis of the alkaloid in question (Aniszewski, 2007; Richard,
2001). Alkaloids show great variety in their botanical and biochemical origin, in chemical
structure, and in pharmacological action, and this may be a major reason why they have been
used for the treatment of various diseases and are lead compounds in the manufacture of syn-
thetic drugs in the pharmaceutical industries. Previous scientific reports show that alkaloids
have various biological activities such as antitumor (Tohme, 2011; Kaur, 2015), antioxidant
and anticholinergic (Berdai et al., 2012; Adefegha et al., 2016e), diuretic (Melendez-Camargo,
et al., 2014), sympathomimetic (Simpson, 1975), antiviral (Orhana et al., 2007), antihyper-
tensive (Awaad et al., 2007), hypnoanalgesic (Hayfaa et al., 2013), antidepressant (Nesterova
et al., 2011), myorelaxant (Dzhakhangirov and Bessonova, 2002), antimicrobial (Karou et al.,
2006), antiemetic (Malhotra and Sidhu, 1956), and anti-inflammatory properties (Barbosa-
Filho et al., 2006).
Carotenoids
Carotenoids are a widespread group of naturally occurring fat-soluble pigments found in
plants and animals (Mortensen, 2006). They belong to the class of bioactive compounds
known as isoprenoid polyenes and are classified by the following characteristics: (a) vitamin
A precursors that do not pigment such as β-carotene; (b) pigments with partial vitamin A
activity such as cryptoxanthin, β-apo-8′-carotenoic acid ethyl ester; (c) non–vitamin A pre-
cursors that do not pigment or pigment poorly suchas violaxanthin and neoxanthin; and (d)
non–vitamin A precursors that pigment such as lutein and zeaxanthin (Omayma and Singab,
2013). Carotenoid is one of themost complex bioactive compounds due to its structure, which
bears multiple conjugated double bonds and cyclic end groups, which makes them capable of
forming various stereoisomers with different chemical and physical properties (Omayma and
Singab, 2013). Reports have revealed that over 700 carotenoids have been identified; however,
only 50 can be found in the human diet and are absorbed and metabolized effectively (Grune
et al., 2010; Eroglu and Harrison et al., 2013). Examples of these metabolizable carotenoids
often made available to the blood include lycopene, xanthin, beta-carotene, alpha-carotene,
lutein, zeaxanthin, beta-cryptoxanthin. These carotenoids can also be found in plant foods
such as vegetables, tomatoes, and watermelon (Yeum and Russell, 2002; Roodenburg et al.,
2000). Epidemiological studies indicate that a high intake of carotenoids is beneficial to human
health and is due to their antioxidant activities (Miller et al., 1996)
Roles of functional food bioactive compounds on critical enzymes linked to
degenerative diseases
Degenerative/chronic diseases such as cancer, platelet aggregation, thrombosis, sexual dys-
function, arthritis, diabetes, obesity, stroke, and respiratory, cardiovascular, and neurodegen-
erative diseases (Figure 3) are among the leading causes of morbidity and mortality globally
(WHO, 2002). Degenerative diseases have a high significant impact on health, quality of life,
and life expectancy (Somrongthong et al., 2016).
These diseases are rapidly increasing worldwide and have contributed approximately 60%
of the 56.5 million total reported deaths in the world and approximately 46% of the global
burden of disease (Sofi et al., 2013; WHO, 2002). About half of the total deaths arising from
chronic diseases are associated with cardiovascular diseases and a high percentage can also
be attributed to obesity and diabetes, which now occur early in life (Sofi et al., 2013). Cardio-
vascular disease (CVD) and cancer are the top two leading causes of death in many countries
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8 S. A. ADEFEGHA
Figure . Some degenerative/chronic diseases.
of the world (Twombly, 2005; Moyad, 2005). It has been projected that by 2020 chronic dis-
eases will account for almost three-quarters of all deaths worldwide and that 71% of deaths
due to ischemic heart disease (IHD), 75% of deaths due to stroke, and 70% of deaths due to
diabetes will occur in developing countries (WHO, 1998). Epidemiological and experimen-
tal studies have shown that high consumption of fruits, vegetables, spices, beverages, legumes,
whole grains, and fish, a high fiber diet, and other food-related products can be strongly linked
to reduced risk of chronic diseases such as CVD, cancer, diabetes, Alzheimer’s disease, sex-
ual dysfunction, cataracts, and age-related functional decline (Block et al., 1992; Hung et al.,
2004; Webb, 2013), which can be attributed to the bioactive compounds present in the foods
(Hooper and Cassidy, 2006; Liu, 2013; Kris-Etherton et al., 2002; Ros and Hu, 2013).
Foods with medicinal components required for human health promotion and disease pre-
vention (Figure 4), in addition to their nutritional significance, can be regarded as functional
foods (Cencic and Chingwaru, 2010; Shahidi, 2012). These foodsmay have health-promoting
Figure . Biological properties of functional food bioactive components/compounds.
