FUNCTIONAL FOODS,

NUTRACEUTICALS AND
NATURAL PRODUCTS
CONCEPTS AND APPLICATIONS

Edited by

Professor Dhiraj A. Vattem, Ph.D.

Texas State University

Vatsala Maitin, Ph.D.

Texas State University
Functional Foods, Nutraceuticals and Natural Products

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 Preface

The demand for foods with a positive impact on human health and
wellness has exploded globally over the past two decades. This growth
is driven by socioeconomic and scientific factors, including increas-
es in population, disposable income, life expectancy and healthcare
costs. The market for healthier foods is also enhanced by advance-
ments in our understanding of dietary bioactive ingredients and their
effects on various aspects of human health at a systems and molecu-
lar level. This book examines the rapidly growing field of functional
foods in the prevention and management of chronic and infectious
diseases. It attempts to provide a unified and systematic account of
functional foods by illustrating the connections among the different
disciplines needed to understand foods and nutrients, mainly: food
science, nutrition, pharmacology, toxicology and manufacturing tech-
nology. Advances within and among all these fields are critical for the
successful development and application of functional foods. Chap-
ters in the present volume explore the varied sources, biochemical
properties, metabolism, health benefits and safety of bioactive ingre-
dients. Special emphasis is given to linking the molecular and chemi-
cal structures of biologically active components in foods to their nu-
tritional and pharmacological effects on human health and wellness.
In addition to discussing scientific and clinical rationales for different
sources of functional foods, the book also explains in detail scientific
methodologies used to investigate the functionality, effectiveness and
safety of bioactive ingredients in food. This text is intended for food,
nutrition, medical specialists as well as students, and will give the
xv
xvi Preface

reader a systematic and in-depth understanding of basic and advanced

concepts in functional foods.

DHIRAJ A. VATTEM, PhD

VATSALA MAITIN, PhD
 CHAPTER 1

Functional Foods—History and

Concepts
S. ARAI, D.A. VATTEM and H. KUMAGAI

1.1.  BACKGROUND

The concept originating in ancient China and transported to Japan

long ago—“Medicine and food are isogonics” (Arai 2005)—as well as
the doctrine of Hippocrates (460–377 B.C.), “Let food be thy medicine
and medicine be thy food,” (Hasler 2001)—has had a resurgence. The
advent of up-to-date science and sophisticated technology has made it
possible to recognize food as supplying us with more than nutrition.
Food can even help reduce the risk of chronic lifestyle-related diseases
such as diabetes, dyslipidemia, hypertension, obesity, etc., caused
by inadequate metabolic modulation, and cancer, allergies, infection
diseases, etc., caused by broken body-protection systems. The recent
trend of reconsidering foods and their proper intakes as the first line
of defense against these abnormal modalities has grown from our in-
creased understanding of physiological rather than nutritional ben-
efits of foods. Against this backdrop, the terminology and concept of
“functional food” were born in Japan about two dozen years ago (Arai
2005).

S. Arai; Department of Nutritional Science, Tokyo University of Agriculture,

1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan.
D.A. Vattem; Nutrition Biomedicine and Biotechnology, Texas State University,
San Marcos, TX, USA, 78666.
H. Kumagai; Department of Chemistry and Life Science, College of Bioresource
Sciences, Nihon University, 1866 Kameino, Fujisawa-shi 252-0880, Japan.
1
2 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

In 1984, a large-scale national project to be carried out by an ad hoc

research team headed by Professor S. Arai at the University of Tokyo
and other leading food scientists was launched under the egis of the
Japan Ministry of Education, Science, and Culture. The project was
headquartered at the University of Tokyo which has studied “food for
health” since 1910 when the outstanding biochemist Dr. Umetaro Su-
zuki investigated rice bran and found an antiberiberi principle oryzanin
(Suzuki et al. 1912) which was then renamed thiamin (vitamin B1).
With it as a background, the project had humble beginnings to trace a
unique path of development through special insights into physiologi-
cally functional non-nutrients originating in common foods (see Table
1.1). The research team first proposed three categories of food func-
tionality (see Figure 1.1) and then pinpointed its study on the “tertiary”
function to be evoked by non-nutritive components. Political actions
for new legislation followed. In 1991, the Japan Ministry of Health and
Welfare initiated the world-first policy of legally permitting the com-
mercialization of selected functional foods named “food for specified
health use” (FOSHU). Each of the FOSHU products can claim a certain
degree of health benefit. These scientific and political activities were
reported in Nature news (Swinbanks and O’Brien 1993) with the head-
line, “Japan explores the boundary between food and medicine;” this
reminded us of the old day’s saying, “Medicine and food are isogonic.”

FIGURE 1.1.  Three categories of food functions proposed.

 Scientific Perspectives 3

TABLE 1.1.  Common Non-nutritive Components with Possible

Functions for Disease Risk Reduction.
Component Example (origin) Disease
Carotenoid
Carotene Lycopene (tomato) Oxidative stress
Xanthophyll Lutein (vegetable) Oxidative stress
Flavonoid
Flavonol Quercetin (vegetable) Oxidative stress
Flavone Nobiletin (citrus fruit) Oxidative stress
Isoflavone Daidzein (soybean) Osteoporosis
Flavanone Naringin (grapefruit) Diabetes
Catechin Epigallocatechin gallate Allergy
3- or 4-methyl ester (tea)
Anthocyanin Cyanidin (kidney bean) Oxidative stress
Simple polyphenol Chlorogenic acid (coffee) Cancer
Phenyl propanoid Curcumin (turmeric) Cancer
Isoprenoid Ubiquinone (ubiquitous) Oxidative stress
Triterpenoid Soyasaponin (soybean) Oxidative stress
Phytosterol β-Sitosterol (soybean) Hypercholesterol-
emia
Chromanol derivative Tocotrienol (soybean) Oxidative stress
Isothiocyanate Sulforaphane (broccoli) Detoxification
Sulfoxide Alliin (garlic) Coagulation
Vanilloid Capsiate (chili) Obesity
Alkaloid Caffeine (coffee) Obesity
Lignan Sesamin (sesame) Hangover
Organic acid Acetic acid (vinegar) Hypertension
Amino acid γ-Aminobutyric acid (rice) Hypertension
Protein β-Conglycinin (soybean) Obesity
Oligopeptide Val-Pro-Pro (sour milk) Hypertension
Lipid 3-Diacylglycerol (cooking oil) Obesity
Polysaccharide Alginic acid (seaweeds) Hypercholesteremia
Prebiotics Manno-oligosaccharide (coffee) Obesity
Probiotics Bifidobacterium lactis (yogurt) Constipation
Sweetening Neoculin (Curculigo latifelia) Diabetes

1.2.  SCIENTIFIC PERSPECTIVES

What may be most important at present is the evaluation of the func-

tion of a food. Since any functional food must be based on scientific
principles, its evaluation should essentially depend on data from bio-
chemistry, physiology, molecular biology, and most other modern bio-
4 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

sciences. A key approach to the development of a functional food is the

identification and validation of relevant markers, including biomarkers,
which can predict its potential benefits relating to a target function in
the body. If a marker represents an event directly involved in the pro-
cess, it should be considered as a functional “factor.” However, if a
marker represents a correlated event, it should be considered as a func-
tion “indicator” (Bellisle et al. 1998; Anonymous 2002).
A similar but even lager national project, headed by Professor Arai,
started with the title “Non-nutritive functional components in foods:
analysis and systematization.” It emphasized the significance of troop-
ing a variety of methodologies, with research targets hierarchized as in
Figure 1.2 (Arai 2006). The project was successfully undertaken, with
its administration operated by Professor M. Uehara at Tokyo University
of Agriculture. Scientifically, the research teams investigated hundreds
of fruits and vegetables for functional food components and in particu-
lar, Professor K. Kanazawa at Kobe University, presented an interesting
polyphenol pyramid (see Figure 1.3) (unpublished).
Meanwhile, the genome programs on humans and other representa-
tive organisms for scientific and industrial uses were almost completed,
enabling us to obtain the genome information by internet services. The

FIGURE 1.2.  Systematized methodologies for analysis of the “tertiary” functions of food
and hierarchal targets of analysis.
 Scientific Perspectives 5

FIGURE 1.3.  Polyphenol pyramid.

use of the DNA microarray technique has made it possible to qualita-

tively and quantitatively investigate statistically significant changes in
gene expression that took place at target tissues of the body after in-
gesting individual foods or their components. A new science, coined as
“nutrigenomics,” has thus come into being (Maller and Kersten 2003);
the term “functional food genomics” is sometimes used in the particular
case that the physiological functionality of a whole food is emphasized
more than its nutrition.
In the meantime, Professor K. Abe at the University of Tokyo or-
ganized the International Life Science Institute (ILSI) Japan-endowed
chair “Functional Food Genomics” (with Professor Y. Nakai in charge)
which aims to explore a new dimension of food science in the form of
academia-industry consortium (Nakai et al. 2010). This laboratory has
publicized DNA microarray data on soy protein isolate (Tachibana et
al. 2005), cocoa as a whole (Matsui et al. 2005), sesamin (Tsuruoka et
al. 2005), apple polyphenol (Ohta et al. 2006), grape seed (Sano et al.
2007), royal jelly as a whole (Narita et al. 2006), fructo-oligosaccharide
(Fukasawa et al. 2007), vinegar as a whole (Nakano et al. 2004), tomato
(Aizawa et al. 2009), and others. What may be extremely interesting
would be the data on inhaled linalool as an aroma that reduces a kind of
 TABLE 1.2.  Foods for Specified Health Uses, with Their Numbers
Bracketed in Italic Type.
Category 1 Modulation of gastrointestinal conditions
1. Oligosaccharides: lactosucrose [28]; galacto-oligosaccharides [14];
coffee bean manno-oligosaccharides including mannobiose [14];
fructo-oligosaccharides [7]; soybean oligosaccharides [6]; xylo-oligo-
saccharides [4]; isomaito-oligosaccharides [4]; lactulose (Hassler et
al. 2004); raffinose (Hassler et al. 2004)
2. Lactic acid bacteria: Lactobacillus casei Shirota [30]; L. acidophilus
CK92 and L. helveticus CK60 [7]; Bifidobacterium lactis Bb-12 [7];
L. delbrueckii subsp. bulgaricus 2038 and Streptococcus salivarius
subsp. thermophilus 1131[6]; B. breve Yakult [6]; B. longum BB536
[6]; L. casei SP and B. SP (Hassler 2002); B. lactis LKM512 (Has-
sler 2002); B. lactis FK120 (Hassler 2002); L. casei NY1301 (Has-
sler 2002); L. GG (Hassler 2002); L. casei LC1 (Hassler 2002)
3. Dietary fibers: indigestible dextran [141]; psyllium husk [22]; wheat
bran [4]; gum guaic hydrolysate [6]; agar (Katan and De Roos
2002); polydextrose (Hassler 2002); low-molecular-weight sodium
alginate (Hassler 2002); low-molecular-weight sodium alginate and
water-soluble corn fiber (Hassler et al. 2004); indigestible dextran
and wheat bran (Hassler et al. 2004); dietary fiber from beer yeast
(Hassler et al. 2004); indigestible dextran, reduced type (Hassler et
al. 2004); indigestible starch (Hassler et al. 2004)
4. Other components: milk whey fermented by propionic acid bacte-
rium (Katan and De Roos 2002); Bacillus subtilis K-2 (Hassler et al.
2004)
5. Combination of chemically defined components: galacto-oligosac-
charide-polydextrose (Hassler et al. 2004)
Category 2 Modulation of serum cholesterol level
Chitosan [47]; soybean protein [27]; phospholipid-binding soybean
peptides including Cys-Ser-Pro-His-Pro [19]; low-molecular-weight
sodium alginate [6]; phytosterol [5]; phytosterol ester (Katan and De
Roos 2002); broccoli-cabbage peptide Ser-Mer-Cys-Ser (Hassler
2002); tea catechin [4]
Category 3 Modulation of serum cholesterol level and gastrointestinal conditions
Dietary fiber from psyllium husks [19]; low-molecular-weight sodium
alginate [9]
Category 4 Modulation of blood pressure
Sardine peptide including Val-Tyr [65]; lactotripeptides Val-Pro-Pro
and Ile-Pro-Pro [12]; dried bonito “katsuobushi” oligopeptides [7];
“wakame” seaweed peptides including Pro-Tyr-Val-Tyr and Ile-Tyr [4];
γ-aminobutyric acid [9]; casein dedocapeptide (Hassler et al. 2004);
Ile-Tyr [4]; acetic acid [5]; sesame peptides including Leu-Val-Tyr
(Hassler 2002); “nori” seaweed oligopeptides including Ala-Lye-Tyr-
Ser-Tyr (Hassler 2002); “tochu” loaf glycoside [4]; royal jelly peptide
including Val-Tyr, Ile-Tyr and Ile-Val-Tyr (Hassler 2002); yanlong
tea flavonoids including hyperoside and isoquercitrin (Hassler et al.
2004); chlorogenic acid (Hassler 2002)
(continued)

6
 Scientific Perspectives 7

TABLE 1.2 (continued).  Foods for Specified Health Uses, with Their
Numbers Bracketed in Italic Type.
Category 5 Acceleration of mineral absorption
Casein phosphopeptides (Katan and De Roos 2002); heme iron (Ka-
tan and De Roos 2002); calcium citrate-malate (Hassler et al. 2004)
Category 6 Acceleration of mineral absorption and modulation of gastrointestinal
conditions
Lactosucrose (Hassler 2002); fructo-oligosaccharide (Hassler et al.
2004)
Category 7 Promotion of bone health
Soybean isoflavones [13]; vitamin K as menaquinone-7 [7]; fructo-
oligosaccharides [5]; polyglutamic acid (Hassler et al. 2004); milk
basic protein (Hassler et al. 2004); and calcium [13] vitamin K-2 as
menaquinone-4 (Hassler 2002)
Category 8 Maintenance of healthy teeth
Combined xylitrol-maltitol-calcium monohydrogen phosphate-
“fukuronori” seaweed furanone [23]; maltitol (Hassler 2002); green
tea fluorine [7]; combined xylitol-calcium monohydrogen phosphate-
“fukuronori” seaweed flavanone (Hassler et al. 2004); combined
maltitol-palatinose-green tea polyphenols (Hassler et al. 2004);
combined maltitol-hydrogenated palatinose-erythritol-green tea poly-
phenols (Hassler et al. 2004); soybean isoflavone-calcium (Hassler et
al. 2004);
Combined palatinose-green tea palatinose polyphenols (Hassler et al.
2004); combined xylitol-reduced palatinose calcium monohydrogen
(Katan and De Roos 2002); milk protein hydrolysate containing casein
phohphopeptide [27]; phosphorylated oligosaccharide calcium [6]
Category 9 Modulation of blood sugar level
Indigestible dextrin [136]; wheat albumin [5]; bean extract (Hassler
2002); arabinose (Hassler et al. 2004); guava leaf polyphenol (Has-
sler et al. 2004); resistant recrystallized amylose (Hassler et al. 2004)
Category 10 Modulation of serum triacylglycerol level and blood fat percentage
Globin hydrolysate containing Val-Val-Tyr-Pro [14]; tea catechin [15];
middle-chain fatty acid [5]; coffee bean manno-oligosaccharides
including mannobiose [20]; oolong tea polymerized polyphenol includ-
ing oolong homo-bis-flavan B (Hassler 2002); fermented soy bean
extract (Hassler et al. 2004); β-conglycinin [5]; EPA and DHA [4]

restrained stress (Nakamura et al. 2009), and those on a kind of isola-

tion stress that induces dyslipidemia (Motoyama et al. 2009).
The use of genomics is already an international trend. Nutrigenomic
research institutions around the world are forming consortia to consoli-
date their activities aiming at evidence-based functional food science
through cooperation in the development of systems biology. In North
America, the National Institutes of Health (NIH) provides financial sup-
8 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

port for an ongoing research project that is focused on the relationship

between diet and gene and between diet and disease in collaboration
with nine research centers and four external affiliated organizations.
Europe witnessed a launch of a large-scale, 6 year project in January
2004 that was kicked off with the participation of 22 research institu-
tions from ten countries. The European Union earmarked a budget of
17.3 million Euro for this project. New Zealand and Australia play a
leading role in Oceania to set up a research organization that specializes
in gut health research. These initiatives drew in Canada, China, South
Korea, Singapore, and other countries to form a global network. These
countries have each launched a clear strategy to exchange information
with each other and to invest their research resources in the domains
where they can capitalize on their own strengths (Kuwata 2006). Glob-
ally, a myriad of papers have been presented so far; some selected re-
ports even within the recent few years are listed as references (Jew et
al. 2009; Boue et al. 2009; Sirtori et al. 2009; Eusson et al. 2010; Schi-
epers et al. 2009; Berendschot et al. 2009; Naito et al. 2009; Johnston
2009; Porrini 2008; Medic-Saric et al. 2009; Laparra and Sanz 2010;
Mullie et al. 2009; Minervini et al. 2009). The readers are also recom-
mended to consult several volumes (in English) with the term “func-
tional foods” in their book titles (Goldberg 1994; Mazza 1998; Gibson
and Williams 2000; Wildman 2001; Hurst 2002; Shi et al. 2002; Watson
2003; Korver et al. 2004; Eisenbrand 2004; Neeser and German 2004;
Hasler 2005).

1.3.  POLITICAL STATES

The implementation of the FOSHU policy, as well as the initiation of

functional food science in Japan, had a strong impact on many countries
in the world, particularly in Europe. In 1995, the UK Ministry of Agri-
culture, Fisheries, and Food defined (although temporarily) functional
foods as those having components incorporated that confer specific
medical or physiological benefits, other than nutritional effects (Bel-
lisle et al. 1998). Greater interest was shown by ILSI Europe which
addressed the present status by claiming that we stand today at the
threshold of a new frontier in nutritional science. They also stated that
the concept of food is changing from a past emphasis on eating to sate
hunger, into an emphasis on the potential uses of food to reduce the risk
of chronic illness (Anonymous 2002). This new concept is of extreme
importance in view of the demands of the elderly population for an
 Political States 9

improved quality of life, increased life expectancy, and reduced costs

for health care. A key approach for the science of functional food to
develop in compliance with these demands is, among others, the iden-
tification and validation of relevant markers which can predict some
potential benefits in the body. It is thus of crucial importance to define
the health claim for each functional food by the three different phrases:
(1) nutrient function claims, (2) other function claims, and (3) reduc-
tion of disease risk claims. The former two would be defined based on
genomics data as well as biochemical biomarkers (Bellisle et al. 1998).
Health claims should always be scientifically defined in harmonization
with global standards. Talking of the FOSHU system, the goal is to
evaluate its physiological functionality for formal approval. On the oth-
er hand, the enhanced functional claims and the disease risk reduction
claims were proposed by both the Codex and EU project in 1999. The
structure/function claims were expressed in the Dietary Supplement
Health Education Act in the United States in 1994. The nutrient func-
tion claim was included in the guidelines adopted by the Codex in 1997.
The generic claims primarily include nutrient function claims based on
well-established, generally accepted knowledge and could be standard-
ized without specific, individual substantiation. Innovative claims such
as enhanced function claims or structure/ function claims, however,
should be evaluated individually by independent experts in order to
protect consumers from false or misleading descriptions. For this sci-
entific substantiation, in addition to animal studies and in vitro studies,
we also need human intervention studies (Shimizu 2003). The FOSHU
system has been making good progress. Up to the present time (June
1, 2010), the Ministry has approved 941 FOSHU products categorized
into 10 health claims (see Table 1.2) (Arai et al. 2008). Each product
is permitted to claim a certain degree of health benefit as long as the
claim does not overestimate its efficacy for disease risk reduction. The
legal framework is also expected to stop ill-defined, misleading product
advertisements. It is added that a close attention has been nationally and
internationally paid to the safety of functional foods. In particular, the
ILSI Annual Meeting 2010 in Rio Grande has had a scientific session of
“Risk Assessment and Functional Foods,” which comprises topics on
the mode of action of functional foods in human relevance framework,
their threshold of toxicological concern, and so on.
As discussed above, the name of “functional food” as well as its
concept has been globally accepted enthusiastically, and the science is
in progress for further development. However, it will be of crucial im-
10 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

portance to add some modification to the current status of functional

food science which is going for pharmacology. Food is quite different
from medicine in various respects. It is necessary for implementation
of functional food research to take into consideration the differences in
terms of sensory properties. A new trend has come into being, which
emphasizes the significance of studying the “secondary” function (see
Figure 1.1). Since this per se is the most representative food attribute,
even the science of functional food should consider taste and smell in
a large measure. In the meantime, it was found that our body expresses
taste receptors in the gut as well as in oral taste buds (Margoskee et
al. 2007). Interestingly enough, it is possible that the gut’s sweet taste
receptor, T1R2-T1R3, functions to induce insulin secretion shortly af-
ter taking even artificial sweeteners and sweet protein (Shimizu-Ibuka
et al. 2006). We now need some integrative studies on all the three
categories of food functions (see Figure 1.1) and future research along
this line will no doubt add a new dimension in the science and policy
of functional foods.