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JOURNAL OF DIETARY SUPPLEMENTS 9
and disease-preventing effects against several chronic diseases and disorders (Das et al., 2012
Shahidi, 2012). Several agricultural and industrial residues represent a great alternative as raw
material of bioactive compound production and have been reported to be sources of poten-
tially safe natural additiveswith different biological activities for the food industry (Kalra et al.,
2014; Teixeira et al., 2014). Furthermore, plant extracts containing bioactive compounds can
be used as functional food ingredients and for production of drugs in the food and pharma-
ceutical industries (Helkar et al., 2016; Bitencourt et al., 2014). In recent times, more than 80%
of functional food bioactive compounds and more than 30% of drugs were produced from
bioactive natural products (Qilong, 2013). The bioactive compounds are produced as sec-
ondary metabolites, which are substances that have bioactivity in cells and different organs
of the body and are referred to as phytochemicals (Qilong, 2013; Azmir et al., 2013). Plant
extracts containing bioactive compounds can be used as functional food ingredients or for
production of drugs for the treatment and/or management of various degenerative diseases
(Nirmala et al., 2014; Bitencourt et al., 2014; Nasri et al., 2014).
Diabetesmellitus
Diabetes mellitus is a chronicmetabolic disease associated with increase in blood glucose that
is due to insufficient or inefficient insulin secretion, with alterations in carbohydrate, protein,
and lipid metabolism (Shobana et al., 2009; Awasthi et al., 2016; American Diabetes Associa-
tion, 2009). Type 2 diabetes is the non–insulin dependent type of diabetes and the most com-
mon form of this chronic disease (American Diabetes Association, 2009). Studies have shown
that only 10% of people who have diabetes mellitus have the insulin-dependent diabetes,
which is also known as type 1 diabetes (Brownlee and Cerami, 1981; Niedowicz and Daleke,
2005). Hyperglycemia is caused by defects or alterations in either the secretion or action of
insulin (Ozougwu et al., 2013). Previous reports have shown that increased oxidative stress
plays a major role in the early onset and progression of diabetes (Shradha and Sisodia, 2010;
Martinez et al., 2005). Oxidative stress could occur via peroxidation of cellular organelles, β-
cell apoptotic pathways activation oxidative damage to pancreatic β-cells since the pancreas
has been known to be susceptible to free radical attack due to its low antioxidant capacity
(Valko et al., 2007; Henriksen et al., 2010). β-cell dysfunction can also be induced by long-
term exposure to high levels of glucose, free fatty acids, or the combination of both (Evans
et al., 2003). In diabetic conditions, low levels of glucose in the muscle and adipose tissue can
cause extracellular hyperglycemia, which can lead to tissue damage and diabetic complica-
tions such as heart disease, artherosclerosis, cataract formation, neurodegenerative diseases,
and diabetic retinopathy (Brownlee andCerami, 1981). In this same condition, hyperglycemia
can cause the development of diabetic complications by stimulating the generation of free
radicals via different pathways andmechanisms involving oxidative phosphorylation, glucose
autooxidation, NAD(P)H oxidase, lipooxygenase, cytochrome P450 monooxygenases, and
nitric oxide synthase (NOS) (Valko et al., 2007; Matough et al., 2012). It is worthy to note that
the different pathways leading to the incidence and pathogenesis of diabetes mellitus could
represent therapeutic targets for functional food bioactive compounds (Valko et al., 2007;
Henriksen et al., 2010; Adefegha and Oboh, 2013). A good approach to reduce postprandial
hyperglycemia involves prevention of carbohydrate absorption after a meal (Oboh et al.,
2010c, Adefegha and Oboh, 2011; Adefegha and Oboh, 2012b). Carbohydrate-hydrolyzing
enzymes such asα-amylase andα-glucosidase catalyze the breakdownof complex polysachar-
rides and oligosacharrides to glucose, which is absorbed into the intestinal epitheliumand
finally goes into blood circulation (Kwon et al., 2007; Oboh et al., 2010c). Inhibition of these
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10 S. A. ADEFEGHA
enzymes by plant phenolics will delay the absorption of glucose in the blood and reduce
postprandial hyperglycemia (Chipiti et al., 2015). Some phenolic compounds from plant
foods and food-related products have been reported to be good inhibitors of α-amylase and
α-glucosidase activities (Nair et al., 2013). Numerous studies have shown that polyphenols
are potent natural inhibitors of α-amylase and α-glucosidase activity. Ademiluyi and Oboh
(2011) reported that soybean phenolic-rich extracts inhibited key enzymes (α-amylase and
α-glucosidase) linked to diabetes. Furthermore, plant foods and food-related products such
as bitter leaf (Vernonia amygdalinaDel), Ethiopian pepper (Xylopia aethiopica), calabash nut-
meg (Monodoramyristica), clove bud (Syzygium aromaticum), black pepper (Piper guineense),
bastered melegueta (Aframomum danielli), and alligator pepper (Aframomum melegueta),
ginger (Zingiber officinale), shaddock fruit and peels (Citrus maxima), and so on, have been
reported to have strong antidiabetic activity. The antidiabetic properties of some of these plant
foods were reported to be associated with their phenolic constituents as well as other bioactive
components that may have synergistically or additively interacted to elicit the observed bio-
logical effects (Oboh et al., 2010c; Oboh and Ademosun, 2011; Adefegha and Oboh, 2012b;
Ademiluyi andOboh, 2013; Oboh et al., 2015b; Adefegha et al., 2016a; Adefegha et al., 2017a).