1.4.  DEFINITIONS AND LIMITATIONS

Currently, there is no general, worldwide definition of functional

foods; however, there are multiple definitions developed by various or-
ganizations. The International Food Information Council (IFIC) states
that functional foods “provide health benefits beyond basic nutrition
(Hassler et al. 2004).” The limitation of this definition is that it lacks
an explanation of how the food or what part of the food provides health
benefits. The definition should differentiate whether the whole food or
only food components are beneficial. The International Life Sciences
Institute of North America (ILSI) states that functional foods are “foods
that, by virtue of physiologically active food components, provide
health benefits beyond basic nutrition (Hassler et al. 2004).” This defi-
nition is vague, but encompasses the realm of functional foods. There
is no delineation between different types of functional foods, such as
whole foods and foods that are enhanced with added ingredients. How-
ever, this definition provides insight into how the food or what part of
the food is beneficial by stating “by virtue of physiologically active
food components,” (Hassler et al. 2004), this statement encompasses
components of whole foods and components that are added to foods,
which have beneficial effects. However, the statement about individual
food components fails to demonstrate the role of synergy in providing
 Definitions and Limitations 11

health benefits. The concept of synergy is important to include in func-

tional food definitions because the coordination of the “physiologically
active food component” with the other components present in the food
is what provides the health benefit.
Health Canada states that functional foods are “similar in appearance
to a conventional food, consumed as part of the usual diet, with dem-
onstrated physiological benefits, and/or to reduce the risk of chronic
disease beyond basic nutritional functions,” (Hassler et al. 2004). One
limitation to this definition is the narrowness of stating that a functional
food must look similar to a conventional food. If a functional food ap-
pears similar to a recognizable food, consumer acceptance is likely in-
creased; however, foods that do not appear similar to a conventional
food should not be excluded since they may still act as functional foods.
In addition, this definition is regional because appearance of conven-
tional food differs according to location, culture, and religion. Accord-
ing to this definition, two foods may have the exact same physiological
function and provide the exact same health benefit; however, if one of
these foods has an unconventional appearance, it cannot be classified as
a functional food. Another limitation to this definition is that the food
must be “consumed as part of the usual diet,” (Hassler et al. 2004).
The usual diet of consumers varies from person to person, and a food
should not lose classification as a functional food because it is not part
of the usual diet of a consumer. If a functional food is part of the usual
American diet, but not part of a usual European diet, is the same food
not considered functional in Europe?
The Institute of Medicine of the National Academy of Sciences
(IOM) states that functional foods are “those in which the concentra-
tions of one or more ingredients have been manipulated or modified to
enhance their contribution to a healthful diet,” (Hassler et al. 2004).
This definition does not differentiate functional foods from any other
food; according to this definition, a reduced fat food can be a func-
tional food (Katan and De Roos 2002). In addition, this definition only
states that functional foods contribute to a healthy diet, not that they
have specific functions regarding disease (Katan and De Roos 2002).
Moreover, this definition excludes whole foods and foods that have for-
eign ingredients added; rather than only stating, “One or more ingredi-
ents have been manipulated or modified,” the definition should include
whole foods and functional ingredients that have been added to a food
(Hassler et al. 2004).
In Japan, the FOSHU organization states that functional foods are
12 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

“processed foods containing ingredients that aid specific body func-

tions in addition to being nutritious.” The limitation to this definition is
that all unprocessed, whole foods are excluded.
The American Dietetic Association (ADA) states that functional
foods include “whole foods and fortified, enriched, or enhanced foods,
have a potentially beneficial effect on health when consumed as part of
a varied diet and on a regular basis, at effective levels,” (Hassler et al.
2004). The limitation to this definition is that for a food to be functional,
it must be “consumed as part of a varied diet,” (Hassler et al. 2004).
The statement about a varied diet was likely incorporated to impart the
importance of an overall healthy diet; however, a functional food re-
tains its functionality as part of any diet. The definition should be for a
functional food, not a healthy diet.
The American Council on Science and Health states that functional
foods are “whole, fortified, enriched, or enhanced foods that provide
health benefits beyond the provision of essential nutrients, when they
are consumed at efficacious levels as part of a varied diet on a regular
basis,” (Hassler 2002). The limitation of this definition is the same as
the limitation of the definition offered by ADA.

1.5.  RELEVANCE OF FUNCTIONAL FOODS

The concept of functional foods stems from the traditional paradigm

of providing methods to prevent nutritional deficiencies; this paradigm
encompasses foods that provide health benefits through fortification
with micronutrients. Today, functional foods are designed to promote
health by being targeted at specific physiological processes that may
lead to disease prevention; this is known as the new paradigm. With
the increase in diseases related to excess energy consumption, an ag-
ing population, and the increasing cost of health care and pharmaceu-
ticals, consumers are turning to food to replace or augment traditional
health care for health promotion and disease prevention. With increas-
ing consumer interest in self-care of health, functional foods research
will continue to expand as will the availability of functional foods to
the consumer. The concept of functional foods needs to be incorpo-
rated into an overall healthy lifestyle for maximum benefit of disease
prevention. Functional foods, an overall healthy diet including fruits,
vegetables, unrefined grains, fish, and low-fat dairy products, and foods
low in saturated fats and sodium (Katan and De Roos 2002), and ex-
ercise, combine to encompass the healthy lifestyle needed for disease
 Impact on Health Care and Society 13

prevention. The definition of functional foods expands on one aspect of

a healthy lifestyle; this definition is meant to recognize foods and food
ingredients, whether natural, added, or modified, that provide disease
prevention and health promotion benefits.

1.6.  FUNCTIONAL FOOD VERSUS PHARMACEUTICALS

As the population ages, the incidence of chronic diseases associated

with caloric excess and the cost of healthcare increases, and consum-
ers increasingly desire self-care regarding health and an alternative to
pharmaceutical management of disease (Hassler et al. 2004). Lifespan,
incidence of obesity, and age are increasing, which results in an insur-
gence of chronic diseases such as cardiovascular disease (CVD) and
diabetes mellitus. Each of these factors combines and occurs, leading
to an increased cost of health care and pharmaceuticals. This increased
cost of health care for disease management, coupled with pharmaceuti-
cal side effects, and consumer interest in self-care health management
and healthy foods result in a demand for functional foods. Compounded
to the expense of pharmaceuticals is their limited availability, since they
are only available via prescription and their ineffectiveness for some
consumers; moreover, consumers desire the preventable approach of
functional foods over the symptomatic treatment approach of pharma-
ceuticals. The utilization of functional foods for health care encompass-
es the use of functional foods to replace or decrease dependence on
pharmaceuticals. The use of functional foods rather than pharmaceuti-
cals for health benefits will decrease healthcare costs, promote health
without inducing pharmaceutical side effects, aid in disease prevention,
and provide a method of self-care for consumers. In addition, the use of
functional foods for health care has a broad spectrum due to food being
necessary for survival, and the flexibility of foods for adaptation to suit
specific demographic characteristics.

1.7.  IMPACT ON HEALTH CARE AND SOCIETY

Functional foods are currently influencing healthcare through their

incorporation into medical treatments, usually alongside pharmaceuti-
cals. As the functional food industry expands, their use in healthcare
will increase, allowing functional foods to act as a first line of defense
against disease rather than pharmaceuticals. In addition, as functional
food use for disease prevention continues, the incidence of chronic dis-
14 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

ease will decrease leading to a reduction in spending on health care

and pharmaceuticals. Overall, the scope of healthcare will shift from
treatment to prevention. However, an increase in the use of probiotics
may exacerbate antibacterial resistance. Probiotic bacteria such as Lac-
tobacillus casei, upon ingestion select for the survival and growth of
L. casei, therefore “crowding out” other normal gut microflora. This
gives probiotics antibiotic activity; some of the bacteria that are tar-
gets of this probiotic will survive, which leads to “super bugs” that
are resistant to antibiotics. The use of probiotics and the excess use
of pharmaceutical antibiotics compound to exacerbate the problem of
antibiotic resistance. Overall, the shift away from pharmaceuticals and
toward dietary intervention is necessary for health care in America; this
shift will help to remove some of the governmental and societal burden
of increasing health care costs, the inability to depend on social security
benefits after retirement, and budgeted funds for Medicare.

1.8.  FUNCTIONAL FOOD: SOURCES AND

CLASSIFICATION

Functional foods are classified by source of origin, including plant,

animal, microbial, and miscellaneous (algae, mushrooms, other). Re-
gardless of the source of origin, the target of functional foods includes
CVD, cancer, immune enhancement, gastrointestinal and women’s
health, aging, diabetes mellitus, and stress management.

1.8.1.  Plant-Derived Functional Foods

Plant-derived functional foods are separated into primary and sec-

ondary metabolites; primary metabolites are plant compounds nec-
essary for growth, while secondary metabolites are not essential for
growth, but are used for plant survival mechanisms. Primary metabo-
lites include plant proteins, beta-glucans, and omega-3 fatty acids. Plant
proteins include texturized vegetable protein, soy protein isolate, and
amino acids; these proteins act as functional foods by helping to de-
crease the amount of meat consumption, which decreases the consump-
tion of fat and cholesterol. Beta-glucans, found in oats, act as functional
foods by decreasing cholesterol absorption. Omega-3 fatty acids, found
in flaxseed, act as a functional food by reducing platelet aggregation.
Secondary metabolites include phytoestrogens, antioxidants, vitamins,
tocopherols, steroids, gamma-linolenic acid (GLA), and phase II en-
 Functional Food: Sources and Classification 15

zyme inducers. Phytoestrogens, estrogen-like compounds in plants, are

found in soybeans and flaxseed and act as functional foods by decreas-
ing post-menopausal cancer development. Antioxidants, such as antho-
cyanins, act as functional foods by quenching reactive oxygen species.
Vitamins, which are abundant in fruits and vegetables, act as functional
foods by preventing deficiencies; certain vitamins, such as vitamins C
and E, also act as quenchers of reactive oxygen species. Tocopherols,
which are vitamin E compounds found in oilseeds, act as quenchers
of reactive oxygen species. Steroids are also found in oilseeds and act
as functional foods by competing for cholesterol absorption. GLA is a
fatty acid involved in the formation of prostaglandins and acts as an in-
flammatory modulator (4). Phase II enzyme inducers, found in Brassica
vegetables, act as functional foods by glycosylating insoluble toxins to
produce soluble compounds that are excreted. Consumption of foods
containing phase II enzyme inducers also limits the phase I enzyme
detoxification system; the phase I enzyme system produces reactive
oxygen species.

1.8.2.  Animal-Derived Functional Foods

Zoochemicals, which are animal-derived functional foods, include

omega-3 and six fatty acids, conjugated linolenic acid (CLA), small
peptides, whey and casein, and glucosamine and chondroitin sulfate.
Omega-3 fatty acids include alpha-linolenic, docosahexaenoic (DHA),
and eicosapentaenoic (EPA) fatty acids (4). Sources of alpha-linolenic
acid include soy and canola oils, walnuts, and flaxseed (4). The main
source of EPA and DHA is fatty fish, such as salmon. Omega-6 fatty
acids include linolenic, gamma-linolenic, and arachidonic fatty acids
(4). Sources of these fatty acids include some vegetable oils, nuts, and
whole grains (4). Omega-3 and six fatty acids act as functional foods by
enhancing immunity, modulating inflammation, and protecting against
neurodegenerative diseases. CLA is a fatty acid present in milk that
reportedly acts as a functional food by reducing cancer risks and adi-
pose differentiation; however, a fatty liver may develop as a side effect
(Hassler 2002). Whey and casein are milk proteins that act as functional
foods by being easily digested and absorbed, and help build muscle
mass; small peptides function in the same manner. Glucosamine and
chondroitin sulfate are required for collagen formation and were stated
to act as functional foods by alleviating pain associated with osteoar-
thritis; however, this claim has been disproved (4).
16 FUNCTIONAL FOODS—HISTORY AND CONCEPTS

1.8.3.  Microbial Functional Foods

Microbial-derived functional foods include probiotics, prebiotics,

symbiotics, and synbiotics. Probiotics are natural microflora that occur
in the gut, such as L. casei or numerous Bifidobacter species, which
promote health (Hassler 2002). Prebiotics are dietary components that
promote growth of probiotic bacteria. Symbiotics contain probiotics
and prebiotics combined randomly, while synbiotics contain specific
probiotics and prebiotics mixed together to benefit one another. Func-
tional foods of microbial origin act by promoting the growth of probi-
otic bacteria so that the growth of pathogenic bacteria is limited.

1.8.4.  Miscellaneous Functional Foods

Some functional foods are derived from miscellaneous compounds

such as algae and mushrooms. Algae function by proving omega-3
fatty acids, which enhance immunity, modulate inflammation, and
protect against neurodegenerative diseases. Functional foods derived
from mushrooms contain antiviral, antibacterial, and anti-inflammatory
properties.

1.9.  ACKNOWLEDGMENTS

We wish to express our sincere thanks to Professors K. Abe, Y. Nakai

and T. Misaka for pertinent discussion.

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 CHAPTER 2

Prebiotics and Probiotics:

Concepts and Advances
A.L. CARVALHO-WELLS and D.M.A. SAULNIER

2.1.  INTRODUCTION

Any epithelial surface in the human body which is exposed to the

external environment is subject to interaction with exogenous micro-
organisms. This occurs particularly on the respiratory, genital, and gut
mucosal surfaces. The intestinal mucosa is the main site of interaction
with the external environment and therefore is an important intermedi-
ary in the maintenance of health. The gut was traditionally thought of
as a relatively simple organ comprising an epithelial tube surrounded by
a layer of muscle. However recent research has unraveled the diverse
functions of the gut and demonstrated the human gastrointestinal tract
as a highly dynamic ecosystem, which is central to immune develop-
ment, host defense, and human nutrition.

2.1.1.  Location and Diversity of the Gut Microbiota

There are four main microhabitats in the gastrointestinal tract: the

epithelial surface, the mucus layer which overlays the epithelium, the

A.L. Carvalho-Wells; Hugh Sinclair Unit of Human Nutrition, Institute for

Cardiovascular and Metabolic Research (ICMR), Department of Food and
Nutritional Sciences, University of Reading, Reading RG6 6AP, UK.
D.M.A. Saulnier; Departments of Pathology, Baylor College of Medicine,
Houston, TX, USA; and Department of Pathology, Texas Children’s Hospital,
Houston, TX, USA. (Current address: Department of Gastrointestinal Microbiology,
German Institute of Human Nutrition, Nuthetal, Germany.)
19
20 PREBIOTICS AND PROBIOTICS: CONCEPTS AND ADVANCES

crypts (of the ileum, caecum, and colon), and the intestinal lumen, re-
spectively. The levels and diversity of the microbial community within
the gastrointestinal tract can differ according to the location as different
physicochemical properties and substrate availability dictate the envi-
ronmental conditions. Not surprisingly, the stomach mucosa is occu-
pied by relatively few organisms due to the high level of acidity which
requires a more acid tolerant organism; stomach contents (per gram)
have been estimated to contain 103 colony forming units (CFU), reach-
ing 104–107 in the small intestine and 1010–1012 in the large intestine
where the microbial numbers are highest (Holzapfel et al. 1998). The
total area of the mucosal surface of the human gastrointestinal tract is
300 m2 which makes it the largest surface area in the body that inter-
acts with the external environment (Bjorksten 2006). The distal large
intestine is the area of highest colonization with more than 500 differ-
ent species (with some estimates suggesting up to 1,000 species) with
potentially up to 100 billion microbial inhabitants (Boyle and Tang
2006). This enormous microbial community has been estimated to be
in the region of 1014 microorganisms, the collective gene set of which
is termed the “microbiome” and is thought to contain approximately
100 times the number of genes in the human genome (Backhed et al.
2005; Xu and Gordon 2003). Based on a meta-analysis covering several
large Sanger-sequencing studies of human gut samples from different
populations the most numerically dominant phyla within the intestinal
microbial community are the firmicutes and bacteroidetes that comprise
more than 90% of the total bacteria. Other bacterial phyla that have
been isolated include also actinobacteria, gammaproteobacteria, verru-
comicrobia, and betaproteobacteria (Hamady and Knight 2009).
Although the major dominant bacterial groups have been described,
there is considerable species variation between individuals. For exam-
ple, all humans possess several hundred species within each genus in
their gut, however the foremost species within that genus will differ
considerably between individuals (Simon and Gorbach 1984). The re-
lationship between the human host and microbial symbionts is complex
and a focus of modern biology. This has led to collaborative research
projects the largest of which is probably the Human Microbiome Proj-
ect, which is a worldwide strategy aiming to further delineate the extent
of both human and microbial diversity. As it is a collaborative project
the techniques used are sophisticated and will result in a vast data set,
it is hoped that the project will be able to identify common features of
the microbiome at a global level. This will help determine the impact
 Introduction 21

of host genetics on the development and stability of the microbiome by

using genetically linked individuals evolutionary lineages (Ley et al.
2008; Turnbaugh et al. 2007).

2.1.2.  Techniques Used to Elucidate the Commensal Microbiota

Microbiological techniques traditionally relied on the ability of a

bacterium to grow on sterile semi or defined media in order to observe
colonies. This enabled preliminary classification of bacteria on the ba-
sis of culture phenotype and biochemical characteristics. This was also
the case for pioneering work in the area of gut microbiology; however,
the majority of bacteria in the gut are anaerobes, therefore they present
more of a challenge to grow in standard laboratory conditions. More
recently, use of a culture-independent approach has revealed the com-
plexity of the resident microbial communities; this was enabled by use
of oligonucleotide probes based on 16S rRNA gene sequences. Further
classification of bacteria based upon phylogenetic comparisons of the
16S rRNA sequences has been possible using qualitative and quanti-
tative techniques. For example, PCR reactions and fluorescent in situ
hybridization (FISH) use primers and probes respectively which tar-
get bacteria based on their 16S rRNA sequences. It is estimated that
these specific probes have enabled identification of up to 80% of the
total microbial diversity within the intestinal microflora, which would
not have been possible with cultural techniques alone. Recent metage-
nomic techniques with high-throughput pyrosequencing have further
explored functional genes encoded by the microbiome using annotation
schemes such as Kyoto Encyclopaedia of Genes and Genomes (KEGG)
pathways or Clusters of Orthologous Groups (COGs) (Turnbaugh et
al., 2006, 2007, 2009). Molecular analysis has shown that the aerobic
species present reach relatively high cell densities and metabolic activ-
ity in the human caecum, in fact 50% of total bacterial ribosomal RNA
was found to correspond to these species in this region of the gut. This
is in contrast to feces in which only 7% of the total bacterial rRNA from
these species is found (Marteau et al. 2001).

2.1.3.  Factors Affecting the Composition of the Gut Microbiota

In a healthy gut, there is a balance between potentially harmful, com-

mensal and beneficial bacteria. Probably the most important factors in
determining the initial colonization pattern are the type of delivery at
22 PREBIOTICS AND PROBIOTICS: CONCEPTS AND ADVANCES

birth (either vaginal or caesarean section) and the initial diet (whether
the newborn is fed mother’s milk or infant formula). The newborn mi-
crobiota changes rapidly during the first few weeks and during weaning
(Boyle and Tang 2006). Other important factors include the environ-
ment, age, gender, and diet (Santosa et al. 2006). Differences in mi-
crobiota composition have been found between infants born in differ-
ent countries and raised with different diets and even between hospital
wards (Adlerberth et al. 1991; Lundequist et al. 1985; Santosa et al.
2006; Simhon et al. 1982). The composition of the adult microbiota is
thought to be more stable, however acute effects can disrupt this ho-
meostasis for example, during antibiotic treatment, after gastrointes-
tinal surgery, exposure to radiation, and in some infectious (diarrheal)
disease states (Mombelli and Gismondo 2000). The stability of the mi-
crobiota is compromised in the elderly, demonstrating significant vari-
ability over time and between individuals; as well as lower species di-
versity (Claesson et al., 2011; Makivuokko et al, 2010).

2.2.  ROLES OF THE COMMENSAL MICROBIOTA

The presence of the gut microbiota has influenced human evolution

in that the human host cannot perform certain vital intestinal functions
without them. Germ-free animal models have provided useful insights
into the roles of the microbiota and the extent of interaction between the
host and the gut microbiota. It can be thought of as a ‘microbial organ’
as the processes performed by this diverse population are extensive; it
can communicate with itself (bacteria: bacteria) and with the host (bac-
teria: human). Maintenance of homeostasis is an interactive process
between the bacteria and host epithelia which influences both intesti-
nal physiology and the derivation and distribution of energy. Landmark
studies in recent years have shown that the composition of the microbi-
ome can have an impact on energy balance and obesity (Turnbaugh and
Gordon 2009; Turnbaugh et al. 2006).