Enzyme inhibitory activities of plant foods have been attributedmainly to their phenol con-
tent/constituents as well as their distribution in plant parts (Shori and Baba, 2013; Kwon et al.,
2007; Kwon et al., 2008). Previous experimental investigations with clonal herbal extracts have
proposed that the antioxidant activity of phenolicsmay affect the five disulfide bridges located
on the external surface of amylase and therein induce inhibition by modulating changes in
the structure of the enzyme (McCue et al., 2004). Wang et al. (2013) have also shown that
flavonols and their glycosides are potent glucosidase inhibitors. Structure-activity relation-
ship has shown that flavonoids with more hydroxyl groups have higher inhibitory effects on
α-amylase activity (Cao and Chen, 2017). Similarly, Taktaz (2014) attributed the inhibitory
effects of quercetin, daidzein, and myricetin on α-amylase activity to the number of hydroxyl
groups on the B ring and the formation of hydrogen bonds between these hydroxyl groups
and amino acid residues on the active site of the enzyme. Some reports have also revealed
that phenolic compounds with unsaturated 2,3-bond in conjugation with a 4-carbonyl group
have been associated with stronger enzyme inhibition (Guerrero et al., 2012). In addition,
galloylated catechin derivatives, catechol-type catechin derivatives, catechin derivatives with
2,3-trans structure, and ellagitannins with β-galloyl groups at glucose C-1 positions have dis-
played high inhibitory effects on α-amylase activity (Xiao et al., 2013). Green tea has been
reported to be rich in catechin and its derivatives, which are potential antidiabetic agents
(Pandey and Rizvi, 2009; Chacko et al., 2010). Moreover, catechin, epicatechin, and procyani-
din isolated from Toona sinensis have been reported to have high α-glucosidase inhibitory
activity (Zhao et al., 2009). Akkarachiyasit et al. (2011) reported that the inhibition of pancre-
atic α-amylase by some flavonoids and flavonesmay be attributed to a covalent and/or nonco-
valent interactionwith the polar groups such as amide, guanidine, amino, and carboxyl groups
at the active site of the enzyme. Interestingly, cyanidin and its glycosides can inhibit pancre-
atic α-amylase and intestinal α-glucosidase activity. Structure-activity relationship revealed
that the presence of glucose moiety at the 3-O-position of cyanidin markedly increased the
inhibition of pancreatic α-amylase (Adisakwattana et al., 2011; Akkarachiyasit et al., 2011).
Other flavonoids such as xanthones, quercetin, genistein, apigenin, luteolin, isoquercitirin,
and vitevin isorhamnetin-3-O-rutinoside (Ichiki et al., 2007; Kato et al., 2008;Watanabe et al.,
1997; Kang et al., 2010; Shibano et al., 2008) have been shown to have high α-glucosidase
inhibitory activity. In addition, in silico docking analysis has shown that quercetin, myricetin,
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JOURNAL OF DIETARY SUPPLEMENTS 11
and rutin have stronger α-glucosidase activities than acarbose (Jo et al., 2009; Hyun et al.,
2014).
Phenolic acids such as gallic, caffeic, chlorogenic, and rosmarinic acids have been shown
to have strong α-glucosidase inhibitory activity in vitro and in vivo. However, the inhibitory
effects of these phenolic acidswere lower than that of acarbose (Seo et al., 2007; Adefegha et al.,
2015a; Oboh et al., 2015a). Furthermore, sarcodonins and sacrcoviolins isolated from the
edible mushroom Sarcodon leucopus showed strong α-glucosidase activity. Their inhibitory
activities were attributed to the number of hydroxyl groups present on the structure (Wu et al.,
2013). These hydroxyl groups have been shown to contribute immensely to the inhibition of
the enzyme (Ma et al., 2014). In addition, antidiabetic activity of stilbene dimmers such as
cassigarol, scirpusin, and scirpusin that were isolated from the rhizomes of Cyperus rotundus
L. (Cyperaceae) have been investigated. The study showed that the three dimers had higher
α-glucosidase inhibitory activity than acarbose (Tran et al., 2014). Phenolic compounds (hip-
pomaninA, geninD, and phloridzin) isolated from the flowers of pomegranate have also been
shown to have higher α-glucosidase inhibitory activity than acarbose (Yuan et al., 2013).
The enzyme inhibitory effects of some alkaloids have been reported and documented in
the literature. Piperumbellactam B and piperumbellactam C isolated from branches of Piper
umbellatum showed moderate α-glucosidase inhibitory activity, while vasicine and vasicinol
have been shown to have high sucrase activity (Maeda et al., 1985; Kumar et al., 2011). More-
over, the maltase inhibitory activity of 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid,
and 4,5-dicaffeoylquinic acid have been attributed to the number of caffeoyl groups on the
structure (Gao et al., 2008a, 2008b). Fujii et al. (2009) reported that conophylline, a vinca
alkaloid from Ervatamia microphylla, decreased blood glucose level and increased plasma
insulin level in streptozotocin-induced diabetic rats by inducing the differentiation of pan-
creatic precursor cells to insulin-producing cells. Oxidative stress via free radical genera-
tion has also been implicated in the development of diabetic complications, insulin resis-
tance, and β-cell dysfunction (Bensellam et al., 2012; Ullah et al., 2016). The islet β-cells
are susceptible to oxidative damage by reactive oxygen species (ROS) due to low antioxidant
enzymes, which can lead to dysregulation of insulin secretion (Akbar et al., 2011; Newsholme
et al., 2012). Dysregulation of insulin secretion could also be influenced by protein tyrosine
phosphatase-1B (PTP-1B), a negative regulator of the insulin signaling pathway that has been
implicated in the progression of diabetes mellitus (Dadke and Chernoff, 2002; Patel et al.,
2014). Some alkaloids such as vindoline, vindolidine, vindolicine, and vindolinine have been
reported to inhibit PTP-1B, thereby ameliorating insulin resistance and enhancing cellular
glucose uptake activity (Tiong et al., 2013). Cooper etal. (2003) reported that berberine from
Tinospora cordifolia exerts its antihyperglycemic effect via the inhibition of disaccharidases,
thereby retarding the absorption of glucose across the intestinal epithelium in Caco-2 cells
(Singh et al., 2003; Pan et al., 2003). The hypoglycemic activity of catharantine, vindoline, vin-
dolinine, and arecoline have also been reported (Chempakam, 1993). Similarly, trigonelline
and 4-hydroxyisoleucine isolated from Trigonella foenum graecum seeds have been reported
to show hypoglycemic activity in alloxan-induced diabetic rats (Mowla et al., 2009). These
two compounds showed glucose-lowering effect in hyperglycemic condition (Neelakantan
et al., 2014). Moreover, oral administration of 4-hydroxyisoleucine to alloxan-induced dia-
betic rats brought about the regeneration of beta cells in the pancreas compared to the con-
trol rats, which had damaged cells (Shah et al., 2006). Previous work on natural antidia-
betic agents has shown that β-carboline alkaloids have antihyperglycemic activity (Osigwe
et al., 2015). Harmane, norharmane, and pinoline, which are members of the β-carbolines,
are capable of increasing insulin secretion in human islets of Langerhans (Nandkarni, 1992;
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12 S. A. ADEFEGHA
Cooper et al., 2003). Triterpenoids are known to be potent antihyperglycemic agents. Many
studies have revealed the andiabetic activity of triterpenoids and their glycosides (Tan
et al., 2008). The hypoglycemic effects of triterpenoids and their glycosides such as 5-β ,19-
epoxy-3-β ,25-dihydroxycucurbita 6,23-(E)-diene,3-β ,7-β ,25-trihydroxycucurbita-5,23-(E)-
dien-19-al,3b-Acetoxy-16b-hydroxybetulinicacid, betavulgaroside, and boussingoside have
also been reported (Rao and Gurfinkel, 2000; Yoshikawa et al., 1994; Yoshikawa et al.,
1995). The hypoglycemic effect of steroidal glycosides pseudoprototimosaponin and pro-
totimosaponin isolated from the rhizomes of Anemarrhena asphodeloide in streptozotocin-
induced diabetic rats was linked to the inhibition of gluconeogenesis and/or glycogenoly-
sis (Narender et al., 2011; Nakasima et al., 1993). Charantin, a steroidal saponin present in
Momordica charantia, elicited its antidiabetic effects by inducing the release of insulin and
inhibiting the absorption of glucose in the bloodstream (Ng et al., 1986; Saifi et al., 2013).
The inhibition of aldose reductase is another relevant therapeutic approach for the man-
agement of diabetes (Tang et al., 2012). Aldoreductase catalyzes the reduction of glucose to
sorbitol via polyol pathway (Tang et al., 2012; Dunlop, 2000). Hyperglycemia may influence
high levels of glucose into the polyol pathway, thereby leading to the accumulation of sor-
bitol (Kador et al., 1985; Yabe-Nishimura, 1998). Moreover, accumulation of sorbitol has been
implicated in the development of diabetic complications such as neuropathy, nephropathy,
retinopathy, and cardiovascular diseases (Engerman and Kern, 1984; Xiao et al., 2015). Some
natural bioactive compounds have been shown to be potent inhibitors of aldose reductase.
Over the years, flavonoids and their derivatives (Matsuda et al., 2002; Enomoto et al., 2004;
Liu et al. 2007) have gained the interest of researchers as aldose reductase inhibitors. Recent
reports have revealed that the hydroxylation, glycosylation, and hydrogenation of the C2 =
C3 double bond in the flavonoid structure are responsible for their inhibitory effects on aldose
reductase activity (Scotti et al., 2011). Polyphenolic compounds from green tea leaves are also
potent inhibitors of aldose reductase (Liu et al., 2006). Themajor polyphenols in green tea are
epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), epigallocatechin gallate
(EGCG), and gallocatechin gallate (GCG) (Du et al., 2012). However, Matsui et al., (2007)
and Kamiyama et al. (2010) reported that galloylated catechins have higher inhibitory effects
than nongalloylated catechins. The higher inhibitory effects were attributed to the glycosy-
lation of the catechins (Plumb et al., 1998). Phenolic compounds such as hispidin, hispolon,
and inotilone isolated from ethanol extract of Phellinus merrillii are also strong inhibitors of
aldose reductase (Huang et al., 2011). Phenolic acids such as caffeic acid, chlorogenic acid,
gallic acid, and caffeoylquinic acid, and p-coumaric acids identified in coffee beans have been
reported to be potent inhibitors of aldose reductase (Oksana et al., 2002). In another study,
gallic acid and protocatechuic, p-hydroxy benzoic, p-coumaric, vanillic, syringic, ferulic, and
trans-cinnamic acids from Eleusine coracana were shown to inhibit aldose reductase activity
(Chethan et al., 2008). The inhibitory effects of Paulownia coreana seeds on aldose reduc-
tase activity have also been reported (Kim et al., 2011). The inhibitory effects were attributed
to phenylpropanoids such as verbascoside, isoverbascoside, and isocampneoside, which were
identified in the seeds (Kim et al., 2010). Polydatin, resveratrol, and its derivatives, naturally
known as stilbenes, are important polyphenols present in plant foods that are also potent
aldose reductase inhibitors (Wang et al., 2010; Glauert et al., 2010; Cottart et al., 2010). Aldose
reductase inhibitory activity of these bioactive compounds has been linked to the hydro-
genation of the α = β double bond and glycosylation on C-5 position of the stilbene struc-
ture (Matsuda et al., 2002). A friedelane-type triterpene, kotalagenin 16-acetate, maytenfolic
acid, 3β ,22α-Dihydroxyolean-12- en-29-oic acid, and Salacinol isolated from the roots of
Salacia oblonga and steroidal saponins were isolated from the fruiting bodies of Ganoderma
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JOURNAL OF DIETARY SUPPLEMENTS 13
Figure. The renin-angiotensin-aldosterone systemwithpossible therapeutic site for functional foodbioac-
tive components/compounds.