2.2.1.  Fermentation

A major role of the microbiota is to ferment nondigestible dietary

components and endogenous mucus produced by the gut epithelium.
This is an example of a symbiotic relationship as the human host bene-
fits from a wide array of microbial enzymes which are outside the host’s
own biochemical repertoire. This provides the host with a source of
 Roles of the Commensal Microbiota 23

energy from the food ingested and also to the microflora which in turn is
used to sustain the microbial community. Fermentation differs accord-
ing to the site within the gut as shown in Figure 2.1. The major source of
energy from colonic fermentation is from carbohydrates, which include
large polysaccharides (such as plant derived pectin, hemicellulose, cel-
lulose, gums, and resistant starch) and also less complex carbohydrates
such as oligosaccharides and nonabsorbed alcohols and sugars (Cum-
mings et al. 1996; Cummings et al. 1987). Fermentation is not limited
to carbohydrates but also other dietary components such as proteins and
glycoproteins.

2.2.2.  Short Chain Fatty Acids

The main fermentation end products are short chain fatty acids
(SCFA) which are small organic molecules absorbed by diffusion; car-
riers mediated exchange or ion exchange processes. Common examples
include acetate, butyrate, and propionate, and are considered mainly as
compounds which provide a source of energy to the host. Fermenta-
tion activity differs according to area within the gut, the most metaboli-

FIGURE 2.1.  Fermentation in the colon. Fermentation activity differs accord-

ing to the specific location within the gut. The most metabolically active area
is the caecum and right (proximal) colon. The left side has a different pH
which favors a more proteolytic fermentation (Gibson and Roberfroid 1995).
24 PREBIOTICS AND PROBIOTICS: CONCEPTS AND ADVANCES

cally active area is the caecum and right colon, consequently this is an
area of rapid bacterial growth, low pH (5–6) and rapid generation of
SCFA as a result of carbohydrate fermentation (Cummings et al. 1987;
Macfarlane et al. 1992). Fermentation can also occur with noncarbo-
hydrate substrates, therefore proteolytic fermentation (of proteins and
peptides) also generates potentially damaging compounds such as am-
monia, amines, and phenolic compounds (Macfarlane et al. 1986). In
contrast, the left side of the colon has less carbohydrate fermentation,
the pH is less acidic, and it is associated with an increase in proteolysis
which has been linked to the production of harmful nitrogenous prod-
ucts, which accounts for the recommendation to eat a carbohydrate and
fiber enriched diet (Guarner and Malagelada 2003). The absorption of
ions such as calcium, magnesium, and iron in the caecum is improved
in the presence of SCFA (Roberfroid et al. 1995; Younes et al. 2001).
The presence of adequate SFCA causes colonic water and sodium ions
to be absorbed, therefore producing solid stools therefore having an
effect on intestinal transit time, although the mechanisms are unclear
(Elsen and Bistrian 1991). SCFA are not only a source of energy for
tissues but can also have important effects on host physiology as one
SCFA in particular, butyrate has been shown to inhibit the development
of colonic cancer cells in vitro (Pool-Zobel and Sauer 2007a). The co-
lonic epithelium almost entirely consumes the butyrate that is produced
as it is a preferred energy source (Cummings et al. 1987). SCFA have
a positive effect on epithelial cell differentiation and proliferation in
vivo. Some members of the gut microbiota also produce vitamins such
as folate, biotin, and vitamin K-2 (Conly et al. 1994; Hill 1997).

2.3.  THE GUT MICROBIOTA AND AUGMENTATION OF

HOST DEFENSE

2.3.1.  Barrier Function

One role of the commensal flora is to protect against infection from

exogenous organisms, of which there is a higher risk within the gastro-
intestinal tract. Several mechanisms are thought to contribute to this
process, which is collectively termed colonization resistance. The im-
portant role of the commensal microbiota in boosting host defense has
been confirmed in germ-free animals which demonstrate an increased
rate of susceptibility to infections relative to a wild type microflora
(Baba et al. 1991; Taguchi et al. 2002). Adhesion is thought to be a
 CHAPTER 7

Extraction and Purification of Bioactive

Ingredients from Natural Products
G. K. JAYAPRAKASHA and BHIMANAGOUDA S. PATIL

7.1. INTRODUCTION

Bioactive compounds are expected to play an important role as one

of the major sources of new drugs in the years to come because of
their incomparable structural diversity, the relatively small dimensions
(< 2000 Da), and their “drug-like” properties, i.e., their ability to be
absorbed and metabolized [1]. Isolation of natural products from higher
plants, marine organisms, and microorganisms is critical, using state-
of-the-art methodologies. The plant kingdom contains approximately
80–100,000 plant bioactive compounds and the separation and isolation
processes are cumbersome and tedious. Isolation of natural products
generally combines various separation techniques, which depends on
the solubility, volatility, and stability of the compounds to be separated.
The choice of different optimization parameters of separation is critical
and essential

7.2.  EXTRACTION OF BIOACTIVE INGREDIENTS

Isolation of bioactive ingredients from the plant materials is a trial

and error excise in which different solvents are tried under a variety of
conditions such as time and temperature. The main objectives of the

G. K. Jayaprakasha and Bhimanagouda S. Patil; Vegetable & Fruit Improvement

Centre, Department of Horticultural Sciences, Texas A&M University,
College Station, TX 77843-2119, USA.
153
154 EXTRACTION AND PURIFICATION OF BIOACTIVE INGREDIENTS

extraction and purification of unique/unstudied bioactive components,

exploring the potential of secondary metabolites for chemical finger-
printing or metabolomics studies, and bioassay derived identification
of bioactives.
Isolation of bioactive compounds involves dissolution of solutes
from the plant matrix, diffusion of the compounds into the extractant,
and separation of solutes using chromatographic techniques.

7.2.1.  Selection of Solvent

In choosing a solvent for the extraction of bioactives, the ability to

extract components has to be considered. For instance, ionic solutes can
be extracted from aqueous solvents. The general features of the bioac-
tive molecule that are helpful to ascertain the isolation process include
partition coefficient, acid-base properties, charge, stability, and molecu-
lar size. In literature, many basic extraction procedures are available
[2]. Solvent choice for the extraction is a critical step. Single solvent is
unlikely to extract all groups of bioactive compounds from the natural
plant materials. In most of the cases, these methods will be refined to
our requirements in terms of plant materials and solutes of our interest.
The expected outcome from this extraction process should be high pu-
rity product, adequate quantity of bioactive compound, and confirming
the stereochemistry of the molecule.
In general, three conventional methods were used for the extraction
of bioactive compounds such as solvents, steam, and supercritical flu-
ids. On a global level, water extraction is practised while making coffee
or tea. Basically, pretreated plant material is extracted with hot water
which takes up the flavor, taste, and color of the components. After
filtration, the extract is ready for consumption. In case of the isolation
of certain bioactive compounds from plant material by means of liquid
extraction, some technological problems needs to be resolved [3]. First
the plant material has to be pretreated in order to obtain reasonable
extraction yields. Another problem is the need for special solvents to
be used in the extraction procedure [4]. More recently, attention has
been focussed towards the isolation of specific compounds that can be
used in the food industry. Of particular interest is the isolation of bioac-
tive compounds, aromas, and fragrances from plants and fruits [5,6].
The sequential extractions of bioactives using nonpolar to polar sol-
vents are depicted in Figure 7.1. Various polarity solvents are reported
as follows: (1) nonpolar solvents (hexane, heptanes, petroleum ether,
 Extraction of Bioactive Ingredients 155

FIGURE 7.1.  Schematic flow sheet of bioassay directed isolation, characterization of bo-
tanicals by successive extraction with different solvents.

benzene, and toluene); (2) medium polar solvents (dichloromethane,

chloroform, ethyl acetate, acetone, and methyl ethyl ketone); and (3)
polar solvents (methanol, ethanol, acetonitrile, and water).

7.2.2.  Selection of Raw Materials

In a typical extraction process, the selection of raw material is criti-

cal. For instance, extraction of compounds sensitive to heat and light
such as carotenoids needs fresh raw materials, while certain fatty acids,
sterols, and phenolics can be isolated from dried material. Thus, drying
and grinding of plant material or homogenization of fresh raw material
is critical. Prior to choosing a method, it is necessary to establish the
main objective of the extraction [7,8].
156 EXTRACTION AND PURIFICATION OF BIOACTIVE INGREDIENTS

7.2.3.  Fractionation

After extraction from the plant, the bioactive components have to be

separated from the crude mixture. It involves further solvent partition-
ing and extensive chromatography by retaining their properties of the
desired compound, such as acidity, alkalinity, polarity, stability, molec-
ular size, and structure. This may involve simple crystallisation of the
compound from the crude extract, e.g., isolation of the glycoside dianel-
lin from Dianella caerulea [9] as well as crystallization of limonin from
citrus extract [10]. In some cases, the isolation can be assisted by the
preparation of suitable derivatives, imparting more easily manageable
properties of the desired compound, e.g., isolation of the swainsonine
as its triacetate from Rhizoctonia leguminicola and isolimonoic acid
was isolated as methyl isolimonate [11]. Finally, purification will be
performed to provide compounds of high purity for structural analysis,
which may be accompanied by appropriate techniques such as crystal-
lisation, sublimation, or distillation [12]. According to Pettit et al., the
isolation of bioactive compounds from natural sources is, “always chal-
lenging and every step require judgement, improvisation to discover
novel components,” [13].

7.3.  CONVENTIONAL EXTRACTION TECHNIQUES

Traditionally-used techniques for the extraction of bioactive com-

pounds are discontinuous, continuous, and hybrid approaches. The
discontinuous techniques include the use of either organic solvents
(sometimes assisted by ultrasound) or water, while steam distillation
and vacuum distillation are continuous methods. Some methods involv-
ing both continuous and discontinuous approaches, such as distillation–
extraction; Soxhlet extraction has also been reported [14].
Solvent extraction is a traditional method for extracting bioactive
compounds from different plant materials [15–17]. However, less polar
components present in most plant tissues may interfere with the subse-
quent separation [17,18]. The conventional methods for the extraction
of natural products are Soxhlet extraction, cold percolation, hot extrac-
tion, and sonication. These methods have certain drawbacks, including
long extraction time, use of large amounts of organic solvents, unsatis-
factory extraction efficiency, and potential degradation of labile com-
pounds. Therefore, the sequential solvent extraction is recommended
for efficient separation of bioactive compounds [19]. For this reason,
 Conventional Extraction Techniques 157

lipophilic compounds are removed with nonpolar organic solvents such

as hexane or dichloromethane [17, 20–23]. Meanwhile, the hydrophilic
constituents are extracted with polar solvents such as acetone, metha-
nol, ethanol, and water [21,24,25].
In some cases, the addition of a polar solvent, such as water, to the
sample may increase the recovery of more polar compounds [24,26].
Meanwhile, some bioactive compounds of low or medium polarity can
be extracted efficiently with more nonpolar solvents [27–29]. Direct ex-
traction of bioactive compounds of a low polarity can also be obtained
with polar solvent at high temperature [18,30]. However, the subse-
quent cleanup step to separate the low polar bioactive compounds from
the polar extract is a challenge [31].

7.3.1.  Continuous Techniques

This technique involves steam distillation along with solvent extrac-

tion for the isolation of essential oils from plants. This technique has
been applied extensively as a step prior to compositional studies of es-
sential oils, such as curcuma [32], marjoram [33], grapes [34], soybeans
[35], and lavender [36].

7.3.2.  Discontinuous Techniques

Solvent extraction has long been used for the isolation of essential
oils from natural products. This technique uses either pure organic sol-
vents or mixtures. Organic solvent extraction assisted by ultrasound,
also known as sonication, is another technique widely used for the iso-
lation of essential oils/extracts from plants. Thus, sonication methods
based on 20–30 minutes of extraction with methanol–chloroform mix-
tures have been used for the isolation of white clove essential oil [37]
and cyanogenic glucosides [38].
The use of organic solvent extraction has certain limitations such as
solvent residues in the extract, with the subsequent toxicological risk
and the long extraction time required in most cases for achieving ef-
ficient extractions. In addition, organic solvents have a low selectivity.
Thus, apart from the desired substances, high molecular weight, non-
volatile components, such as fatty oils, resins, waxes, and coloring mat-
ters, are coextracted. The nonfeasibility of automation of the technique
is another important drawback to be taken into account.
Water extraction (under ambient conditions, without the application
 CHAPTER 11

Mechanism of Neuroprotection by
Bioactive Compounds
R.C. STAVINOHA, B.Y. JAMISON, Y. GOMADA, V. MAITIN and
D.A. VATTEM

11.1. INTRODUCTION

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two
most prevalent neurodegenerative diseases worldwide [1]. These dev-
astating diseases are characterized by progressive and irreversible neu-
rodegeneration of particular neuronal networks in the brain that lead to
severe cognitive and behavioral dysfunction [1]. The etiology behind
the development of these diseases remains elusive [2]. Although ge-
netic susceptibility has been identified in both PD and AD, the majority
of cases are sporadic and without certain cause. It is thought that aging,
oxidative stress, and environmental factors are involved in the initia-
tion of the diseases; however, the molecular mechanisms that underlie
the pathogenesis are not clear. The current treatments for AD and PD
offer symptomatic relief, but do not affect the underlying neurodegen-
eration or natural course of the disease [2]. As such, the development of
treatments that can slow or reverse the pathological processes of these
diseases is currently a significant focus of research.

11.2.  ALZHEIMER’S DISEASE

AD is the most common neurodegenerative disease in the world. At

R.C. Stavinoha, B.Y. Jamison, Y. Gomada, V. Maitin and D.A. Vattem;

Nutrition Biomedicine and Biotechnology, Texas State University,
San Marcos, TX, USA, 78666.
251
252 MECHANISM OF NEUROPROTECTION BY BIOACTIVE COMPOUNDS

present, the disease affects 24% of the population over age 85.3 In the
year 2000, it was estimated that 4.5 million individuals in the United
States had AD, a number that is projected to rise to 14 million by 2050
[3]. This disease involves pathological events that affect the anatomy,
biology, and function of selective regions of the brain [4]. Specifically,
widespread neurodegeneration is observed in the cortex and hippocam-
pus [5]. AD is clinically characterized by a progressive loss in cognitive
function that typically begins with memory loss, anxiety, and depres-
sion. As the disease progresses, the symptoms evolve to severe motor
dysfunction, profound cognitive deterioration, and loss of independent
function [4]. Pathologically, AD involves a cascade of events that lead
to modifications in the metabolism of the amyloid precursor protein
(APP) and the tau protein [4]. These changes result in the characteristic
development of extracellular amyloid beta-protein (Aβ) deposits and
intraneuronal neurofibrillary tangles (NFTs), respectively [4,3]. Con-
sequently, common cell signaling pathways are affected and result in
neuronal network dysfunction, neuronal loss, neurotransmitter failure,
and cell death [4].

11.2.1.  Amyloid Beta-Protein Deposits

The APP is a transmembrane protein expressed ubiquitously in cells,

indicating that it has a normal biological role; yet, its function is un-
known [6]. In cases of AD, the APP is found to be aberrantly processed
to yield soluble Aβ oligomers and insoluble Aβ fibrils that aggregate
extracellularly in the brain [6]. The metabolism of APP normally oc-
curs through a cleavage by α-secretase, a membrane-bound protease
that acts on APP within the Aβ domain, therefore it does not produce
the Aβ peptide [4,7]. For unknown reasons, in AD, APP is processed
in an alternate pathway that involves two subsequent cleavages [7].
In this pathway, referred to as the amyloidgenic pathway, the enzyme
α-secretase first cleaves APP, releasing a membrane bound C-terminal
fragment consisting of 99 amino acid residues, referred to as C99 [4].
Gamma-secretase subsequently cleaves C99 and releases Aβ, typically
containing 40, 42, or 43 amino acids, into the transmembrane domain
[4]. The Aβ peptide can oligomerize to form soluble oligomers, but may
also converge to form insoluble fibrils in a beta-sheet conformation that
are deposited extracellularly [7]. It has recently been found that the sol-
uble Aβ oligomers accumulate in synapses and behave as a pathogenic
ligand to membrane proteins, which disrupts synaptic transmission and
 Alzheimer’s Disease 253

downstream events that are required for memory formation [7]. The
insoluble Aβ fibrils that form are deposited as plaques extracellularly
and contribute to neurodegeneration in several ways. Aβ plaques are
thought to directly contribute to synaptic dysfunction by altering syn-
aptic plasticity [4]. The plaques are thought to promote oxidative stress
by decreasing antioxidant enzymes, increasing free radical production,
and/or causing mitochondrial dysfunction [3]. Additionally, inflamma-
tion surrounding the plaque is believed to promote the degeneration of
nearby neurons [4]. Aβ plaques are also thought to disrupt cellular func-
tions by interacting with cell membranes and promoting oxidation [6].
Furthermore, Aβ plaques form poorly selective channels in the lipid
bilayer that disrupts the membrane potential responsible for generating
action potentials, which results in an influx of calcium into the cell that
promotes apotosis [6].

11.2.2.  Neurofibrillary Tangles (NFTs)

NFTs are intraneuronal protein aggregates primarily composed of

the hyperphosphorylated cytoskeletal protein, tau. The main function of
tau relates to microtubule stability. Tau is intimately involved in main-
taining the balance between assembly and disassembly of the micro-
tubules, a function that is essential to the stability of the cytoskeleton
and to the integrity of neurons [6]. The phosphorylation state of tau
modulates the stability of the microtubules and is regulated by various
protein kinases and phosphatases. However, in the case of AD, tau is
found to be aberrantly hyperphosphorylated, rendering it incapable of
microtubule interaction, consequently impacting normal neuronal func-
tions, morphology, and viability [6]. Recent evidence suggests that, in
addition to being a microtubule stabilizer, tau may regulate neuronal
excitability and serve as a master regulator of the trafficking of mol-
ecules within the cell that contribute to synaptic function [8]. These ad-
ditional functions are also disrupted by the hyperphosphorylation of tau
and contribute to the dysfunctional regulation of neuronal signaling and
synaptic function common to AD. This is evidenced by a strong correla-
tion between the hyperphosphorylated tau and a decrease in presynaptic
protein expression [9]. Interestingly, studies have shown that reduction
in the levels of tau prevents the neurotoxic effects of Aβ oligomers, sug-
gesting that the damage induced by Aβ oligomers on the synapses may
be mediated by the aberrant phosphorylation of tau. In addition, both
oxidative stress and soluble Aβ oligomers are believed to promote the
254 MECHANISM OF NEUROPROTECTION BY BIOACTIVE COMPOUNDS

actions of the kinases ERK, p38, and JN, which are capable of phos-
phorylating tau [8].The hyperphosphorylation of tau promotes its ag-
gregation and represents the main component of the insoluble NFTs
characteristic of AD [4].

11.2.3.  Pathological Mechanisms

Convincing evidence reveals that oxidative stress plays a key patho-

genic role in the dysfunction and death of neurons that drives neuro-
degenerative diseases. Free radicals are highly reactive and unstable
molecules formed constantly in cells and must be neutralized by an
antioxidant defense system to maintain redox homeostasis [1]. Oxi-
dative stress occurs when there is an imbalance between the produc-
tion of free radicals and the ability of the cells to neutralize these toxic
compounds [1]. When redox homeostasis is lost, the overabundant free
radicals react with and damage cellular components with destructive
consequences, such as lipid peroxidation, enzyme inactivation, nucleic
acid breakage, and altered membrane fluidity [6]. Oxidative stress can
cause damage to all biomolecules and eventually leads to cell death, if
not resolved [6]. The brain is particularly susceptible to conditions of
oxidative stress since it consumes approximately 20–30% of the oxy-
gen inspired [5]. Ninety percent of free radicals formed in the cell are
produced by the mitochondria, an organelle that neurons are highly reli-
ant on for oxidative phosphorylation and the maintenance of membrane
polarity [1]. Additionally, the brain contains a high concentration of
polyunsaturated fatty acids (PUFAs) that are particularly vulnerable to
oxidation [5]. Although oxidative stress is known to be a key factor in
AD pathology, it remains unclear if it is a cause or result of the disease
[6]. Evidence suggests that oxidative stress promotes the formation of
Aβ plaques and NFTs; however, it has also been observed that the pres-
ence of these protein aggregates promotes oxidative stress [6]. This re-
lationship creates a detrimental cycle of free radical production that
overwhelms the antioxidant defense system [6]. Many proteins have
been identified that are damaged by oxidative stress in AD, including
proteins involved in cell signaling, neuronal communication, antioxi-
dant defense, regulation of neurotransmitters, pH regulation, energy
metabolism, phosphorylation of tau, and processing of APP [5]. The
oxidative damage to these important proteins disrupts their activity and
contributes to the molecular dysfunction seen in AD [5]. An increase in
lipid peroxidation has also been observed in the brains of individuals
 Alzheimer’s Disease 255

with AD [6]. The peroxidation of the particularly susceptible PUFAs in

the cell membrane result in alterations in the membrane composition
and is thought to contribute to the decreased expression of the nicotinic
acetylcholine receptors commonly seen in AD [6]. In addition, byprod-
ucts of lipid peroxidation such as HNE and acrolein are capable of co-
valently modifying proteins and inhibiting enzyme activity [6]. HNE
has also been shown to upregulate the expression of β-secretase, thus
promoting the processing of APP to form Aβ peptide [6]. Oxidative
stress can also cause modifications to DNA, including strand break-
age, cross-linking, base modification, and oxidation of deoxyribose
[1]. Oxidative damage to mitochondrial DNA further promotes oxida-
tive stress by causing modifications in the electron transport chain that
lead to the leakage of electrons [6].
Originally, inflammation was thought to be a consequence of neuro-
degeneration, but recent evidence suggests that it may also be a primary
pathogenic factor [2]. The persistent formation of plaques and progres-
sive neuronal damage that occurs leads to the overactivation of microg-
lia, the immune cells of the central nervous system. The overactive mi-
croglia release large amounts of proinflammatory and cytotoxic factors,
which causes damage to the neurons and further activate microglia,
creating a vicious cycle of uncontrolled and prolonged inflammation
which drives neurodegeneration [10]. Excitotoxicity is another patho-
logical factor common to many neurodegenerative diseases, including
AD. Excitotoxicity results from the excessive activation of N-methyl-
D-aspartate (NMDA) receptors by glutamate; as a result, calcium levels
in the cell increase and triggers apoptosis [11].