applanatum, which have been discovered to be the bioactive components responsible for the
inhibition of aldose reductase in rat lens (Matsuda et al., 1999; Lee et al., 2005). Essential oils
from clove buds and Ethiopian pepper were reported to inhibit α-amylase and α-glucosidase
activities in vitro (Adefegha et al., 2016e).
Cardiovascular diseases
Cardiovascular disease (CVD) is a complex and multifactorial disease and is characterized
by multiple factors (Rahman and Lowe, 2006). Epidemiological studies have shown that
prevalence of CVD is on the increase. CVD is the major cause of death in both developing
and developed countries (Reddy and Yusuf, 1998; Bernard et al., 2010). It is characterized by
different risk factors such as family history, ethnicity, age, unhealthy diets, high blood pressure
(BP), obesity, type 2 diabetes (T2D), elevated serum lipids (cholesterol and triglycerides),
increased plasma fibrinogen and coagulation factors, increased platelet activation, alterations
in glucose metabolism, smoking, and oxidative stress (WHO, 2002). On the other hand,
hypertension is a common cardiovascular disease that has become a worldwide problem.
However, there are limited comparable data on the global prevalence of hypertension; the
estimated prevalence of hypertension in different European countries appears to be about
30%–45% of the general population, with gradual increase with age. The renin-angiotensin
system (RAS) is another important enzyme involved in the regulation of blood pressure,
water and salt balance, and pathophysiology of cardiovascular and renal diseases (Volpe et al.,
2002; Harrison-Bernard, 2009). Angiotensin I, released from angiotensinogen by renin, is
acted upon by angiotensin I converting enzyme (ACE)to produce a potent vasoconstrictor,
angiotensin II (Figure 5) (Brown and Vaughan, 1998). Thus, ACE inhibition is regarded as a
vital therapeutic strategy in the treatment and management of hypertension in both diabetic
and nondiabetic patients (Gupta and Guptha, 2010). The renin-angiotensin-aldosterone
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14 S. A. ADEFEGHA
system (RAAS) is a hormonal cascade that functions in the homeostatic control of arterial
pressure, tissue perfusion, and extracellular volume (Figure 5) (Atlas, 2007). Dysregulation of
the RAAS plays an important role in the pathogenesis of cardiovascular and renal disorders
(Ma et al., 2010; Atlas, 2007). Renin activates the release of angiotensin I from angiotensino-
gen, which is subsequently cleaved by ACE for the production of angiotensin II (a potent
vasoconstrictor) (Figure 5) (Sparks et al., 2014). ACE inhibitors (ACEIs) competitively block
the action of ACE and thus the conversion of angiotensin I (Ang I) to angiotensin II (Ang
II), thereby reducing circulating and local levels of Ang II (Santos and Silva, 2014). ACEIs
also decrease aldosterone and vasopressin secretion and sympathetic nerve activity, but there
is controversy regarding their efficacy in blocking other “tissue” actions of the RAAS (Di
Raimondo et al., 2012). ACEIs are currently indicated for the treatment of hypertension,
diabetic nephropathy, and chronic heart failure, and their use has been associated with
improved survival and considerable cardiovascular and renal benefits in high-risk patients
(Sica, 2003). These remarkable benefits have been obtained even though blocking RAAS with
currently available agents may be incomplete, raising the possibility that additional therapeu-
tic modalities for RAAS blockade might help to further slow progression of cardiovascular
and renal diseases (Tomkin, 2010). Tomkin (2010) also reported that diabetes mellitus and
hypertension are interrelated diseases that may predispose an individual to atherosclerotic
cardiovascular disease. Functional foods and food products such as cocoa, coffee, and
condiments are beneficial in the prevention and treatment of hypertension and heart-related
diseases (Figure 5) (Pastor-Villaescusa et al., 2015). Moreover, the therapeutic effects exerted
by these functional foods have been attributed to their bioactive constituents (Bawa et al.,
2015). Recent investigations show that these bioactive compounds play a beneficial role by
normalizing the abnormal lipids, lipoproteins, blood pressure, and inhibition of platelet
aggregation and increasing antioxidant status (Gebhardt, 1993; Lawson, 1996; Vinson et al.,
2001; Rahman, 2003; Banerjee et al., 2003; Dhawan and Jain, 2004; Qidwai andAshfaq, 2013).