11.2.4.  Risk Factors

The greatest risk factor for the development of AD is age [3]. It is

thought that the increase in oxidative stress that occurs with aging con-
stitutes a large part of the risk. Vascular diseases, such as hypertension,
hypercholesterolemia, and diabetes, also increase the risk of AD [3].
On top of vascular complications, diabetes poses an additional risk for
AD due to the effects of hyperinsulinemia and insulin resistance on
amyloid metabolism [3]. This correlation is evidenced by a significantly
high incidence of AD development among individuals with diabetes. It
has been suggested that hyperinsulinemia and insulin resistance leads
to decreased clearance and increased deposition of the Aβ peptide [12].
Additionally, impaired insulin-signaling results in abnormal glucose
256 MECHANISM OF NEUROPROTECTION BY BIOACTIVE COMPOUNDS

FIGURE 11.1.  Possible molecular mechanisms behind development of Alzheimer’s Dis-

ease.

and energy metabolism, oxidative stress, mitochondrial dysfunction,

and hyperphosphorylation of tau via increased activity of glycogen syn-
thase kinase 3 [7]. Although the majority of cases of AD are sporadic
and without certain cause, approximately 10% of cases can be ascribed to
genetic susceptibility [6]. Mutations in APP, presenilin 1, and presenilin 2
located on chromosome 21, 14, and 1, respectively, have been identified
to promote the abnormal processing of APP that leads to aggregation
[6]. Additionally, inheritance of the ε4 allele of the apolipoprotein E
gene on chromosome 19 increases the risk for the development of AD
[6].

11.3.  PARKINSON’S DISEASE

PD is the second most common neurodegenerative disease that af-

fects 0.3% of the population of industrialized countries [2]. The preva-
lence increases to 1% of the population over 60 years of age, and to 4%
of the population over 80 years of age [2]. PD involves a progressive
loss of neurons in the brain manifesting into characteristic motor and
 Parkinson’s Disease 257

non-motor symptoms. Motor symptoms include akinesia, bradykinesia,

rigidity, resting tremor, postural instability, and gait impairment [11].
Nonmotor symptoms include anosmia, depression, anxiety, sleep disor-
ders, gastrointestinal symptoms, autonomic dysfunction, and cognitive
impairment [11].

11.3.1.  Dopaminergic Pathway and Lewy Bodies

PD is a neurodegenerative disease of the central nervous system

hallmarked by the degeneration of dopaminergic neurons, dopamine
deficit, and the presence of Lewy bodies in remaining neurons [13]. Al-
though there are signs of pathology in multiple neuronal systems in PD,
the cardinal symptoms developed are ascribed to the progressive degen-
eration of dopaminergic neurons in the substantia nigra pars compacta
(SNpc) and subsequent loss of the neurotransmitter dopamine [10]. The
SNpc is critical for the control of motor function, since it promotes
voluntary movement and inhibits involuntary movement by affecting
the basal ganglia loops, a process mediated by dopamine receptor D1
activation and D2 inactivation [10]. Neurodegeneration in this dopa-
minergic pathway leads to dopamine depletion, which has shown to
alter the proportions of the D1- and D2-receptors [14]. Specifically, the
loss of dopamine results in reduced activity of the D1-receptor and in-
creased activity of the D2-receptor [14]. These pathological changes
in the dopamine receptors alter the balance in the basal ganglia loops
and result in the characteristic motor symptoms of the disease [10].
Lewy bodies are found in the cytoplasm of the remaining neurons of
the SNpc; however, they are also found in other nondopaminergic neu-
rons, including neurons of the amygdala, basal nucleus of Meynert,
hippocampus, and brain stem [10]. The presence of Lewy bodies in
these nondopaminergic neurons indicates that they play a role in the
development of the nonmotor symptoms associated with PD [2]. Alpha-
synuclein (α-syn) has been identified as the primary protein aggregate
found in Lewy bodies [11]. The exact cause of aggregation is unclear;
however, overexpression of the protein, genetic mutations, and oxida-
tive stress are thought to contribute [11]. Alpha-syn has been identified
as a key factor implicated in PD, because it plays an important role in
controlling the function of dopaminergic neurons; thus, the dysfunction
of this protein at dopaminergic synapses is thought to contribute to the
initiation of neurodegeneration [15]. Additionally, it is suggested that
the aggregation of α-syn has a pathogenic role in PD through exerting
258 MECHANISM OF NEUROPROTECTION BY BIOACTIVE COMPOUNDS

negative effects on the cell membrane and proteasomal functionality,

disrupting gene expression regulation, influencing cell signaling and
cell death pathways, promoting inflammation, and modifying the stor-
age and release of dopamine [11].

11.3.2.  Pathological Mechanisms

No single pathogenic event has been found to be the primary fac-

tor in the development of PD [11]. Rather, the process appears to be
multifactorial involving several mechanisms that act synergistically
in a complex manner to foster neurodegeneration [11]. Similar to AD,
mechanisms involved in the pathogenesis of PD include oxidative
stress, inflammation, and excitotoxicity [11]. Oxidative damage to lip-
ids, proteins, and nucleic acids has consistently been observed in the
SNpc of individuals with PD [11]. The cause of increased oxidative
stress in PD is unclear, but it has been suggested that mitochondrial
dysfunction and accelerated dopamine metabolism play a role [10]. The
exact cause of mitochondrial dysfunction in PD is also unknown, but
results in further production of free radicals, presumably by defects in
the electron transport chain that lead to the leakage of electrons [10].
Dopamine metabolism is accelerated in PD, and contributes to oxida-
tive stress through the concurrent production of free radicals such as
quinones and peroxides [10]. The vulnerability of dopaminergic neu-
rons to neurodegeneration in PD compared to other neuronal systems
may be linked to unique morphological and physiological properties
[10]. The dopaminergic neurons consist of long, narrow, branched pro-
jections that have higher basal energy requirements than other neurons,
rendering them more susceptible to damage caused by mitochondrial
dysfunction [10]. Additionally, dopaminergic neurons are particularly
susceptible to oxidative stress due to a high rate of oxygen and cal-
cium metabolism, elevated iron concentrations, and reduced levels
of antioxidants, specifically glutathione [10]. Inflammation is another
mechanism involved in PD, as evidenced by microglia activation in the
striatum and elevated levels of proinflammatory cytokines in the cere-
brospinal fluid and basal ganglia in individuals with PD [11]. Microglia
can become activated in PD in response to toxins, protein aggregates, or
damaged neurons and become chronically active as a result of positive
feedback from dying neurons, as seen in AD. Excitotoxicity is also im-
plicated in PD. Dopaminergic neurons have particularly high levels of
receptors for glutamate, the principle excitatory neurotransmitter of the
 Parkinson’s Disease 259

central nervous system, rendering them vulnerable to glutamate-medi-

ated toxicity [11]. As with AD, over activation of the NMDA receptors
by glutamate leads to increased intracellular calcium levels, which pro-
motes apoptosis [11].

11.3.3.  Risk Factors

The etiology behind PD is largely unknown, but there are some ge-
netic and environmental factors identified that contribute to the devel-
opment of the disease [10]. Similar to AD, age represents the biggest
risk for developing PD [11]. Environmental factors, such as the neuro-
toxin MPTP and certain pesticides are known to cause PD through the
inhibition of complex 1 in the mitochondria [1]. The active metabo-
lite of MPTP, MPP+, exerts toxic effects on the dopaminergic neurons
causing mitochondrial membrane potential impairment, altered calcium
handling, excessive free radical production, and ultimately cell death
[11]. Rotenone is an example of a pesticide that also exhibits detrimen-
tal toxic effects on complex 1 in the mitochondria [2]. Other environ-

FIGURE 11.2.  Possible molecular mechanisms behind development of Parkinson’s dis-

ease.
260 MECHANISM OF NEUROPROTECTION BY BIOACTIVE COMPOUNDS

mental risk factors include carbon monoxide poisoning, exposure to

solvents, and hydrogen sulfide intoxification [2]. Although rare, various
genetic mutations have been identified to cause PD in about 5–10% of
cases [16]. Specifically, mutations in α-syn, parkin, DJ-1, and LRRK2
are associated with the development of PD [1]. These mutations are
believed to cause mitochondrial dysfunction and increased oxidative
stress, and thus contribute to the development of PD [1].
A recent study reported that dysfunction of p38 or JNK of MAPK
signaling is involved in development of AD, PD, and amyotrophic lat-
eral sclerosis (ALS) due to its effects on development and apoptosis
[17]. It is reported that overexpression of p38 in microglia, astrocyte
and neuron may increase inflammation, excitotoxicity, and synaptic
plasticity via upregulation of TNF-α, IL-1β, and nitric oxide [18]. Also,
accumulation of amyloid β plaques and overexpression of p38 were
reported to involve tau phosphorylation, thus it is suggested that p38
MAPK signaling dysfunction may contribute to PD [18]. Also, acti-
vation of p38 MAPK signaling and inflammation via NF-κB was ob-
served in a MPTP-treated mice brain, and it is reported upregulation of
JNK mediated by ASK1 and MAPK increase neuronal cell death, thus,
p38 MAPK is considered to play important role in PD. Also, p38 can
phosphorylate GSK-3 along with PI3K/AKT, p38 MAPK is shown to
be involved in axonal regeneration [19]. As described, the activity of
p38 MAPK regulate many cellular functions, however, during several
pathologies, p38 MAPK is shown to be hyperactive, which has results
in the progression of neurodegenerative disease, therefore proper regu-
lation of MAPK signaling may become a therapeutic target of neuro-
degenerative disease. In an AD patient brain, reduced TGF-β signaling
are seen and suggested to progress formation of neurofibrillary tangles
of aggregates of Aβ, especially Aβ1-42 [20]. It is reported that the reduc-
tion of TGF-β signaling reduces trophic support of neuron from glial
cell and also reduces anti-inflammatory proteins, thus it is considered
to promote the progression of AD [21]. However, overexpression of
TGF-β signaling is reported to increase neuronal apoptosis and reduce
phagocytosis, thus increases accumulation of aggregated Aβ which may
contribute to AD ( Lee et al. 2010). Also, reduction of TGF-β is reported
to trigger apoptosis and is suggested to contribute to the development
of PD due to increase of ROS formation of microglia [23]. Activation
of TGF-β in macroglial cells attributes to inhibit PHOX induced ROS
production via prevention of Erk activity, thus activation of TGF-β may
play an important role in preventing PD progression through reducing
 CHAPTER 15

Therapeutic Potential of Green and

Black Tea in the Prevention and
Treatment of Various Diseases
A. SHEHZAD, M. UL-ISLAM, N. SHAH and Y. SUP LEE

15.1.  INTRODUCTION

Tea, derived from Camellia sinensis, is one of the most widely con-
sumed beverages in the world. It is cultivated mostly in China and In-
dia, as well as parts of some Asian and African countries [1,2]. Tea
has received interest from both scientific and consumer communities
for its health benefits. Tea is rich in substances with antioxidant prop-
erties and contains small quantities of proteins, carbohydrates, amino
acids, vitamins, and minerals [3]. Currently, high levels of tea drink-
ing throughout the world are attributed to its biological functionality,
rather than to habitual tea drinking, which is generally driven by its
flavor and stimulant effect. The presence of polyphenolic compounds
has given tea impressive therapeutic properties, including antioxidant,
anti-inflammatory, antitumor, and metabolic regulatory effects [4].
Although originating from the same plants, tea is categorized into
three main types based on their levels of oxidation [5]. Green and black
teas are processed differently during manufacturing. To produce green
tea, the freshly harvested leaves are steamed and dried to inactivate the

A. Shehzad and Y. Sup Lee; School of Life Sciences, College of Natural Sciences,
Kyungpook National University, Daegu 702-701, Korea.
M. Ul-Islam; Department of Chemical Engineering, College of Natural Sciences,
Kyungpook National University, Daegu 702-701, Korea.
N. Shah; Department of Chemistry, Abdul Wali Khan University, Mardan, K.P.K,
Pakistan.
343
344 THERAPEUTIC POTENTIAL OF GREEN AND BLACK TEA

polyphenol oxidase enzyme. This process retains the polyphenols in

their monomeric form. In manufacturing black tea, the tea leaves are
allowed time for extended fermentation, allowing polyphenol oxidase
to catalyze the catechin polymerization, resulting in the formation of
polymeric compounds [4]. The composition of black tea is thus depen-
dent on the production process. Oolong, a third type of tea, results from
the partial fermentation of tea leaves, and represents a mixture of green
and black tea compounds.
Both green and black teas are rich in flavonoids, which are water sol-
uble pigments belonging to a larger group of polyphenolic compounds
[6,7]. Flavanols are the main class of flavonoids found in tea. Although
the total flavonoid content in green and black tea is similar, their chemi-
cal structures vary. The main reason for this is that the additional fer-
mentation in black tea manufacturing facilitates the oxidation process
and leads to the conversion of flavonoids (catechin) found in green tea
into more complex varieties, mainly thearubigins and theaflavins [8,
9]. In green tea, catechin comprises 80–90% of the total flavonoids,
whereas in black tea it accounts for 20–30% of the total flavonoids [10].
The constituent components and their respective quantities in green and
black tea are presented in Table 15.1.
Green and black teas are associated with numerous health benefits.
The main factor responsible for the effective therapeutic potential of
both teas is attributed to catechins and theaflavins. The catechins and
theaflavins vary in their structures and properties [11]. Among cate-

TABLE 15.1.  Principal Components of Green and Black Tea.

Black Tea Green Tea
Compounds (% weight of extract solids) (% weight of extract solids)
Catechins 3–10 30–42
Theaflavins 3–6
Thearubigens 12–18
Flavonols 6–8 5–10
Phenolic acids, depsides, 10–12 6–8
and other Organic acids
Amino Acids 13–15 8–12
Methylxanthines 8–11 7–9
Carbohydrates 15 10–15
Protein 1 6–8
Mineral water 10 6–8
Volatiles < 0.1 0.02
 Chemistry and Stability 345

chins, the medicinal values are usually attributed to the epicatechins,

rather than catechins shown in Figure 15.1. In trials with animals and
humans, catechin and theaflavins showed health benefits, specifically in
reactive oxygen species (ROS) scavenging, reducing inflammation, en-
hancing heart function, blood purification, lowering body temperature,
strengthening teeth and bones, boosting the immune system, and slow-
ing aging [4,10,11]. These activities of tea constituents are dependent
on various factors, including metal-reducing potential, chelating behav-
ior, pH, solubility characteristics, and bioavailability and stability in
tissues and cells [12,13]. At present, the mechanisms of a number of tea
activities have yet to be elucidated, and the exact structural features of
certain theaflavins remain to be determined. The results of various stud-
ies showing the structural features and therapeutic potentials of green
and black teas are summarized.

15.2.  CHEMISTRY AND STABILITY

15.2.1.  Chemistry of Tea Compounds

The chemical composition of tea leaves is well known. As men-

tioned, the origin of both green and black tea is the same and they have
approximately similar chemical components. Table 15.1 presents a
comparative quantitative analysis of chemical compounds contained
in green and black tea. The main constituents of tea leaves are poly-
phenols, polysaccharides, proteins, chlorophyll, and alkaloids [14,15].
Among these, the polyphenols are considered to be the major active
constituents of tea and are well recognized as tea catechins that make up
approximately 25–35% of the dry weight of green tea leaves [16–18].
Catechins primarily belong to the flavonoid family, consisting of two
benzene rings (A and B) with a central dihydropyran heterocycle (C
ring). The structure of some basic catechins is shown in Figure 15.1.
Rings A and B are identical to resorcinol and catechol moieties, re-
spectively. It can be seen that carbon 2 and 3 of the catechin molecule
possess chiral centers that govern n2 (4) diastereoisomers, with two
each for the cis and trans configurations. Catechin is the name given to
the trans isomers, whereas cis isomers are known as epicatechin. The
most important of the catechins are epigallo catechin gallate (EGCG),
epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin
(EC) [4]. The antioxidant activities of the tea polyphenols are mainly
attributed to the chemical structures and functional groups attached at
FIGURE 15.1.  Chemical structure of green tea catechins. The eight different types of
catechins are (a) (+)-catechin, (b) EC, (c) GC, (d) EGC, (e) CG, (f) ECG, (g) GCG, (h)
EGCG.

346
 Chemistry and Stability 347

various positions, including a di- or tri- hydroxyl group in the B-ring,

an OH group at 5th and 7th carbon of the A ring, and a gallate group
located at the 3 position of the C-ring [19]. The attachment of a gallate
group governs additional catechins. All of these are shown in Figure
15.1.
As the manufacturing processes of green and black tea are very dif-
ferent, the types of polyphenols contained by both types of tea are also
different. The major chemical changes in the black tea constituents take
place during its extended fermentation process. It has been suggested
that during the fermentation process, the catechins undergo phenolic
oxidative coupling reactions and are converted to o-quinones. Further,
the continued oxidation process results in the development of polymer-
ic compounds, including polyphenols, theaflavins, and thearubigins. It
has been suggested that theoflavins are the coupling oxidation products
of EC and EGC [20]. The simplified oxidative mechanism of theaflavin
production is shown in Figure 15.2. Whereas, Figure 15.3 illustrates the
structures of four main theaflavins identified from black tea. These in-
clude theaflavin, theaflavin-3-gallate, theaflavin-30-gallate, and theafla-
vin- 3,30-digallate [11] .

FIGURE 15.2.  A proposed mechanism of theaflavins formation from catechin oxidation.

348 THERAPEUTIC POTENTIAL OF GREEN AND BLACK TEA

FIGURE 15.3.  Chemical structure of the four major black tea theaflavins. These include
(a) theaflavins (TF1), (b) Theaflavin-3-gallate (TF2a), (c) Theaflavin-3′-gallate (TF2b) and
(d) Theaflavin-3,3′-gallate.

15.2.2.  Stability of Tea Compounds

The stability of tea catechins is highly dependent on pH and tempera-

ture. Generally, the catechins are found to be unstable in neutral and
alkaline pH environments, and show good stability under acidic condi-
tions. A variety of chemical changes occur in catechins, mainly isom-
 Chemistry and Stability 349

erization (epimerization), oxidation, decomposition to small molecules,

and polymerization to oligomers or polymers under various conditions.
It has commonly been observed that the color of tea changes from green
(green tea) to brown upon boiling. The reason for this change is the
degradation of molecules.

15.2.2.1.  Effect of pH on the Stability of Tea Catechins

pH is very critical factor affecting the stability of catechins. In fact,

catechins are extremely stable in acidic solutions (pH < 4), whereas in
neutral or alkaline solutions (pH > 6), they are highly unstable [21,22].
It has been observed that green tea catechins were reduced to less than
10% when kept in a Krebs-Ringer buffer at pH 4, whereas they re-
mained almost unchanged in water, and only a 15% reduction was ob-
served after boiling for 7 hours [21,22]. The complete degradation of
EGCG and EGC were reported in sodium phosphate buffer at pH 7.4
for 3 hours, whereas the ECG decreased by 20% and (–)-EC remained
unchanged under the same conditions. Although the acidic conditions
markedly increase the stability of catechins, the effect differs with the
nature of the acids. The stability of green tea catechins was significantly
increased with the addition of ascorbic acid, while citric acid did not
provide any positive effect on the stability. Under alkaline conditions,
the dimerized products of EGCG are converted to theasinensin (A and
D rotational isomers) and P-2. Figure 15.2 illustrates the formation of
products from EGCG. The proposed mechanism illustrates that EGCG
was first dehydrogenated and then decarboxylated under oxidative con-
ditions in an alkaline medium [23,24].
The capacity of various catechins for variation differs in similar en-
vironments. Among the four catechins examined in alkaline solutions,
EGCG and EGC were equally unstable whereas EC and ECG were rela-
tively stable. The exact reason for the observed diverse stability is yet
to be clarified; however, the existence of an additional OH group at
position 5 in EGCG is considered to be one of the factors. The three
adjacent OH groups in EGCG and EGC were more susceptible to dev-
astation than the two OH groups in EC and ECG [21]. Further studies
have also shown the higher semiquinone free radical formation suscep-
tibilities of ECG in alkaline media [25].
In addition to degradation or polymerization, the catechin (EC, ECG,
EBC, and EGCG) molecules also exhibit small amounts of epimers pro-
duced from epimerization. The rate of epimerization varies under cer-
350 THERAPEUTIC POTENTIAL OF GREEN AND BLACK TEA

tain conditions that ultimately affect the relative amounts of the epimers.
The rate of epimerization is also largely dependent on temperature, pH,
buffer type, and concentrations of metal ions. The rate of epimerization
was much higher at pH 6 than the rate in distilled water [26].