Endothelial dysfunction
Endothelial dysfunction is one of the biomarkers that contributes to the pathogenesis and
clinical expression of cardiovascular diseases such as atherosclerosis, myocardial infarc-
tion, and erectile dysfunction (Vita and Keaney, 2002; Rajendran et al., 2013). The vascular
endotheliumplays a key role in the regulation of vascular homeostasis by releasing factors that
act locally in the vessel wall and lumen, preventing adherence of leukocytes and inhibiting
expression of adhesion molecules at the endothelial surface (Ignarro et al., 1987; Gokce and
Vita, 2002; Vita, 2005; Kar et al., 2006). Endothelium-derived nitric oxide modulates vascular
homeostasis, acts as a potent vasodilator in the endothelial tissues, prevents lesion formation
and hypertrophy of the vessel wall, and exhibits anti-inflammatory, antithrombotic, and
growth-suppressing properties (Dharmashankar and Widlansky, 2010; Rajendran et al.,
2013). This shows that loss of nitric oxide (NO) due to changes in regulatory mechanism
can lead to endothelial dysfunction (Yang and Ming, 2006). Furthermore, some reports
have suggested that other pathological conditions such as dyslipidemia, hypertension,
diabetes mellitus, oxidative stress, aging, systemic inflammation, hyperhomocysteinemia,
and infectious processes can also contribute to endothelial dysfunction (Hadi et al., 2005;
Vita et al., 2005). Other risk factors that influence endothelial dysfunction include dietary,
genetic, and environmental factors. However, improving endothelial function can alleviate
some effects caused by CVDs (Balzar et al., 2008). Vita et al. (2005) reported that long- and
short-term consumption of tea tends to improve endothelial function. Some investigations
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JOURNAL OF DIETARY SUPPLEMENTS 15
also revealed that phenolic beverages can reverse endothelial dysfunction (Pandey and
Rizvi, 2009; Habauzit and Moran, 2012). A study carried out by Hogson et al. (2002) on
brachial artery flow–mediated dilation in a group of healthy patients with minimal levels of
hypercholesterolemia revealed that long-term consumption of tea by these subjects improved
flow-mediated dilation. Flow-mediated dilation improves NO production in the endothelium
(Corretti et al., 2002). Impairment of this physiological response could pose a great risk to
coronary heart diseases. Moreover, impaired physiological responses in the brachial artery
could lead to the onset of cardiovascular events in high- and low-risk patients (Gokce et al.,
2002; Modana et al., 2002; Gokce et al., 2003; Brevetti et al., 2003). Meanwhile, consumption
of tea has been linked to the production and improvement of NO bioactivity. Green tea
contains bioactive compounds such as quercetin rutin kaempferol, catechins which have
been reported to be responsible for its bioactivity (Thilakarathna and Rupasinghe, 2013).
Furthermore, flavonoid-containing beverages from grape juice also improved endothelial
function and brachial artery–mediated dilation in patients with coronary artery disease
(Stein et al., 1999; Chou et al., 2001). Beverages made with cocoa are rich in procyanidin
and can reverse endothelial dysfunction (Balzer et al., 2008). A study carried out by Heiss
et al. (2003) on patients with endothelial dysfunction–induced cardiovascular diseases
revealed high levels of flavan-3-ols in the cocoa, which brought about significant increase
in flow–mediated dilation and NO production. Phenolics from olive oil and nuts can act
on inflammation and endothelial dysfunction, thereby preventing plaque formation and
reducing the risk of atherosclerosis (Estruch et al., 2006; Dell’Agli et al., 2006; Mena et al.,
2009; Dell’Agli et al., 2010). Increase in vasoconstriction and decrease in vasodilators will lead
to decrease in endothelial-derived NO and endothelial dysfunction (Muniyappa and Sowers
2013). However, bioactive compounds with vasodilatory properties will prevent or reverse
endothelial dysfunction (Balzer et al., 2008; Pandey and Rizvi, 2009). Some polyphenols have
been reported to possess vasodilatory properties (Yao et al., 2004; Tangney and Rasmussen,
2013). Phenolics from red wine (quercetin, resveratrol, and delphinidin) can activate the
enzyme involved in NO production and improve endothelial function (Romero et al., 2009;
Chalopin et al., 2010; Andriantsitohaina et al., 2012). These findings corroborate that dietary
interventions could reduce CVDs and improve endothelial function via differentmechanisms
such asNOproduction, lipid-lowering effects, inhibition of angiotensin-I converting enzyme,
angiotensin receptor blockers, and mediation of anti-inflammation (Murea et al., 2012).