15.2.2.2.  Effect of Temperature on the Stability of Tea Catechins

The stability of tea catechins is adversely affected at higher tempera-

tures. As mentioned earlier, the color of green tea turns brown at high
temperatures; an effect mainly attributed to the thermal variations in the
chemical structure of catechins. The most predominant change upon
heating is the conversion to isometric forms through epimerization.
An important study demonstrated that epimerization of catechin was
achieved when tea is subjected to a temperature of 40°C for an extended
period of time [27]. The study clarified that not only temperature, but
also time, are involved in the epimerization process. An example of
the epimerization process is the conversion of epigallocatechin gallate
to its epimer component gallocatechin gallate. It is also worth men-
tioning that the thermal process sometimes causes both epimerization
and degradation to occur simultaneously [28]. It has been reported that
epimerization of the four tea catechins, (–)-EC, ECG, EGC, EGCG,
and 3″-O-methyl- EGCG, increased with increasing time at 90°C [29].

15.2.3.  Effects of Oxygen Concentration and Metal Ions on the

Stability of Tea Catechins

In addition to conditions (pH and temperature), the stability of tea

catechins is also influenced by oxygen concentration and the presence
of free radicals and metal ions. The catechins are oxidized more effi-
ciently in the presence of higher oxygen levels and at lower antioxidant
concentrations [30]. It is more appropriate to say that oxygen concen-
tration is the main factor that facilitates the degradation of catechins,
even at a suitable temperature and pH. In an N2 atmosphere (low O2
concentration) at 37°C and pH 7.4, EGCG showed only a 5% reduction
after 6 hours. This small reduction in EGCG concentration was also
attributed to epimerization because no degradation product (dimers)
was detected. In contrast, under normal conditions (O2 atmosphere),
an EGCG aqueous solution drastically degraded (90%) in 2 hours and
completely diminished after 6 hours (no EGCG was left after 6 hours).
Metal ions are very reactive species. They react with catechins to
 CHAPTER 22

Bioactivity, Bioavailability, and Human

Health Effects of Berries’ Bioactive
Compounds
M.A. VAZQUEZ-CRUZ, S.N. JIMENEZ-GARCIA,
A.A. FEREGRINO-PEREZ and R.G. GUEVARA-GONZALEZ

22.1.  BIOACTIVE COMPOUNDS RESPONSIBLE FOR FUNC-

TIONAL PROPERTIES OF BERRIES

Berry fruits, such as bilberry (Vaccinium myrtillus), blackberry (Ru-

bus fruticosus), blackcurrant (Ribes nigrum), blueberry (Vaccinium
corymbosum), chokeberry (Aronia melanocarpa), cranberry (Vaccini-
um macrocarpon), grape (Vitis vinifera), raspberry (Rubus idaeus), and
strawberry (Fragaria x ananassa) are a particularly rich source of an-
tioxidants. Those compounds are mainly represented by vitamin C and
polyphenols such as anthocyanins, phenolic acids, flavonols, and tan-
nins. They are known as natural antioxidants, and due to their high con-
centration and qualitative diversity, berry fruits are increasingly often
referred to as natural functional foods. These findings have been con-
firmed in the research of Häkkinen and Törrönen (2000), Wang and Lin
(2000), and Taruscio et al. (2004). As demonstrated by clinical research,
the bioavailability of those naturally occurring compounds significantly
exceeds the health benefits carried by their corresponding supplements
in pharmaceutical form (Wang et al. 1996). Due to climatic conditions,
fresh berries are generally available several months a year, while some

M.A. Vazquez-Cruz, S.N. Jimenez-Garcia, A.A. Feregrino-Perez and

R.G. Guevara-Gonzalez; Division de Estudios de Posgrado, C.A. Ingenieria
de Biosistemas, Facultad de Ingenieria, Universidad Autonoma de Queretaro,
C.U. Cerro de las Campanas S/N, Colonia Las Campanas, C.P. 76010, Santiago
de Queretaro, Queretaro, Mexico.
561
562 BIOACTIVITY, BIOAVAILABILITY, AND HUMAN HEALTH EFFECTS OF BERRIES

of the harvested fruit is processed to juice, fruit beverages, frozen prod-

ucts, wine, jam, marmalade, and jelly (Da Silva et al. 2007).
Epidemiological studies indicate that persons who consume a diet
rich in fruits, vegetables, and whole grains have a reduced risk of chron-
ic diseases (Rui 2013). Fruits and vegetables are major sources of phy-
tochemicals. Phytocemicals are defined as bioactive non-nutrient plant
chemicals in fruits, vegetables, grains, and other plant foods that may
provide desirable health benefits beyond basic nutrition to reduce the
risk of major chronic diseases (Liu 2004). Among the fruits with this
type of phytochemicals or bioactive compounds are berries. Commer-
cially, the most important berries include members of the genus Vac-
cinium (blueberry, lingonberry, cranberry, bilberry), Rubus (blackberry,
black raspberry, red raspberry, arctic raspberry/bramble, cloudberry),
Fragaria (strawberry), and Sambucus (elderberry, red elderberry), and
are usually consumed in fresh and in processed forms in the human diet
(Stoner et al. 2008). The bioactive phytochemicals in berries fall into
several structural and chemical classes including phenolic acids (hy-
droxycinnamic and hydroxybenzoic acids), flavonoids (anthocyanins,
flavanols, flavonols), condensed tannins (proanthocyanins), hydrolyz-
able tannins (ellagitannins and gallotannins), stilbenoids, lignans, tri-
terpenes, and sterols (Seeram 2006; Tulipani et al. 2008). In addition
to the bioactives, berries contain many other constituensts including
vitamins, such as A, C, E, and folic acid, and minerals, such as calcium,
selenium, and zinc (Kresty et al. 2001). Berries contain high levels of
a diverse range of phytochemicals, most of which are phenolic mol-
ecules, mainly anthocyanins and ellagitannins that, collectively, are re-
sponsible for much of their antioxidant activity (Connor et al. 2002;
Wada et al. 2002; Cerda et al. 2005; Aaby et al. 2005), well as its color
and flavor (anthocyanins and tannins, respectively). Studies reported
that instrumental and sensory qualities of berries are affected by many
factors such as cultivars, geographic region, storage conditions, ripe-
ness, climate, and others may affect the concentration of phenolic com-
pounds and in the antioxidant capacity (Castrejon et al. 2008; Seeram
2008; Zhang et al. 2008)
Berry fruits are good source of phenolics. Phenolics are defined as
compounds possessing one or more aromatic rings with one or more
hydroxyl groups in the estructures. Generally categorized as phenolic
acids, flavonoids, stilbenes, coumarins, and tannins (Seeram 2006).
Phenolic compounds are secondary metabolism ubiquitous in all higher
plants. These compounds have numerous defense functions in plants,
 Bioactive Compounds Responsible for Functional Properties of Berries 563

e.g., they act as defense mechanisms against pathogens, parasites, pred-

ators, and UV irradiation, and also contribute to the color of plants.
They are often induced as a response to various stress conditions, e.g.,
light, temperature, humidity; and internal factors including genetic dif-
ferences, nutrients, hormones, etc., contribute to their synthesis (Strack
1997). Phenolics occur in plant tissues as simple substituted phenols,
mainly as glycosides, or as complex polymerized molecules with high
molecular weights. The concentration of phenolic compounds varies
between each species and varieties of berries, and is also affected by
factors such as climate, geographic region, storage conditions, etc.
(Kalt et al. 1999; Seeram 2008; Battino et al. 2009; Paredes-Lopez et
al. 2010; Kim et al. 2013).
The chemistry of berry phenolics directly influences their bioavail-
ability, metabolism, and biological effects in vivo (Manach et al. 2004,
2005). However, in general, the berries contain the following com-
pounds: flavonoids such as anthocyanidins (pelargonidin, cyanidin, del-
phinidin, peonidin, petunidin, malvidin), flavonols (quercetin, myric-
etin, kaempferol), flavonols (catechines) ((+)-catechin, (–)-epicatechin,
gallocatechin, epigallocatechin), phenolic acids such as cinnamic ac-
ids (caffeic acid, p-coumaric acid, ferulic acid), benzoic acids (proto-
catchuic acid, p-hydroxybenzoic acid, gallic acid), lignans such as se-
coisolariciresinol, and complex phenolic polymers (polymeric tannins)
such as ellagitannins (casuarictin) and proanthocyanidins (procyanidin
trimer [flavonols]) (Seeram 2006; Paredes-Lopez et al. 2010).
Anthocyanins are one of the dominant groups of flavonoids in berries
(up to 2,000–5,000 mg kg–1 fresh weight [FW]) (Määttä et al. 2001).
They are good absorbers of visible light, comprise a large group of wa-
ter-soluble pigments, and are responsible for the characteristic orange/
red/blue colors of berries such as strawberries, raspberries, blueberries,
and red and black currants. Their concentration is usually higher in the
epidermis and in the tissue directly under the skin compared to the cen-
tral part of the fruit (Paredes-López et al. 2010; Slatnar et al. 2012). For
example, anthocyanins represent 44% of phenolic compounds present
in strawberries. Anthocyanins comprise aglycones, anthocyanidins, and
their glycosides anthocyanins (Viskelis et al. 2009). In Berry fruits, an-
thocyanins are found in the form of mono-, di-, or triglycosides, where
glycoside residues are usually substituted at C3, or less frequently, at
C5 or C7. The most prevalent sugars are glucose, galactose, rhamnose,
arabinose, rutinose, sambubiose, and sophorose (Battino et al. 2009).
Anthocyanin glycoside residues are often acylated by acids: P-cou-
564 BIOACTIVITY, BIOAVAILABILITY, AND HUMAN HEALTH EFFECTS OF BERRIES

maric acid, caffeic acid, ferulic acid, and by p-hydroxybenzoic acid,

malonic acid or acetic acid (Viskelis et al. 2009). Caffeic and ferulic
acids are the most common phenolic acids in berries, and they are rarely
found free; in general they are esterified with other molecules as car-
bohydrates and organic acids. The most common esters of hydroxy-
cinnamic acids are chlorogenic acid, which is an ester between caffeic
acid and quinic acid, and is a commonly occurring compound in many
berries. For example, chokeberry is a good source of hydroxycinnamic
acid derivatives. They are represented by caffeic acid derivatives, chlo-
rogenic acid (301.85 mg/100 g dry weight), and neochlorogenic acid
(290.81 mg/100 g dry weight) (Lohachoompol et al. 2008). In cranber-
ry fruit, the hydroxycinnamate esters are present in quantities averaging
about 15 mg/100 g of fresh fruit (Pappas and Schaich 2009).
On the other hand, flavonoids and phenolic acids form the building
blocks for polymeric tannins, which can be classified into hydrolysable
and condensed tannins. Hydrolysable tannins are either gallotannins or
ellagitannins, are less frequently encountered, and have been found in
strawberries, raspberries, and blackberries (Holt et al. 2008). Berries,
especially those of Rosaceae family genus Rubus (red raspberry, arc-
tic bramble, and cloudberry), are rich in ellagitannins (Häkkinen et al.
200; Mullen et al. 2002). These berries and strawberries produce only
ellagitannins based on stable glucose conformation. In addition to pen-
tagalloylglucose, these berries contain dimeric or polymeric ellagitan-
nins with amounts of monomers (Haslam 1989). Some berries, such
as cranberry, also contain condensed tannins, called proanthocyanidins.
Small quantities of tannins were found in honeyberry and blackberry.
Lingonberry, strawberry, and cranberry are examples of berries rich in
diphenolic compounds called lignans (10–15 mg kg–1 dry weight) (Ma-
zur et al. 2000). Some other compounds found in berries is resveratrol
(stilbenes), the compound found in grapes mainly, however also found
small amounts of trans-resveratrol in bilberry (6.78 µg/g), cowberry
(30 µg/g), redcurrant (15.72 µg/g), cranberry (19.29 µg/g), and strawber-
ry (3.57 µg/g) (Ehala et al. 2005). The carotenoids are other compounds
present in berries. Cloudberry, blueberry, cranberry, and cowberry con-
tains 2,840, 2,140, 200, and 140 µg/100 g dry weight, respectively.
These berries also contain β-carotene but this pigment prevailed greatly
in cloudberry (83% of total carotenoids content). Lutein was the major
carotenoid in blueberry (71%). Cranberry contains β-carotene (28%),
lutein (23%), and neoxanthin (20%) (Lashmanova et al. 2012). On the
other hand, chokeberry also of β-carotene and lutein contains lycopene,
 Antimicrobial Activity of Berry Bioactive Compounds 565

β-cryptoxanthin, ζ-carotene, 5,6-epoxylutein, transviolaxanthin, cis-

violaxanthin, and neoxanthin (Lashbrooke et al. 2010).
The presented characteristics of various berry fruit species point to
vast differences in the type of their bioactive compounds. Such differ-
ences are observed with regard to both the content and the qualitative
composition of those compounds. The most significant health benefits
are ascribed to phenolic compounds and vitamin C. Owing to the rich
and diversified compositions of bioactive compounds and their health-
promoting properties which result mostly from their antioxidant activ-
ity, berry fruits are widely recognized as natural functional products
(Szajdek and Borowska 2008).

22.2.  ANTIMICROBIAL ACTIVITY OF BERRY

BIOACTIVE COMPOUNDS

The development of food products or ingredients with specific health

promoting benefits (nutraceuticals or functional foods) is currently the
fastest growing and most consumer-driven segment of the food industry
(Hussein et al. 2011). On the other hand, food-borne illnesses, the spread
of antibiotic-resistant pathogens, and concerns regarding safety of syn-
thetic antimicrobial agents have increased consumer demand for the use
of plant extracts as natural antimicrobials and antioxidants in foods (Al-
Zoreky 2009; Staszewski et al. 2011). Nature offers many different types
of antimicrobial compounds that play an important role in the natural
defense of all kinds of living organisms (Rodriguez Vaquero, et al. 2007).
Plant extracts containing flavonols, other phenolic compounds, and or-
ganic acids are potent antioxidants and some of them have shown ad-
ditionally good antimicrobial activity, which makes their possible use in
food systems reasonable (Choi et al. 2006; Kalogeropoulos et al. 2009).
Fruits and berries contain a variety of phenolic compounds located
in plant tissues, often in the surface layer of the plant, fruit, or berry,
which is in connection to their main natural function, to protect the
plant against environmental stress and pathogens. Berries are rich in
phenolic compounds, which are classified into four main groups: flavo-
noids, phenolic acids, lignans, and polymeric tannins (Nohynek et al.
2006). Flavonoid anthocyanins are common in bilberry, black and red
currant, chokeberry, strawberry, and raspberry, in which they appear
as colored substances (Määttä-Riihinen et al. 2004). Ellagitannins are
complex phenolic polymers, which are the main phenolic compound in
red raspberry and cloudberry.
566 BIOACTIVITY, BIOAVAILABILITY, AND HUMAN HEALTH EFFECTS OF BERRIES

Strawberries also contain ellagitannins, although the amounts are

lower (Aaby et al. 2005). The most common phenolic acids present
in berries are derivatives of either hydroxycinnamic acids or hydroxy-
benzoic acids. Lingonberry, strawberry, and cranberry are examples of
berries containing lignans (Nohynek et al. 2006).
Probiotic bacteria are widely used in functional foods. Therefore,
there is an interest in probiotic bacteria such as Lactobacillus aci-
dophilus as well as Bifidobacterium spp. together with plant derived
compounds, especially in their application in food technology, for their
positive impact on human health (Pascual-Teresa et al. 2010).
Antimicrobial activity of plant phenolics has been intensively stud-
ied, and, in addition to controlling invasion and growth of plant patho-
gens, their activity against human pathogens has been investigated to
characterize and develop new healthy food ingredients, medical com-
pounds, and pharmaceuticals (Chung et al. 1998). Berries are an im-
portant part of the Nordic diet, but they have also been used as natural
antimicrobial pharmaceuticals. Bilberry has been used, for example, for
gastrointestinal (GI) disorders, and cranberry has been a well-known
treatment in urinary infections. For example, cranberry has been report-
ed to control the growth of Listeria monocytogenes (Puupponen-Pimiä
et al. 2005; Nohynek et al. 2006) and to possess compounds suppress-
ing adhesion and growth of Helicobacter pylori (Vattem et al. 2005)
and bacteria causing urinary tract infections (Nohynek et al. 2006).
On the other hand, certain berries rich in tannins have been found to
increase bacterial infections. Two different types of polymeric tannins
in these berries protect against pathogenic bacteria. Presence of the A-
type linkage of cranberry (Vaccinium macrocarpon) proanthocyanidins
may enhance both in vitro and urinary bacterial antiadhesion activities
(Nile and Park 2013). Additionally, other tannin-containing berries may
contribute to this effect, as berry juices of a mixture of cranberries (Vac-
cinium oxycoccus) and lingonberries as well as cloudberry juice protect
against urinary tract infection (Kontiokari et al. 2003).
Among the berries, cranberries, cloudberries, red raspberries, straw-
berries, and bilberries possess clear antimicrobial effects against human
pathogens. Berry ellagitannins are strong antimicrobial agents acting as
possible antiadherence compounds in preventing the colonization and
infection of many pathogens (Puupponen-Pimia et al. 2005). The phe-
nolic extract of cloudberry, which is comprised primarily of ellagitan-
nins, has the strongest antimicrobial effect, followed by red raspberry
and strawberry. Salmonella spp., Staphylococcus spp., Helicobacter
 Effect of Berries Consumption Against Chronic Diseases Development 567

spp., and Bacillus spp. are the bacteria that are most sensitive to berry
phenolics. Additionally, the growth of Escherichia spp., Clostridium
spp., and Campylobacter spp., but not the growth of Lactobacillus spp.
and Listeria spp., is inhibited by berry phenolics (Nile and Park 2013).
Red raspberry phenolics and its ellagitannin fraction also have powerful
antimicrobial properties against the growth of human colonial patho-
gens, Klebsiella oxytoca and Proteus mirabilis (Nurmi et al. 2009).
Several mechanisms of action in the inhibition of bacteria are involved,
such as destabilization of cytoplasmic membrane, permeabilization of
plasma membrane, inhibition of extracellular microbial enzymes, di-
rect actions on microbial metabolism, and deprivation of the substrates
required for microbial growth (Kraft et al. 2008). The berry extracts
inhibited the growth primarily of gram-negative bacteria but had no ef-
fect on gram-positive bacteria. However, there is very little information
about the antimicrobial capacity of phenolics present in berries, except
in cranberry. Extracts of the aerial parts of bearberry and lingonberry
were active against the gram-negative bacteria E. coli and P. vulgaris.
The activity is known to be due to the phenolic glycosides arbutin and
metylarbutin.
Cloudberry, raspberry, and strawberry extracts were the strongest in-
hibitors of gram-negative bacteria, especially Typhimurium spp. (Chung
1998). Ellagic acid inhibits a range of pathogenic organisms includ-
ing Vibrio cholerae, Shigella dysenteriae, and Campylobacter spp. It
can be hypothesized that ellagitannins could be one of the components
in cloudberries, raspberries, and strawberries causing the inhibition
against Salmonella. The antimicrobial effects of berry extracts against
gram-negative bacteria decreased in the following order: cloudberry >
raspberry > strawberry > lingonberry > blueberry > cranberry > sea
buckthorn berry > blackcurrant (Nile and Park 2013).