Erectile dysfunction
Erectile dysfunction (ED) refers to the consistent inability to achieve and/or maintain penile
erection for satisfactory sexual performance inmen (NIHConsensus Conference, 1993; Bella
et al., 2015). It has beenestimated that about 150 million men around the globe have been
affected by ED, and this is expected to increase to 322 million by the year 2025 (Kassier
and Veldman 2014). Endothelial dysfunction is a vital mechanism for development of ED
associated with type 2 diabetes mellitus (Gandaglia et al., 2014). ED is usually described as
decrease in bioavailability of nitric oxide (NO) due to decreased expression of endothelial
nitric oxide synthase (eNOS) activity and/or increased removal of NO (Sasatomi et al., 2008;
Musicki et al., 2010). In human cells, both NOS and arginase compete for L-arginine as a
substrate (Giugliano et al., 2010). Arginase converts L-arginine to ornithine and urea while
NOS (endothelial [eNOS] and neuronal [nNOS] isoforms) catalyses the generation of NO
(Giugliano et al., 2010). A recent study suggests that arginase activity in the corpus cavernous
(CC) was elevated by hyperglycemia (Nunes et al., 2011). Thus, inhibition of arginase activity
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16 S. A. ADEFEGHA
Figure . Vasodilatory action and the effect of functional food bioactive compounds.
and possible control of hyperglycemia may be of therapeutic relevance in the management
of ED, as this may positively increase NO production by NOS activity (Torque and Caldwell,
2014).
Inhibition of enzymes linked with type 2 diabetes (α-amylase and α-glucosidase) could
also be of great benefit in type 2 diabetes–related ED, as this may ameliorate prolonged post-
prandial hyperglycemia, a major culprit in the formation of advanced glycation end prod-
ucts (AGEs) (Ige et al., 2010). The control of hyperglycemia, therefore, may diminish the
incidence of ED (Maiorino et al., 2014). Several active peptides, particularly angiotensin II
may be involved in the erectile mechanism (Nunes et al., 2011). ACE converts the decapep-
tide angiotensin I to angiotensin II (a potent vasoconstrictor) in the renin-angiotensin sys-
tem (RAS) (Ribeiro-Oliveira et al., 2008). Production of angiotensin II and its binding to
angiotensin II receptor type1 (AT1) activates nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase and increases reactive oxygen species (ROS) production (De-Queiroz-
Thyago et al., 2013). Inhibition of ACE activity may also be a good therapeutic approach
in the management/treatment of hypertension and ED in both diabetic and nondiabetic
patients (Gupta and Guptha, 2010; Sowers and Epstein, 1995). Increased activity of arginase,
a manganese-dependent metalloenzyme that hydrolyzes L-arginine to L-ornithine and urea,
may suppress the synthesis of NO since both arginase and NOS compete for a common
substrate, L-arginine (Figure 6) (Buga et al., 1996). In studies conducted by Manjolin et al.
(2013) and dos-Reis et al. (2013), flavonoids and their derivatives (quercetin, quercitrin, iso-
quercitrin catechins, and epicatechin) were reported to be efficient in reducing arginase activ-
ity. This may be due to the hydrogen bond and hydrophobic interactions between the hydro-
carbon skeleton and hydrophobic active site of the enzyme (Da-Silva et al., 2012; dos-Reis
et al., 2013). In another study conducted by our research group, extracts of almond fruit parts
(hull and drupe) showed arginase inhibitory activity, and this effect was linked to the pres-
ence of some flavonoids and phenolic acids (Adefegha et al., 2017b), suggesting the protec-
tive effects of almond fruit parts (hull and drupe) on endothelial tissues. Almond fruit parts
(hull and drupe), therefore, could be beneficial for management and/or treatment of ED asso-
ciated with diabetes and hypertension (Bagnost et al., 2000; Adefegha et al., 2017b). Stud-
ies have suggested that treatment of hypertension with ACE inhibitors may enhance erectile
performance (Sowers and Epstein, 1995). Activity of ACE is responsible for production of
angiotensin II, an implicated vasoconstrictor in ED with the ability to degrade bradykinin,
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JOURNAL OF DIETARY SUPPLEMENTS 17
a vasoactive compound known to be active in the human corpus cavernosum (Jin, 2009)
(Figure 6). As a result, ACE inhibitors have been widely developed to prevent angiotensin II
production in cardiovascular diseases (CVD) (Cushman and Cheung, 1971) (Figure 6). Inhi-
bition of ACE activity by the extracts from almond drupe and hull could explain the possible
mechanism for their use in the management/treatment of ED. Rutin, a flavonoid constituent
present in both extracts, has been reported to act as a vasodilating agent and inhibits ACE
activity (Janbaz et al., 2002). Almond fruit (Terminalia catappa L.) parts (hull and drupe)
exhibited erectogenic properties by inhibiting critical enzymes linked to erectile dysfunction.