22.3.  EFFECT OF BERRIES CONSUMPTION AGAINST

CHRONIC DISEASES DEVELOPMENT

Berries are known as being a good source of vitamin C, dietary fiber,

and minerals, and they contain high amounts of phenolic compounds,
including anthocyanins, chlorogenic acids, flavonols, and procyanidins,
resulting in high antioxidant activity that provides health benefits, and
conferring on berries the title of a functional food (Huang et al. 2012).
Berry extracts, rich in phenolic compounds and anthocyanins, have a
range of biological effects which prevent or reduce the incidence of
568 BIOACTIVITY, BIOAVAILABILITY, AND HUMAN HEALTH EFFECTS OF BERRIES

chronic disorders, including cancer, cardiovascular disease, diabetes,

inflammation, cancer, Parkinson´s and Alzheimer´s disease, and oth-
er pathologies (Knekt et al. 1996, 1997; Wang et al. 2000; Krikorian
et al. 2010) These diseases are caused, in part, by the conversion of
cellular macromolecules to specific reactive oxygen species (ROS)
during normal cellular metabolism (Weisburger 1999). ROS and free
radicals are produced in an extensive range of physiological processes.
Oxidative stress is an imbalance between the production of ROS and
antioxidant defense, and may lead to oxidative damage. This biologi-
cal condition may result from an insufficiency of antioxidant defense
mechanisms, intense production of ROS, and excessive activation of
ROS systems, which are implicated in aging and in the pathology of
many chronic disorders (Liu and Hotchkiss 1995; Winterbourn 2008).
In order to confront oxidative stress, human bodies have developed
mechanisms for maintaining redox homeostasis. These mechanisms in-
clude the nonenzymatic and enzymatic antioxidant defenses produced
in the body, that is endogenous, and others supplied by the diet namely
exogenous ones. The exogenous antioxidants include phenolic acids,
flavonoids, stilbenes, and tannins (Seeram 2008; Winterbourn 2008).
Phenolic compounds exhibit many biologically significant mechanisms
of action, such as scavenging or detoxification of ROS, blocking ROS
production, impacting cell cycle, suppression of tumors, modulation of
signal transduction, apoptosis, detoxifying enzymes, and metabolism
(Liu 2004; Hand et al. 2007). Berries contain high levels of natural
polyphenol components that act as potent antioxidants. Berry extracts,
rich in polyphenols, have a range of biological effects that can have
beneficial outcomes on human health.
Studies indicate that extracts of berries cardioprotective effect
(Whitson et al. 2004). For example, mechanisms for the prevention of
atherosclerosis by dietary antioxidants in fruits have been proposed.
In the LDL oxidation hypothesis, oxidized LDL cholesterol by free
radicals has been suggested as the atherogenic factor that contributes
to cardiovascular disease (CVD) (Berliner et al. 1997; Witztum and
Berliner 1998). When circulating LDLs are present at high levels in
blood, they infiltrate the artery wall and increase intimal LDL, which
can then be oxidized by free radicals. This oxidized LDL, in the intima
is more atherogenic than native LDL and serves as a chemotactic factor
in the recruitment of circulating monocytes and macrophages. Dietary
phytochemicals served as antioxidants that are incorporated into LDL
are themselves oxidized when the LDL is exposed to free radicals; this
 Effect of Berries Consumption Against Chronic Diseases Development 569

occurs before any extensive oxidation of the sterol or polyunsaturated

fatty acids can occur (Sanchez-Moreno et al. 2000). Therefore, they
are very effective inhibitors of low density lipoprotein oxidation, a key
step in the development of atherosclerosis as described in the study
by Heinonen et al. (1998) from inhibited human LDL and liposome
oxidation for phenolic extracts of berries (blackberries, red raspberries,
sweet cherries, blueberries, and strawberries), also have beneficial ef-
fects on platelet aggregation. At low levels, they provide protection of
nitric oxide levels in arterial systems. Nitric oxide is crucial for the
maintenance of flexible blood vessels and thereby important in con-
trolling blood pressure. The same author indicates that the antioxidant
activity of a Berry extract in the LDL oxidation was related to the pres-
ence of anthocyanins, but the activity in the liposome oxidation was
correlated with the amount of hydroxycinnamates. In complex lipid
systems where several different antioxidant and pro-oxidant actions oc-
cur simultaneously, it is obviously more difficult to observe the effect
of a single factor than in simplified radical scavenging models. In lipid
oxidation models, peroxyl radical scavenging and metal inactivation
properties are very important mechanistic factors, but the polarity of
the compound and the physical state of the lipid system also affect the
behavior of antioxidants. In addition, synergism, that is, the ability of
antioxidant compounds to reinforce each other, can have a significant
effect on the antioxidant response (Frankel 1998).
In addition, dietary phytochemicals can lower C-reactive protein
(CRP) dramatically. C-reactive protein, a marker of systemic inflam-
mation, has been reported to be a stronger predictor of CVD (Ridker
et al. 2002). An Iranian study in Tehran found that both fruits and veg-
etables were inversely associated with plasma CRP concentrations (Es-
maillzadeh et al. 2006), as did a 2004 study in Massachusetts (Gao et
al. 2004). Therefore, the anti-inflammatory activity of phytochemicals
may play an important role in the prevention of CVD. In addition, di-
etary phytochemicals have been shown to have roles in the regulation of
prostaglandin synthesis, reduction of platelet aggregation, regulation of
cholesterol synthesis and absorption, and reduction of blood pressure.
On the other hand, berry bioactive have many roles in cancer pre-
vention and certain berries are considerably more effective than oth-
ers. For example, the most active components in raspberry were the
ellagitannins, but these components break down readily and the resul-
tant products, including ellagic acid, may be the actual active compo-
nents (Ross et al. 2007). Roles in cancer prevention include protection
570 BIOACTIVITY, BIOAVAILABILITY, AND HUMAN HEALTH EFFECTS OF BERRIES

against oxidative DNA damage by the scavenging of ROS, inhibition

of the formation of carcinogen-induced DNA adducts, enhancement of
DNA repair, inhibition of carcinogen-induced tumorigenesis in animals,
and modulation of signaling pathways involved with cellular prolifera-
tion, inflammation, angiogenesis, modulate cell cycle arrest, and induce
apoptosis (programmed cell death). A study by Seeram et al. (2006),
showed that blackberry, black raspberry, blueberry, cranberry, red rasp-
berry, and strawberry extracts inhibit the growth of human oral (KB
and CAL27), breast (MCF-7), colon (HT29, HCt 116), and prostate
(LNCaP) cancer cell lines in a dose-dependent manner. The extent of
inhibition of cell proliferation was found to vary markedly with both the
type of Berry extract and the specific cell line studied. The effects of the
different berry extract on cell apoptosis was assessed using HT29 cell that
were treated with 200 µg/ml of each Berry extract. Strongest inhibition
of cell growth was observed for the raspberry, lowbush blueberry, and
cranberry juices. The authors reported that the inhibition of proliferation
by the berry juices was independent of caspase-dependent apoptosis but
appeared to involve cell-cycle arrest, as evidenced by down-regulation of
the expression of cyclin dependent kinases, cdk4, cdk6, cyclin D1, and
cyclin D3. Some of the berry juices also significantly inhibited the tumor
necrosis factor-induced activation of the COX-2 enzyme expression and
activation of the transcription factor, nuclear factor kappa B (NF-κB).
The authors concluded that different Berry fruits might act through
different mechanisms in their cancer preventive ability (Boivin et al.,
2007). Ding et al. (2006) investigated the effects of cyanidin-3-O-glu-
coside, isolated from blackberries, on gene expression in JB-6-cells.
Cyanidin-3-O-glucoside pretreatment led to dose-dependent decrease
in the expression of cyclooxygenase-2 (COX-2) and activities of AP-1,
NF-κB, and tumor necrosis factor (TNF)α, when the cells were treated
with 12-O-tetradecanolyphorbol-13-acetate or ultraviolet. Finally, and
anthocyanin-rich preparation from berries (wild blueberry, bilberry,
cranberry, elderberry, raspberry, and strawberry), was found to reduce
vascular endothelial growth factor (VEGF) expression in a spontane-
ously immortalized human keratinocyte cell line (HaCaT) and inhibit
endothelial tube formation in a Matrigel assay (Bagchi et al. 2004).
A study recently investigated whether the regulations of apoptosis
and the phase-II enzymes glutathione-S-transferase (GST) and quinone
reductase (QR) are potential mechanisms through which blueberry
may prevent cancer. Srivastava et al. (2007) showed that anthocyanin-
enriched fractions purified from the blueberries induced apoptosis of
 CHAPTER 27

Emerging Sources for Marine

Nutraceuticals
E. APOSTOLIDIS and C.M. LEE

27.1.  INTRODUCTION: GLOBAL PERSPECTIVE IN

MARINE NUTRACEUTICALS

Jacques Cousteau, who is considered a father of ocean exploration,

once said, “The future of nutrition is found in the oceans.” While the
majority of nutraceutical products in the current market are of botanical
origin, marine-based nutraceuticals are gaining attention due to their
unique features which are not found in the terrestrial-based resources.
In recent years, a series of promising new marine nutraceutical products
have been introduced to the nutraceutical and functional foods markets.
Currently, functional foods are one of the major consumer trends in the
food industry. Consumers continue to seek multiple ways to enhance
their health to prevent diseases, and to promote healthy aging by paying
more attention to what they are eating and how it benefits their health.
Today, consumers are more concerned about their weight, cardio-health,
digestive-health, and immunity than ever before. Since health is a major
concern of consumers, manufacturers are finding new ways to incor-
porate natural and innovative ingredients into food products for health
benefits. The sales of functional foods and beverages have been rising
with a constant 8% per year since 2003. In 2006, the market of func-

E. Apostolidis; Chemistry and Food Science Department, Framingham State

University, Framingham, MA, 01701.
C.M. Lee; Department of Nutrition and Food Sciences, University of Rhode Island,
Kingston, RI 02881.
715
716 EMERGING SOURCES FOR MARINE NUTRACEUTICALS

tional foods and beverages was $195 billion and is estimated to reach
$195 billion by 2013. Functional foods are defined as “those foods that
encompass potentially healthful products including any modified food
or ingredient that may provide a health benefit beyond the traditional
nutrients it contains.” These ingredients vary and include antioxidants
(vitamins and phenolic phytochemicals), omega-3 fatty acids, plant ste-
rols, and many more. In recent years, a series of promising new marine
nutraceutical products have been introduced to the nutraceutical and
functional foods markets. This chapter presents an outline of emerging
sources for marine nutraceutical development. The main sources and
products of primary interest for emerging marine nutraceuticals include
phospholipids bound omega-3 fatty acids, micro/macro algal nutrition
supplements, fish proteins and peptides, and shellfish derived oligo-
molecules of chitin. Also discussed are emerging products, production
methods, the ongoing R&D activities, and challenges in marine nutra-
ceutical markets, along with future developments in marine nutraceuti-
cal industry and research.

27.2.  PHOSPHOLIPID-BOUND OMEGA-3 FATTY ACIDS

Fish oils are a rich source of long-chain omega-3 polyunsaturated

fatty acids (PUFA), which have attracted much attention in the recent
years. Fish oil is produced from various sources of marine fish, i.e.,
anchovy, menhaden, herring, mackerel, salmon, cod liver, and mussel,
and marketed in various forms, most commonly concentrated omega-3
oil in soft gel capsules and microencapsulated powder. Phospholipids
of marine origin or phospholipid-bound omega-3 fatty acids are consid-
ered a good source of more bioavailable and more stable omega-3 fatty
acids when compared to free omega-3 fatty acids. Currently, marine
phospholipids are produced from krill and squid in commercial quanti-
ties.

27.2.1.  Krill Derived Phospholipids

Krill, which means “whale food” in Norwegian, are eucarid crusta-

ceans divided into two families. Krill occur in all oceans of the world.
They are considered an important trophic connection—near the bot-
tom of the food chain—because they feed on phytoplankton and to a
lesser extent zooplankton, converting these into a form suitable for
many larger animals for whom krill makes up the largest part of their
 Phospholipid-bound Omega-3 Fatty Acids 717

diet (Baker et al. 1990; Brinton 1962). The Bentheuphausiidae fam-

ily consists solely of Bentheuphausia amblyops (Brinton 1962), a deep
water krill species that differs from members of the Family Euphausi-
idae in that Bentheuphausia amblyops is not bioluminescent. The Eu-
phausiidae family includes the other 89 known krill species, including
one of the most common, Euphausia superba (Brinton 1962), which is
the most frequent species associated with krill. Well-known species—
mainly because they are subject to commercial krill fishery—include
Antarctic krill (Euphausia superba), Pacific krill (Euphausia pacifica),
and Northern krill (Meganyctiphanes norvegica) (FAO 2010). The
two major krill fisheries are the Antarctic Ocean and the North Pacific
Ocean along with the coasts of Japan and Canada (FAO 2010). While
about 100,000 tons of krill are harvested annually, this represents only
about 0.1% of the estimated existing population (Deutsch 2007). Whole
krill are composed of 60–80% protein, 7–26% lipid, and 12–17% ash
on a dry weight basis (Grantham 1977; Pierce et al. 1969). Krill oil ex-
tracted from Antarctic krill (E. superba) is rich in phospholipid-bound
omega-3 fatty acids, mainly EPA and DHA. Krill oil also contains vari-
ous potent antioxidants, including vitamins A and E, astaxanthin, and
a novel flavonoid (similar to 6,8-di-c-glucosylluteolin but with two or
more glucose molecules and one aglycone) (Bunea et al. 2004; Deutsch
2007; Sampalis et al. 2003). Krill oil for dietary commercial applica-
tions is extracted by a cold vacuum extraction process that protects
the biomass from exposure to heat, light, or oxygen to prevent lipid
oxidation and maintain the original nutrients of krill intact (Deutsch
2007).

27.2.2.  Squid Byproduct Derived Phospholipids

Squid belongs to marine cephalopods of the order Teuthida, which

comprises around 300 species (Clarke et al. 1996). Like all other
cephalopods, squid has a distinct head, bilateral symmetry, a mantle,
and eight arms arranged in pairs and two longer tentacles (Clarke et
al. 1996). According to the FAO, the cephalopod catch for 2002 was
3,173,272 tons of which 2,189,206 tons, or 75.8%, were squid (FAO
2003). In the northeastern United States, approximately 19,100 tons of
squid were landed annually since 1998 with steady landings projected
(Cardin 2000; NOAA 2008). Due to the high demand for cleaned squid
in the United States market, most of harvested squid is processed re-
sulting in 40–50% of unutilized byproducts, causing a serious disposal
718 EMERGING SOURCES FOR MARINE NUTRACEUTICALS

problem. According to Point Judith Fishermen’s Co. (Narragansett, RI)

and Sea Fresh USA (North Kingstown, RI), it is estimated that squid
processing plants, which are located mainly in Rhode Island, New
York, and New Jersey, generate in excess of 4,500 tons of processing
byproduct annually. Squid processors pay to dispose of the squid pro-
cessing byproduct at a rate of $65–$90/ ton (approximately $100,000/
year per processor). The squid processing byproduct consists mainly of
head, fin, and viscera, along with unclaimed mantles and tentacles, and
contains approximately 11–14% protein, 2–3% lipids (mostly phospho-
lipids), with 11.6% EPA and 24.5% DHA omega-3 fatty acids in oil,
0.6–1.3% ash, and 84–85% moisture (Lian et al 2005). The lipid con-
tent of squid byproducts is around 2.5% (De Koning 1993; Lian et al.
2005) and 75% of total lipid is in the form of phospholipids (De Koning
1993; Lian et al. 2005).

27.3.  HEALTH BENEFITS

27.3.1. Bioavailability: Nonphospholipid Bound versus

Phospholipid Bound Omega-3 Fatty Acids

Omega-3 fatty acids are considered essential fatty acids since they
are necessary for human health but the body can’t make them and need
to be delivered either through diet or dietary supplements. However,
in order to have a physiological and health beneficial effect they need
to be first absorbed through the intestinal wall and then from the cells
of interest for the specific health benefit. Several studies indicate the
beneficial role of phospholipids in enhancing the therapeutic efficacy
of some molecules that have poor absorption. Since the 1980s, phos-
pholipid complexes began to be a common method to increase bio-
availability and absorption of several drugs (Ranade 1989). Silibinin,
also known as silybin, is the major active constituent of silymarin, the
mixture of flavonolignans extracted from blessed milk thistle (Silybum
marianum) and is a molecule that has poor water solubility and bio-
availability. It was observed that the silybin-phospholipid complex has
significantly higher therapeutic efficacy over the pure molecule in pro-
tecting the liver and exerting antioxidant activities (Carini et al. 1992;
Comoglio et al. 1995; Conti et al. 1992; Morazzoni et al. 1993; Yanyu
et al. 2006). Quercetin is a flavonol, plant-derived flavonoid, used as
a nutritional supplement that has been reported to have poor absorp-
tion (Hollman et al. 1996, 1997; Manach et al. 1996; Miyazawa et al.
 Health Benefits 719

1999; Scalbert and Williamson 2000). Recent studies have shown that
queretin-phospholipid complex has better therapeutic efficacy than
the compound alone in rat liver injury induced by carbon tetrachloride
(Maiti et al. 2005) and enhanced absorption in rats (Azuma et al. 2002).
Curcumin is a low molecular weight polyphenol derived from the rhi-
zomes of turmeric (Curcuma longa) that has a vast array of beneficial
pharmacological effects (Bush et al. 2001; Gescher et al. 2001; Ireson
et al. 2001; Park et al. 2000; Perkins et al. 2002; Ruby et al. 1995; Shao
et al. 2001; Sharma et al. 2001a; 2001b). Despite the promising bio-
logical effects of curcumin, poor bioavailability in both rodents and hu-
mans was reported by several researchers (Ammon et al. 1991; Ireson
et al. 2001; Pan et al. 1999; Wahlström et al. 1978). Recent studies have
shown that curcumin phospholipid-complex has better hepatoprotective
activity (Maiti et al. 2007) and better bioavailability (Liu et al. 2006)
than free curcumin.
Omega-3 fatty acids have been found to be readily absorbed (Naka-
mura and Nara 2004) in the small intestine once they are released from
lipids, after being hydrolyzed by pancreatic enzymes (Lichtenstein and
Jones 2001). However, research studies have shown that the associa-
tion between phospholipids and long-chain omega-3 fatty acids highly
facilitates the passage of fatty acid molecules through the intestinal
wall, increasing bioavailability and ultimately improving the omega-
3:omega-6 fatty acid ratio (Cansell et al. 2003; Werner et al. 2004),
thus increasing the health beneficial efficacy of omega-3 fatty acids.
Recent studies indicate that phospholipid-bound omega-3 fatty acids
have better efficacy for premenstrual syndrome management (Sampalis
et al. 2003) and hyperlipidemia management (Bunea et al. 2004) when
compared to fish oil non phospholipid-bound omega-3 fatty acids. A
recent clinical study compared the bioavailability of EPA and DHA be-
tween krill oil and menhanden oil (Maki et al. 2009). The daily quantity
of EPA provided in the krill (216 mg) and menhanden oil (212 mg) in
this study was comparable. However, the DHA present in krill oil (90
mg/d) was approximately half of that provided in the menhanden oil
(178 mg/d). At the end of the treatment period (4 weeks), the mean plas-
ma EPA concentration was slightly higher in the krill oil group when
compared to menhanden oil group (377 versus 293 µmol/ L), whereas
the mean plasma DHA concentrations were comparable (476 versus
478 µmol/ L) (Maki et al. 2009). These results suggest that phospholip-
id-bound EPA and DHA from krill oil could be better absorbed thank
those from menhaden oil. Since the concept of phospholipid-bound
720 EMERGING SOURCES FOR MARINE NUTRACEUTICALS

omega-3 fatty acids is emerging and taking into consideration their

positive effect on nutraceutical compound bioavailability, more studies
on the effect of the phospholipid complex on omega-3 fatty acid bio-
availability are expected in the coming years.

27.3.2.  Omega-3 Fatty Acids and Cardiovascular Disease

Cardiovascular disease (CVD) is an abnormal function of the heart or

blood vessels. It can cause an increase in risk for heart attack, heart fail-
ure, sudden death, stroke, and cardiac rhythm problems, thus resulting
in decreased quality of life and decreased life expectancy. The causes
of cardiovascular disease range from structural defects to infection, in-
flammation, environment, and genetics. One in three American adults
has some form of CVD. Heart disease and stroke are the most com-
mon cardiovascular diseases and are the first and third leading causes of
death for both men and women in the United States (Mayo clinic 2010).
CVD is the leading cause of deaths in the Western societies (Delorgeril
2001) and has been linked to the high fat intake, particularly saturat-
ed fats, common in Western diets (Dolecek and Granditis 1991). The
association between omega-3 fatty acids and cardiovascular disease
was first indicated in the 1950s following comparison studies between
Greenland Inuits and Danish settlers of Greenland (Sinclair 1956). Both
groups were consuming approximately the same amounts of fat (40%
of caloric intake), however, the Greenland Inuits had lower incidence of
heart disease, despite the higher intake of dietary cholesterol (Sinclair
1956). Later in the 1970s, the low mortality rate from coronary heart
disease of Greenland Inuit, was reported to be linked to the high ome-
ga-3 fatty acid in the Inuit diet which consisted mainly of fish, seal, and
whale (Dyerberg et al. 1975). There are many theories regarding the
mechanisms of action of omega-3 fatty acids in cardiovascular disease.
It is thought that they have a multifactorial mode of action including an-
tiarrhythmic effects, antithrombotic effects, antiatherosclerotic effects,
anti-inflammatory effects, improvement in endothelial function, lower-
ing of blood pressure, and lowering of triglyceride concentrations (Al-
bert et al. 2002; Harris 2007; 2006; Kang and Leaf 2000; Knapp 1997;
Morris et al. 1993; Nair et al. 1997). In the recent years, clinical trials
have assessed the effects of fish and fish oil on CVD prevention. The
diet and reinfarction trial (DART) showed a 29% reduction of mortality
rate among 2,033 men with a recent myocardial infarction, linked to the
omega-3 fatty acid consumption (Burr et al. 1989). The Gruppo Italiano
 Health Benefits 721

per lo Studio della Sopravvivenza nell’Infarto Miocardico Prevenzione

(GISSI-Prevenzione) trial that lasted for three-and-a-half years showed
30% reduction of risk of cardiovascular disease death and 45% reduc-
tion of sudden death incidence among 11,324 patients after myocardial
infarction and was linked to omega-3 fatty acid consumption (Grupo
Italianoperlo Studio 1999). In the Asian population, patients with a sus-
pected myocardial infarction showed a significant reduction in mortality
rate from coronary heart disease due to omega-3 fatty acid supplemen-
tation (Singh et al. 1997). A clinical trial compared the effect of krill oil
derived phospholipid bound omega-3 fatty acids with fish oil and ac-
cording to Bunea et al. (2004), krill oil was significantly more effective
than fish oil for the reduction of glucose, triglycerides, and LDL levels.
Another clinical study with 76 overweight and obese adults compared
the effect of krill oil phospholipid-bound omega-3 fatty acids and men-
handen oil and according to Maki et al. (2009), krill oil supplementa-
tion produced significant elevations in plasma levels of EPA and DHA.
The above findings confirm the better potential of phospholipid-bound
omega-3 fatty acids for cardiovascular disease prevention, mainly due
to better bioavailability.