This biological effect was attributed to the phenolic constituents (Adefegha et al., 2017b)
Neurodegenerative diseases
Neurodegenerative diseases are characterized by loss of integrity of the neurons from the brain
and spinal cord over a period of time and could lead to dementia (Woulfe, 2008; Tretter et al.,
2004). The aging process originating from excess reactive oxygen species (ROS) production
has been attributed to the global increase in neurodegeneration (Manton et al., 2004; Valko
et al., 2007). Theories of aging mechanisms have suggested that cumulative oxidative stress
might cause mitochondrial dysfunction and oxidative damage leading to neurodegenerative
diseases, characterized by memory impairment and cognitive dysfunction (Wickens, 2001;
Lee et al., 2012). It is generally accepted that the brain is prone to oxidative stress because of
the high level of fatty acids, high oxygen consumption, and low level of antioxidant defense
(Uttara et al., 2009; Teixeira et al., 2013). Cognitive enhancement, also known as intelli-
gence enhancement, could be defined as the amplification of one’s power to learn or retain
knowledge by increasing internal or external information processing systems (Bostrom and
Sandberg, 2009). The brain is an important organ in the body that controls physiological and
cognitive functions via interconnections among billions of neurons in the brain to form com-
munication networks (Pushpalatha et al., 2013). Therefore, regulation of the chemical mes-
sengers, also known as neurotransmitters, and propermaintenance/control of oxidative stress
are major ways of ensuring successful regulation and coordination of body activities (Colovic
et al., 2013). The most common form of dementia is known as Alzheimer’s disease (AD),
which is the progressive loss of intellectual and social behavior severe enough to interfere
with daily activities of the patients (Chan et al., 2013). The cholinergic hypothesis is the most
accepted theory to explain pathogenesis of AD (Humpel, 2011). Acetylcholinesterase (AChE)
is the key enzyme responsible for breakdownof acetylcholine (Scarpini et al., 2003). Inhibition
of AChE is considered one of the targets for the treatment of AD (Scarpini et al., 2003). The
most prescribed drugs for treatment ofADare the cholinesterase inhibitors (Grossberg, 2003).
This has led to the continuous and comprehensive search for novel inhibitors from plant
sources to discover new drug candidates (Mukherjee et al., 2007). Attention has recently been
shifted by food scientists and researchers to tropical plant foods with antioxidant-rich and
health-promoting phytochemicals as potential therapeutic agents (Gülçin et al., 2003; Kumar
and Khanum, 2012; Kumar and Pandey, 2013; Mahomoodally, 2013). Both experimental and
epidemiological evidence have indicated that consumption of vegetables, fruits, teas, spices,
and herbs is associated with low risk of several neurodegenerativediseases (Morris et al.,
2006; Joseph et al., 2007; Caracciolo et al., 2014). Acetylcholinesterase (AChE) is an enzyme
bound to the membrane and hydrolyzes the neurotransmitter acetylcholine (ACh) into
choline and acetate after their function in cholinergic synapses at the brain region (Cˇolovic´
et al., 2013; Lionetto et al., 2013). Hypoinsulinemia (decreased level of insulin in the blood),
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18 S. A. ADEFEGHA
as well as insulin resistance, account for the decreased level of ACh and provide the possible
biochemical link between diabetes mellitus and Alzheimer’s disease (Akter et al., 2011; Kim
and Feldman, 2015). The response of AChE to oxidative insults may lead to the incidence
and pathogenesis of a variety of central nervous system disorders, such as stroke, Alzheimer’s
disease, and diabetes mellitus (Mushtaq et al., 2015). Our investigation on the possible effect
of protocatechuic acid revealed that protocatechuic acid altered Na+/K+-ATPase, choliner-
gic, and antioxidant enzyme activity in rats (Adefegha et al., 2016d). We also reported that
alkaloid extracts from shea butter and breadfruits were able to inhibit monoamine oxidase,
cholinesterase, and lipid peroxidation in an in vitro model (Adefegha et al., 2016e).
Conclusion
In this review, we have discussed extensively the biological activities of functional foods and
nutraceuticals as well as different natural bioactive compounds from many plant sources.
Novel therapeutic targets and possible mechanisms of action of these food products and com-
pounds have been well documented in this review as well. This review may give a compre-
hensive insight into the paradigm shift from the conventional view of foods and food-related
products to recognizing their medicinal role.
Declaration of interest
The authors declare no conflicts of interest. The authors alone are responsible for the content andwriting
of the article.
About the author
Dr. Adefegha bagged a Bachelor of Science (B.Sc.) degree in Biochemistry from the University of Ado-
Ekiti, Ekiti State, Nigeria in 2004 and a Masters (M.Sc.) degree in Biochemistry(Xenobiochemistry)
from the University of Ibadan, Ibadan, Oyo State in 2008. He won a sandwich training educational pro-
gramme (STEP) by the Abdus Salaam International Centre for Theoretical Physics (STEP-(ICTP) and
International Atomic Energy Agency(IAEA) for three successive years (3 months in 2010, 4 months in
2011 & 3 months in 2012) at the University of Trieste, Trieste, Italy. He was awarded an education trust
fund (ETF) scholarship by the Federal Government of Nigeria on pre-doctoral fellowship to the Techni-
cal University of Dresden, Dresden, Germany (2012–2013). In 2014, He bagged a Doctor of Philosophy
(PhD) in Applied Biochemistry from the Federal University of Technology, Akure, Ondo State, Nige-
ria. He had a postdoctoral training at the Department of Biochemical Toxicology, Federal University
of Santa Maria, Santa Maria, Brazil (2015–2016). Dr. Adefegha’s research interests focus on the critical
role of food in disease prevention and health promotion. This focus is immensely contributing towards
the core values and innovations in the areas of Functional foods, Nutraceuticals, Phytomedicine and
Molecular Nutrition. These new innovations in Life Sciences as well as agricultural and food research
have accelerated global food security and proffer solution to some health issues in a suitable environ-
ment. Dr. Adefegha has developed an innovation “Dietary Intervention of Bioactive Food Components
as well as Plant Food Products in the Management of Chronic/ Degenerative Diseases”.
ORCID
Stephen Adeniyi Adefegha http://orcid.org/0000-0003-1339-403X
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