27.3.3.  Omega-3 Fatty Acids and Inflammatory Disease

Inflammation is an important component of the early immunologi-

cal responses, while inappropriate or dysfunctional immune respons-
es underlie chronic inflammatory and autoimmune diseases. Onset of
autoimmune and inflammatory diseases has been linked to omega-3
and omega-6 imbalance (James et al. 2000; Simopoulos 2002; Song
2008),with omega-3 fatty acids exerting anti-inflammatory properties
(Shahidi 2007; Simopoulos 2002; Song 2008). Arachidonic acid, an
omega-6 fatty acid, is the precursor of eicosoanoids that produce com-
pounds that activate macrophages and induce inflammatory response
(Simopoulos 2002; Song 2008). On the other hand, EPA, an omega-3
fatty acid, competes with arachidonic acid (Simopoulos 2002) and has
been shown to inhibit certain immune functions, such as the produc-
tion of ecosanoids and proinflammatory cytokines(Song 2008). Sev-
eral scientific findings have indicated the positive effect of omega-3
fatty acids on inflammatory disease management (Shahidi 2007; Song
2008). These findings have shown that omega-3 fatty acids can reduce
proinflammatory cytokine production (Din et al. 2004; Hulshof et al.
1999; Kamal-Eldin and Yanishlieva 2002; Newton and Snyder 1997;
722 EMERGING SOURCES FOR MARINE NUTRACEUTICALS

Watanabe and Ackman 1974), manage bronchial inflammation (Holmer

1989), and arthritis (Shahidi 2007). In regards to phospholipid-bound
omega-3 fatty acids, a clinical study with 90 patients has shown that
krill oil inhibits inflammation and reduces arthritic symptoms within a
short period of treatment (Deutsch 2007).

27.3.4.  Omega-3 Fatty Acids and Brain Functions

All membranes, whether they are cell surface or form of an intra-

cellular organelle, are composed of phospholipid bilayers. Membrane
lipids provide flexibility and adaptable structure into which are inserted
proteins and glycoproteins such as enzymes, transporter proteins, or re-
ceptors (Farquharson et al. 1995). More specific research has shown
that phospholipids of the brain have an especially high content of the
long chain omega-3 fatty acid, DHA, and that these phospholipids are
involved in brain function (Amaducci et al. 1991; Hirata and Axelrod
1980; Salem and Niebylski 1995) The structural predominance of DHA
in the brain suggests functional significance and according to Young
and Conquer (2008), both DHA and EPA are linked with several as-
pects of neural function, including phospholipase A2 (PLA2) activity,
inflammation, neurotransmission, membrane fluidity, oxidation, ion
channel, enzyme regulation, and gene expression. It has been suggested
that under pathological conditions, seen in neuropsychiatric disorders
such as schizophrenia, an increase in the activity of PLA2 can results in
a decrease in neuronal membrane phospholipid biosynthesis and an in-
crease in phospholipid breakdown (Horrobin 1998). Finnen and Lovel
(1991) have shown that EPA can inhibit PLA2 and according to Mellor
et al. (1996), administration of EPA has shown considerable success
in the treatment of schizophrenia and bipolar disorder. Modulation of
neurotransmitters, such as serotonin and dopamine, has been shown to
be a causative factor for unipolar and bipolar depression (Mundo et al.
2001; Ogilvie et al. 1996; Post et al. 1980). Several studies have shown
that supplementation through diet of DHA and EPA contribute towards
the increased concentrations of serotonin and dopamine (Austed et al.
2000; Chalon and Delion-Vancassel 1998; Zimmer et al. 2000,1999;
Owens and Innis 1999). A clinical study on 70 patients diagnosed with
premenstrual syndrome showed that supplementation of phospholipid
containing krill oil reduced the emotional symptomatology that charac-
terizes premenstrual syndrome (Sampalis et al. 2003). In this study, it
was suggested that the effectiveness of krill oil could be based on po-
 Index

Abiu (Pouteria caimito), 552 Aglycones, 52, 58, 61, 104, 160, 178,
Açaí, 526, 534, 545–546 459, 483–485, 563, 577, 584,
Acerola, 527–529, 534, 543 596–601, 610, 647, 655, 663–664,
Acetate, 23, 35, 52, 83, 92, 98, 130, 155, 167, 717
185, 211, 279, 307, 374, 492, 510, 540, Ajoene, 422, 426, 440–442, 444, 448
570, 580 Akinesia, 257
Acetic acid, 3 Alanine amino transferase (ALT), 380, 405,
Acetylcholine, 238, 255, 261–265 435
Acetylcholine receptors (AchR), 238 Aldolase, 27, 91–92, 141
Acetylcholinesterase, 262 Aldosterone, 106
Acetylsalicylic acid, See Aspirin Algae, 14, 16, 72, 723–725, 728, 731
Acinetobacter spp., 376 Alginate, 6
Acrolein, 237, 255 Sodium alginate, 6
Actinomycetes, 27 Alginic acid, 3, 724
Activator protein-1 (AP-1), 48, 383, 505, Aliphatic, 59, 176, 181, 183, 439, 645,
509–510, 570 653–656, 668, 669
Acyl CoA cholesterol transferase (ACAT), Alkaline phosphatase, 316, 405
66 Alkaloids, 3, 186, 207, 272, 278, 290, 329,
Adipogenesis, 378 345, 440
Adiponectin, 501, 502, 759–761 Allergy, 3
Adrenergic, 275, 542 Allicin (diallyl thiosulfinate), 421–425,
Adsorption, 163–164, 167 440–441
Advanced glycation end products (AGE’s), Alliin, 3, 418, 421, 426, 440, 447
212–215, 466, 528, 543 Alliinase, 417, 421, 426
Aflatoxin, 431 Allium spp.
Agar, 6, 724, 727 A. ampeloprasum, 417
Agaricus spp. A. cepa, 417
A. bisporus, 691, 694, 697, 700–701, 703 A. chinese, 417
A. blazei, 685–687, 696, 702 A. fistulosum, 417
Aging, 12–14, 102, 141–142, 206, 212, 226, A. sativum, 417
251, 255, 281, 294, 345, 380, 458, 504, A. schoenoprasum, 417
506, 568, 578, 581, 582, 656, 683, 715 A. tuberosum, 417

797
798 Index

Allyl sulfenic acid (2-propene-1-sulfenic Antibiotics, 14, 28–29, 175, 328, 374–375,
acid), 422 600, 602
Allyl sulfides, 422, 426, 432, 433, 445–446 Anticancer, 50, 62, 78, 81, 101, 175, 335, 382,
Disulfide(s), 130, 141, 232, 422, 426–427, 402, 406, 428, 439, 463, 481, 505, 510,
431–432 537, 579–586, 643, 655
Trisulfide(s), 422, 426–427, 432–439, Anticarcinogenic, 291–292, 304, 307,
443–444 313–315, 355–356, 406, 428, 431,
Alzheimer’s disease (AD), 204, 206, 210, 215, 583, 623, 644, 651, 653, 662, 668,
233–237, 238, 251–267, 278–281, 329– 736, 781
333, 336, 385–386, 511 Anticholelithogenic, 400
Amygdala, 257, 261 Anticoagulant, 127, 472, 697, 727, 740
α-Amylase, 100, 105–110, 513, 552, 571 Antidepressant, 335
Amyloid beta (Aβ), 204, 336, 386 Antidiabetic, 377, 401, 447–448, 499, 532,
Aggregation, 215 537, 540, 577, 702–705, 727, 772
Fibrils, 252–253 Antidiarrheal, 27
Oligomers, 215–253, 279 Antidyslipidemic, 540
Plaques, 253–254, 262, 336 Antifungal, 64, 68, 100, 311–312, 332– 337,
β1-42, 206, 215, 234, 238 376
Amyloid precursor protein (APP), 238, Antihypertensive, 304, 471, 542, 734, 736
252–256 Anti-inflammatory, 70–71, 76, 78, 81–83,
Amylopectin, 27 138, 142, 146–147, 226, 240, 260, 279,
Amylose, 7, 27 281, 292–293, 304, 307, 329, 332–336,
Amyotrophic lateral sclerosis (ALS), 260 343, 357–359, 382, 384, 388, 397, 402,
Anacardium spp. 406, 411, 464–465, 473, 481, 499, 510,
A. occidentale, 529–531, 543 532, 547, 569, 576, 584, 586, 613, 622,
Ananas spp. 643, 656, 687, 694, 720–721, 727, 730,
A. comosus, 539, 543 735, 736
Anethol, 335 Antimalarial, 77
Anethole, 335 Antimetastatic, 382, 468, 473, 506, 740
Angiogenesis, 48, 70–71, 204, 213, 226–227, Antimicrobial, 25–27, 60, 64, 78, 90–91, 96,
314, 458, 469, 503, 506, 537–539, 570, 100–111, 114–115, 209–210, 227, 235,
616 279–280, 304, 307, 311–313, 317, 319,
Angiotensin–I converting Enzyme (ACE), 58, 329, 332–335, 374–376, 481, 530, 532,
100, 106–111, 700, 734–735, 740 541, 565,–567, 579–580, 586, 656, 694
Antheraxanthin, 528, 725 Antimicrobial peptides (AMP’s), 227
Anthocyanidins, 54, 58–60, 291, 459, 483– Antimutagenic, 64, 335, 406, 428, 431–432,
487, 504, 510, 534, 563, 576, 648, 650 586, 657
Anthocyanins, 3, 15, 49, 54, 58–61, 167, Antimutagenicity, 687
307, 458, 470, 482, 484, 493–499, 528, Antiobesogenic, 759
530, 534, 542–547, 561–567, 569–571, Antiobiotics
575–578, 580–581, 584–585, 648, 650 β-lactam, 28
Antiaging, 294, 464, 481, 506–507 Antioxidant 65–68, 71, 91–95, 99, 100–107,
Antiangiogenic, 62, 464, 469, 473, 539 110–114, 137, 141–147, 202–212, 225–
Antiarrhythmic, 499, 720 226, 253–258, 276–282, 288–295, 304,
Antiatherogenic, 57, 138 307–319, 329–337, 343, 345, 350–358,
Antiatherosclerotic, 449, 499, 584, 720 380–384, 397, 399, 401–411, 428, 441,
Antibacterial, 14, 16, 78, 100, 294, 295, 307, 442, 457, 458, 462, 467, 470–472, 481,
311–312, 317–318, 334–337, 375, 397, 482, 494, 496– 503, 511, 513, 525–532,
422, 530, 579, 736 534–541, 546–551, 561–569, 572–580,
Antibiotic, 14, 22, 27–28, 111, 114, 336, 375, 585–586, 603–604, 610–613, 621, 643,
428, 565 644–652, 656–658, 664–665, 671,
Antibiotic associated diarrhea (AAD), 28 694–695, 701, 707, 716–718, 723–739
 Index 799

Antioxidant defense, 104, 137, 254, 282, 288, Araticum (Annona crassiflora), 552
404, 498, 568 Aromatase, 50, 68
Antioxidant response element (ARE), Aronia spp.
225–226, 511, 652, 686 A. melanocarpa, 561
Antioxidative enzymes, 68 Artemisinin, 76, 77
Antiproliferative 50, 60, 62, 69, 314, 356, 383, Arthritis, 38, 51, 337, 358, 374, 382, 385, 406,
411, 434, 439, 440–441, 463, 466–468, 411, 706, 722
504–506, 571, 579, 584, 655, 728, 735 Ascophyllan, 724, 727
Antisense oligonucleotide (ASO), 205 Ascorbic acid, 308, 310, 314, 349, 492, 528,
Antispasmodic, 335, 397, 532 532, 645
Antithrombotic, 304, 316, 428, 443, 449, 499, Asparagus, 33
503–504, 720, 727 Aspartate amino transferase (AST), 380, 405,
Antitumor, 72, 75–79, 81, 104, 207, 212, 304, 435
343, 355, 397, 406–407, 411, 428, 440, Astaxanthin, 717, 723
506, 530, 536–537, 656, 687, 694, 697, Asthma, 30, 335, 374, 756, 761, 783
740 Astringinin, 68
Antiviral, 16, 29, 30, 60, 100, 293, 295, 304, Atherogenesis, 66, 145–146, 357, 402, 750
307, 329, 334, 336, 536–537, 543 Atherogenic, 316, 398, 400, 568, 612
Anxiety, 252, 257 Atherosclerosis, 65, 138–139, 147, 315, 319,
Apigenin, 49, 50, 209–293, 335–336, 461, 355–357, 399, 402, 443, 457, 499,–501,
463, 466, 468, 483, 533, 543 539, 568, 569, 584, 607–608, 610, 612,
Apolipopretin E (apoE), 138, 146, 586 652, 657, 671, 697, 709, 729, 731
Apolipoprotein A1 (apoA1), 142 Atherosclerotic lesions, 147, 500, 607
Apolipoprotein L1 (apoL1), 142 Atherosclerotic plaque, 146, 357
Apoptosis, 48, 60, 67, 70–71, 76, 79, 83, Atmospheric pressure chemical ionization
102–103, 201–204, 209–212, 227–232, (APCI), 496–497
235, 238–240, 255, 259–260, 279, 288, Auroxanthin, 528
314–315, 331, 353, 356, 383, 404, 411, Autophagy, 226, 229–232
430, 434, 436, 437, 441–442, 462–463, Avarol, 78
482, 503–513, 568, 570–571, 583, 611, Avarone, 78
616, 652, 654, 658, 730 Avicularin, 533, 543
Anti-, 70, 229, 277, 314, 353, 442, 445, Avocado, 57
481, 509 2,2′-azino-bis(3-ethylbenzothiazoline-6-
Apoptotic bodies, 463 sulphonic acid) (ABTS), 104, 380, 498
Chromatin condensation, 463 Azobis (2–amidinopropane) hydrochloride
DNA fragmentation, 293, 383, 442, 463, (AAPH), 352
571, 583, 728 Azo–bisisobutyrylnitrile primaquine, 352
Mitochondrial activation, 463 Azoxymethane, 434
Pro-, 60, 70, 228–229, 230, 353, 356, 439,
445, 509, 652 Bacillus spp., 6, 78, 312–313, 376, 567, 733
Apoptosis signal-regulating kinase-1 (ASK-1), B. cereus, 312
232, 235, 240 B. subtilis, 6, 78, 312
Apoptotic protease activating factor 1 Bacteriocin, 26, 96, 115–16
(APAF1), 70, 229 Bacteriocinogenic, 25, 26
Apoptotic signaling, 228–229, 235 Entericin, 26
Appetite, 263, 373, 386, 755–759 Lacticin, 26
Apple, 57, 61 Nonlantibiotic, 25
Apricot, 57 Variacin, 26
Araçá, 545, 548 Bacuri (Platonia insignis or Scheelea
Araçá–boi, 545, 548–549 phalerata), 545, 550, 552
Arachidonic acid, 15, 70, 81, 406, 411, 444, Baicalein, 49, 468
465, 466, 699, 721 Banana, 57
800 Index

Basal ganglia, 257, 258, 275 Blackberries, 57, 61, 561–564, 570–571, 579,
Basil, 159, 161, 208–210, 293–294, 301, 316, 583
334, 337 Blackcurrants, 57, 61, 561, 567, 582
B–cell lymphoma 2 proteins (Bcl–2), 229, Blood glucose, 100, 105, 208–209, 214, 334,
437, 440, 445, 508–509, 513 377–381, 386, 401, 410, 448, 502, 537,
Bak, 70, 229, 437, 440, 508 542, 571, 658, 696, 701–704, 729, 736,
Bax, 70, 229, 276, 353, 437, 440, 445, 740, 772–778
464, 508–509, 513, 571 Blood pressure, 6, 100, 106, 213–214, 294,
Bcl-2, 229, 232, 265, 277, 353, 383, 434, 357, 377–379, 386, 449, 470, 482,
437, 442, 445, 505, 508–509, 513, 502–503, 569, 604, 609, 625, 697,–700,
652, 728 720, 735–740
Bcl-w, 229, 353 Blueberries, 57, 61, 111, 280, 561–571, 577,
Bcl-xL, 229, 277, 353, 437, 442, 509 580–583
BH (1–4), 229–230 Body mass index (BMI), 50, 132, 738, 752–
Beer 6 Benzo(a) pyrene (BAP), 356 757, 760–769, 774–777, 782–784
Benzoate, 212, 213 Bolinaquinone, 78
Benzoic acid, 63, 99, 291, 305, 482–484, Bone loss, 359, 606, 618
563 Bone mineral content (BMC), 618, 625
Benzo-γ-pyrone skeleton, 457 Bone mineral density (BMD), 606, 618–619,
See also Diphenylpropanes 625
Berries, 51, 55, 59, 63, 490, 492, 514, 545, Bone turnover
561–586 Bone alkaline phosphatise (BAP),
Betaine, 131, 141 618–619, 625
Betulinic acid, 71 Deoxypyridinoline (DPD), 618–619,
Bifidobacterium spp. 3, 6, 16, 27, 30, 33–35, 625
90, 95, 130 Osteocalcin, 619
B. adolescentis, 27 Resorption, 618–619
B. angulatum, 27 Borneol, 335
B. bifidum, 27, 32 Bradykinesia, 257
B. breve, 6, 27, 32 Brassica spp., 15, 643–654, 668, 672
B. breve Yakult, 6 B. carinata, 644, 646, 667
B. catenulatum, 27 B. juncea, 644, 646
B. dentium, 27 B. napus, 644, 646, 650, 655, 667–670
B. infantis, 27, 32 B. nigra, 644, 646
B. lactis, 3, 6, 30, 96 B. oleracea, 644, 646, 648–651, 653, 654,
B. lactis FK120, 6 657, 668–669, 672
B. lactis LKM512, 6 B. rapa, 644, 646, 648–649, 668, 671
B. longum, 6, 27, 32 Broccoli, 3, 6, 291, 644–649, 650–658, 662,
B. longum, BB536 6 668–669, 671–672
B. pseudocatenulatum, 27 Bromocriptine, 273
Biguanides, 377 Brussels sprouts, 644, 646, 651, 655, 657–658,
Bilberries, 60, 561–566, 570, 571, 582–585 671–672
Bile acids, 125, 398–400, 408, 708, 738 Buriti (Mauritia flexuosa), 545, 550
Bile salts, 409 t-Butylhydroperoxide, 352
Binding affinity, 203, 602–603 Butyl hydroxyl anisole (BHA), 308, 317–318,
Bioavailability, 57, 262–265, 270– 282, 304, 536
345, 353, 361–362, 409, 445, 464, 466, Butyl hydroxyl toluene (BHT), 308, 309, 310,
473, 504, 561, 563, 574, 575–578, 584, 317–318, 411
600–602, 658–667, 718–721, 762–763 Butyrate, 23–24, 34–35
Biochanin A, 596, 598, 610
Biomarkers, 4, 9, 131–147, 362, 505, 581, Cabbage, 6, 59, 167, 644–649, 650–658, 662,
604, 608, 611, 614, 617, 622 668–669, 672
 Index 801

Caffeic acid, 64, 65, 99, 100, 161, 208, 293, Cardiovascular disease (CVD), 13–14, 47,
310, 313, 335–336, 483–484, 496, 50, 58, 71, 91, 100, 106, 145, 280, 288,
563–564, 576, 666, 726, 730 290, 294, 315, 319, 329, 331, 335, 354,
Caffeine, 3 357, 358, 360, 381, 397, 399, 401,
Cagaita (Eugenia dysenterica), 552 443, 458, 469, 470, 473, 482, 497,
Calbindin, 262 513, 568–569, 582, 595, 603, 608,
Caloric restriction (CR), 507 609, 613, 618, 621, 622, 624, 625,
Cambuci, 545, 551 696–701, 709, 720–721, 729–731,
Camellia spp. 780, 786
C. sinensis, 343 Carnasol, 209
Campestrol, 336 Carnitine, 141
Camphene, 336, 337 Carnosic acid, 209, 295, 309, 310–311
Camphor, 335 Carnosol, 295, 309, 310, 313–314, 336
Campylobacter spp., 567 Carnosolic acid, 335
Camu–camu, 545–547 γ-Carotene, 542
Cancer ζ-Carotene, 565
Adenoma, 71, 430, 617 α-Carotene, 71, 528, 530, 725
Brain, 429 β-Carotene, 71, 308, 526, 528, 530, 542, 547,
Breast, 54, 62, 68, 81, 204, 205, 210, 564, 645, 725, 728
355, 356, 429, 430, 440, 442, 467, Carotenoids, 3, 155, 329, 332, 481,
504, 505, 506, 509, 605, 613–618, 490–491, 528, 530, 536, 538, 540,
623–625, 696, 730, 735, 750, 781, 542, 564, 572, 645, 724–725, 728,
785 739
Cervical, 383, 510 Carrageenan, 406, 724–725, 727
Colon carcinoma, 83, 210, 463, 537, 654, Carrot, 141, 167, 645
728 Carvacrol, 161, 210, 294, 309, 310, 313, 315,
Colorectal, 59, 71, 429, 430, 440, 605 335–337, 376
Endometrial, 430 Carvone, 71, 76
Gastric, 111, 440, 463 Casein, 6, 7, 15, 94
Leukemia, 60, 209, 213, 383, 441, 463– Cashew, 529, 530–531
464, 504–505, 510, 653–654, 727 Caspases, 60, 70, 228–229, 315, 353,
Melanoma, 71, 81, 213, 383, 467–468, 509 436–437, 441–442, 463–464, 508, 510,
Prostate, 50, 61, 71, 205, 356, 429, 570–571, 652
436–439, 468, 504–505, 571, 595, Catalase (CAT), 27, 68, 91, 104, 146, 202,
605, 615, 626, 728 206–210, 280, 289, 316, 381, 387,
Candida spp., 311, 313, 334, 375–376, 708 433–434, 441, 446, 610, 652
Canola, 15, 669 Cataract, 214, 335, 403–404
Capsaicin, 91, 101, 532 Catechins, 6, 7, 54–57, 292, 344–351, 354,
Capsiate, 3 357, 381, 482, 486–489, 496, 526, 533,
Carbidopa, 269 563, 576, 726
Carbon dioxide (CO2), 25, 92, 160 Catechol, 268, 274, 345
Carbon tetrachloride (CCl4), 402, 433, 435 Catecholamines, 52, 275
Carcinogen, 428, 430, 570, 617, 657 Catechol-O-methyl transferase (COMT), 268,
Carcinogenesis, 63, 70, 102, 139, 313, 315, 274–275, 277
356, 382, 401, 407, 431–434, 462–463, Cauliflower, 644–646, 649–655, 672
473, 482, 504, 605, 615, 651–652, Celery, 49
655–656, 661, 728 Cell
Carcinogens, 100, 406, 432–433, 466, 652, Death, 48, 50, 70, 103, 201, 226–231,
655, 657 239, 240, 252, 254, 258–260, 266,
Cardamom, 373 351–352, 355, 380, 383, 388, 437,
Cardioprotective, 227, 307, 444, 445, 499, 441, 458, 463, 505, 508–509, 570,
500, 503, 568, 603, 610, 697 658, 701, 728
802 Index

Differentiation, 15, 24, 67, 68, 102, 201, Chitosan oligosaccharide (COS), 112–113,
235, 281, 315, 330, 332–333, 359, 737–741
440–443, 510, 583, 615, 622, 624, Chlorogenic acid, 3, 6, 65, 210, 335, 528,
652–653, 728 564, 666
Division, 202, 436, 458, 657 Chlorophyll, 80, 345
Growth 50, 54, 62, 201–204, 234, 439, Chocolate, See Cocoa
443, 458, 465, 468, 505, 508, 537, Chokeberry, 561, 564–565, 578
570, 616, 728 Cholesterol, 6, 14, 15, 62, 66, 95–96, 142,
Membrane, 202, 230, 255, 258, 313–314, 208, 213–214, 315–317, 328, 356–357,
728 374, 377, 380, 398–401, 410, 446–448,
Proliferation, 70, 81–83, 102–103, 472, 481, 498–502, 568–569, 584, 586,
202–203, 226–227, 236, 314, 356, 604–608, 622–623, 685, 693–699, 708,
382–383, 388, 430, 467, 513, 537, 720, 727– 731, 735, 738, 739–741, 759,
570–571, 583–584, 616–617, 652, 763–770, 771, 786–787
656, 735, 778 Cholesterol esters (CE), 212–213, 759,
Shrinkage, 315, 463 763, 779
Cell adhesion molecules (CAMs), 612 Metabolism, 66
E–selectin, 613, 783 Serum, 6, 66, 96, 399, 410, 447, 697, 739
Intracellular adhesion molecule-1 (ICAM– Cholinergic pathway, 261–262, 265
1), 612–613, 625, 783 Cholinesterase inhibitors (ChEIs), 261–262,
Platelet endothelial cell adhesion molecule 267
(PECAM), 500 Chondroitin sulfate, 15, 727
Vascular adhesion molecule-1 (VCAM-1), Chromanol, 3
612–613, 622, 626, 783 Chrysin, 49, 470, 471
Cell cycle, 48, 50, 60, 68–71, 81, 202–204, Cineol, 210, 335
212, 383, 428, 436–438, 441, 462–463, Cinnamaldehyde, 91, 101, 211–215, 279,
482, 505–508, 568, 570, 616, 652–654, 374–378, 382–385, 386–388
728 Cinnamic acids, 59, 63–66, 91, 98, 101,
G0/G1, 441, 508 211–212, 279, 291, 305, 482–484, 563,
G1/S, 69, 508 650, 666, 726, 730
G2/M, 50, 60, 70, 81, 383, 428, 436, 438, Cinnamomum spp., 205, 211, 278, 334,
441 371,–374, 379, 382,–384, 386–388
Mitosis, 81 C. burmannii, 211
Mitotic phase, 81, 437, 440 C. cassia, 205, 211, 373, 379, 384
S/G2, 508 C. loureirii, 211
Cell cycle arrest, 48, 50, 69, 70, 81, 428, C. pauciflorum, 211
436–438, 570, 653–654, 728 C. tamala, 211
Cerebral cortex, 238–239, 261 C. zeylanicum, 184, 211, 215, 372, 375,
Cerrado fruits, 552 385
Ceruloplasmin, 227 Cinnamon, 182–184, 205, 211–216, 278–280,
Chemical ionisation (CI), 185 327, 334, 371–389
Chemopreventive, 60, 72, 76, 313, 402, 406, Cinnamyl acetate, 185, 211, 279, 374
411, 429–430, 507, 513, 537, 653–655, Cinnamyl alcohol, 211, 279
667 Cinnemaldehyde, 212
Chemotherapeutic, 76, 81, 216 Cinnzeylanine, 374
Cherry, 57, 61, 74, 527, 541 Cinnzeylanol, 374
Chicha (Sterculia striata and Naud Acrocomia Citrus spp.
aculeata), 552 C. aurantifolia, 462
Chicory, 33, 36 C. paradisi, 64
Chili, 3 C. reshni, 165
Chitin, 693, 697, 702, 707, 716, 736, 737 C. reticulata, 462–464
Chitosan, 6, 112–114, 736–741 C. sinensis, 165
 Index 803

Clostridium spp., 567 Curcuma spp.

C. difficile, 28–29, 708 C. longa, 333, 397–407, 719
C. perfringens, 313, 376 C. zedoaria, 333
Cloudberry, 564, 567 Curcumin, 3, 100, 332–333, 397–408, 719
Cloves, 157, 373, 447 Curcuminoids, 164, 167, 333, 399, 406
Coagulation, 3 Cyanidin, 3, 58, 60, 484, 499–501, 506, 528,
Cocoa, 5, 56–58, 371, 550 534, 546–547, 563, 570–571, 577, 650
Coffee, 3, 6, 7, 49, 65, 154 Cyanogenic glucosides, 157
Colitis, 28, 30,–32, 335, 337, 388, 727 Cyclin dependent kinases (CDK), 68–69,
Collagen, 15, 294, 401, 444, 471–472, 570
502–503, 612, 700 CDK2, 463
Collagenase, 68 CDK4, 463, 509
β-Conglycinin 3 Conjugated dienes (CD), 317 Cyclins, 68–69, 508
Conjugated linolenic acid (CLA), 15, 138, B1, 436
749–787 Cyclin D1, 50, 69, 463, 508–509, 570
cis-9, trans-11, 138, 749–754, 757–786 Cyclooxygenase (COX), 207, 281, 336, 444,
trans-8, cis-10, 757–759, 769, 777 465, 497, 570
trans-10, cis-12, 138, 750–782, 785–787 COX–2, 50, 60, 70–71, 212, 281, 336,
Constipation, 3, 705 465–466, 472, 509–510, 570, 584
Continuous subcritical water extraction Cyclophosphamide, 402
(CSWE), 158, 161 Cyclosporine, 404
Coquinho (Butia capitata), 545, 550 Cysteine sulfoxide(s), 417–427, 444
Coriander, 327 Cytochrome P450 enzymes, 74, 263–265,
Corn, 6, 59, 99, 447, 572 337, 600
Fiber, 6 CYP1A1, 433
Coronary Heart Disease (CHD), 143, 472 CYP1A2, 276–278, 462
Correlation spectroscopy (COSY), 177, CYP2B1, 431
188–189, 192 CYP2B2, 431
p-Coumaric acid, 59, 64–66, 305, 496, 530, CYP2D6, 265, 276
540, 563, 651, 666 CYP2E1, 433
Coumaric acid, 59, 64–66, 99, 305, 483–484, CYP3A2, 431
496, 530, 540, 563, 651, 666, 730 CYP3A4, 263–265
m-Coumaric acid, 64 Cytokines 31, 55, 59, 62, 71, 146, 212,
o-Coumaric acid, 64 228, 235–236, 240, 258, 315, 337,
Coumarins, 91, 101, 164–167, 334, 562 358–359, 388, 501, 512, 612, 721,
Countercurrent chromatography (CCC), 166, 727, 778–783
167 Granulocyte macrophage colony
Cranberries, 112–114, 280, 291, 561–567, stimulating factor (GM–CSF), 59
570, 573, 579, 582, 736 IFN-γ, 59, 696, 779
C–reactive protein (CRP), 145, 359, 382, Interleukins, 60, 281
501–502, 569, 622, 780–784 IL-1, 334, 380, 778
Creatine, 131, 141 IL-1α, 333, 612
Creatine kinase (CK), 141 IL-1β, 59, 240, 260, 279, 335–337,
Creatinine, 131, 380 386, 779
Crohn’s disease, 30–31, 706 IL-2, 59, 779–780
Cruciferous vegetables, 644–661, 666–672 IL-4, 335, 779
Cryptoxanthin, 528–530, 542, 565 IL-5, 335
Crystallisation, 156 IL-6, 59, 71, 337, 380, 386, 512,
C–S lyase. See Allinase 779–783, 784
Cumene hydroperoxide (CHP), 538 IL-8, 59, 71, 227, 380, 547, 783–784
Cumin, 159, 327 IL-10, 59, 388, 780
Cupuassu, 545, 549–550 IL-12, 59
804 Index

TNF-α, 59, 82, 232, 240, 260, 279– Dimethylhydroxylfuranone, 540

281, 314, 333–335, 380–382, Diode-array detection (DAD), 486, 496
386, 466, 501, 504, 509–510, Diosmetin, 466
612, 626, 696, 760, 779–783 Diosmin, 49, 464–470
Cytotoxicity 81, 82, 265, 351, 381, 463, 468, Dioxins, 602, 685
530, 538 2,2-diphenyl-1-picrylhydrazyl (DPPH), 104,
308–310, 380, 411, 498, 536–538, 547,
Daidzein (DAI), 3, 54, 104, 291, 483, 551
596–604, 610–614, 621–622, 625 Diphenylpropanes, 99
Daidzin, 596–598, 622 Distention, 105
Equol (EQU), 599, 600, 610, 621–622, Distillation, 156–159, 426, 492
625 Distortionless excitation by polarization
O-desmethylangolensin (O-DMA), transfer (DEPT), 177, 190–193
599–600, 611, 626 Diterpenes, 71, 79–80, 293, 304
Delphinidin, 58, 60, 484, 506, 510, 534, 547, Dithiin, 422, 426, 444
563, 650 DNA binding, 509, 612
8-hydroxy-2′-deoxyguanosine (8–ODG), 51, DNA cross-linking, 255, 401
70, 658 DNA damage, 51, 70, 102, 314, 360, 411, 432,
Depression, 252, 257, 272, 278, 436, 722 462, 570, 583, 613, 657–658
Detoxification, 3, 15, 206, 225, 407, 432, 466, DNA fragmentation, 293, 383, 442, 463, 571,
511, 568, 652, 655–657, 665–666 583, 728
Phase I, 15, 72, 82, 432, 433, 600, 602, DNA lesion, 79, 314
652 DNA polymerase, 78, 482, 505
Phase II, 14–15, 79, 225, 407, 432–435, DNA replication, 202
497, 511–513, 600–602, 652–656, DNA synthesis, 79, 432, 505–506
664, 668 Docosahexaenoic acid (DHA), 7, 15,
Dextran, 6 717–722, 729, 762
Diabetes, 1, 3, 13–14, 38, 60, 91, 95, 100–102, Donepezil, 262–265
105–110, 116, 203–205, 208–216, 255, Dopa-decarboxylase inhibitors, 269–270, 274
279, 288, 290, 328, 331–335, 374, 377– Dopamine, 204, 239, 257–258, 267–277, 722
381, 386–388, 397–403, 446–449, 466, Dopamine receptor agonist, 271
469, 503, 512, 528, 533–534, 540–542, Dopamine receptor (D1/D2), 257, 268,
552, 568, 571, 595, 652, 657–658, 701– 271–273, 277
705, 709, 728–730, 739–741, 750–751, Dopaminergic neurons, 239–240, 257– 259,
753, 756–758, 761, 772, 776 269–272, 281
Diacetyl, 25, 96, 115 Dopamine Signaling, 239
Diacylglycerol, 3 Drug resistance, 47, 81
Diallyl disulfide (DADS), 431– 448 Dyskinesia, 271–273, 278
Diallyl monosulfide (DAS), 431–437, 442, Dyslipidemia, 1, 7, 410, 696
446 Dyspepsia, 211, 272, 278, 373
Diallyl trisulfide (DATS), 432–440, 445–448
Diarrhea, 28–30, 105, 263–265, 282, 373–374, Edema, 83, 406, 464, 470
531–532, 552, 708 Eggplant, 99
Traveler’s, 29 Ehrlich’s reagent, 178
Viral, 30 Eicosanoid, 55, 465
Dietary fiber ,6, 66, 549–550, 567, 685, 688, Eicosapentaenoic acid (EPA), 7, 15, 717–722,
693, 697, 702–707, 727 762
Dihydropyran, 345 Elaidic acid, 786
3,4-dihydroxyphenylalanine (DOPA), 239, Elastase, 359
268–269 Electron impact/ionization (EI), 184–85
7,12–dimethylbenz[a]anthracene (DMBA), Electron ionization-Mass spectrometry
314, 434, 462 (EI-MS), 184–185
 Index 805

Electron transport chain (ETC), 255, 258, Escherichia spp., 29, 32, 36, 319, 567–579
287–288 E. coli, 36, 72, 312, 319, 335, 376, 600
Electrospray ionization (ESI), 137, 486, 496, Essential oils (EO), 74–75, 157–162, 176,
513 184, 293–294, 304, 308–319, 335–337,
Elettaria cardamomum, See Cardamom 371, 374–376, 388, 491, 544
Ellagic acid, 100, 291, 530, 534–536, 548, Estrogen, 15, 50, 61–62, 205, 291, 386, 506,
551–553, 567–569, 575–576, 579–580, 511, 595, 602–603, 613, 618, 622–625,
583 785
Embryogenesis, 458 Antiestrogenic, 62, 463, 595, 603, 614
Endoplasmic reticulum (ER), 228 Estradiol, 68, 463, 596, 602
ER stress, 228, 231–233, 240 Estrogenic, 60–64, 481, 595, 602–605,
Lumen, 231–232 614, 620
Membrane, 232 Estrogen receptors (ER), 61, 602
PKR-related ER kinase (PERK), 231–232 ERα, 463, 602–603, 621
Endothelial dysfunction 357, 470–471 ERβ, 602–603, 608, 618, 622–623
Endothelial function, 357–358, 470, 482, Ethnopharmacology, 175
499–500, 503, 609–610, 622, 652, 720, Ethylenediaminetetraacetic acid (EDTA), 127
782 Eugenia spp.
Endothelin-1 (ET-1), 510, 584 E. stipitata, 545, 548
Endothelium-dependent relaxation, 55, 503, E. uniflora, 541–543
510 Eugenol, 161, 211, 279, 335, 374–376, 383
Endothelium-dependent relaxation (EDR), 503 Eukaryotic translation initiation factor 4E
Entacapone, 274–275 binding proteins (4E–BPs), 202–203
Enterobacter spp., 90, 311, 319 Euterpe spp.
E. amnigenus, 312 E. oleracea, 545
E. gergoviae, 312 Excitotoxicity, 255, 258–260, 265, 511
E. aerogenes, 334, 376 Exopolysaccharides, 703
Enterococcus spp., 28, 37, 93, 376, 579 Extracellular signal–regulated kinases (Erk),
E. faecalis, 93, 312, 376 235, 236, 254, 260, 445, 509, 510, See
E. faecium, 28, 93, 96, 376 also Mitogen–activated protein kinase
Enzyme–linked immunosorbent assay (MAPK)
(ELISA), 142 Extraction, 127–128, 154–162, 166–168, 186,
Epicatechin (EC), 50, 54–56, 215, 289–291, 424–426, 492–497, 581, 608, 685, 717,
345–350, 381, 426, 482–483, 486–489, 725, 730
496, 528, 551, 563 Exudates, 176
Epidermal growth factor (EGF), 68, 213, 382
Epigallocatechin (EGC), 3, 54, 207, 291–292, Faecalibacterium prausnitzii, 34
345–352, 483, 486–488, 496, 528, 563 Fatty acids, 7, 15, 34, 137–139, 142, 313,
Epigallocatechin gallate (EGCG), 3, 50, 54, 352, 378, 696, 719–723, 735, 742, 762,
57, 207, 292, 345–346, 349–361, 486 769–783, 786
Epinephrine, 275, 444, 727 Fenton reaction, 287–89, 402
Epithiospecifier protein (ESP), 647, 655 Fermentation, 22–24, 27, 34–35, 89–96,
Equol, 483, 598–600, 604, 625 101–116, 129, 344, 347, 354, 495, 552,
Ergocalciferol, 707 574, 597, 671–672, 706
Ergogenic, 201 Fermented foods, 90, 93–94
Ergolines, 272 Ferric reducing antioxidant power (FRAP),
Ergosterol, 694–695, 699, 707 381
Ergothioneine, 701, 706 Fertility, 335, 373, 386, 623
Eriocitrin, 295, 308 Ferulic acid, 59, 64–66, 291, 307, 313,
Eriodictyol, 52 335–336, 483, 496, 533, 563–564,
Eritadenine, 685, 694, 699 649–651, 666, 670
Erythrocytes, 289, 400, 403, 444, 472, 706, 762 Fish oil, 138, 142–144, 719–721, 742, 786
806 Index

Flame ionization detection (FID), 158, 183 Fructo–oligosaccharide (FOS), 5, 7, 27,

Flammulina spp. 33–35, 130
F. velutipes, 688, 691, 701 Fucoidan, 724, 727
Flash chromatography (FC), 163–168 Fucosterol, 724, 727
Flatulence, 105, 372, 398, 552, 738 Fucoxanthin, 725, 728–731, 742
Flavan-3-ols. See Flavanols Functional foods, 1–16, 116, 132, 301–302,
Flavonoid, 3, 6, 48–55, 60, 65, 98–99, 161, 457, 567, 671–672, 685, 694, 700,
164–166, 178, 181, 186, 208–210, 706–709, 716, 724, 740–741
290–292, 304, 307–313, 332–336, 344, Fungi
359, 388, 457–473, 481–486, 496, 512, Aspergillus spp., 311, 334, 376
526, 530, 533, 536, 542–543, 546, 549, Fusarium spp., 83, 376
562–565, 568, 575–576, 586, 610, 648, Mycoplasma spp., 376
650, 656, 663–667, 701 Penicillium spp., 376
Catechin, 3, 49, 54, 211–212, 291–292, Furcelleran 724
335–336, 344–358, 362, 459, 483,
488, 493– 494, 551, 726 Galacto–oligosaccharides (GOS), 33–37
Flavanols, 49, 50, 54–58, 291, 307, 311, Galactose, 27, 51, 59, 404, 563, 664, 687
459, 470, 482–490, 496, 562, 576, Galactosidases, 33
648 Galantamine, 262, 265
Flavanone,3, 7, 52–53, 467 Gallic acid, 91, 291, 336, 482, 488, 496, 536,
Flavanones, 49, 52–54, 291, 307, 563
458–459, 470, 483, 648 Gallocatechin (GC), 54, 350, 486–488, 563
Flavone, 3, 49–51, 54, 165, 291, 307, Gamma-aminobutyric acid (GABA), 3, 6,
458–459, 461, 467–470, 483, 488, 700
648 Gamma-linolenic acid (GLA), 14–15
Flavonol, 3, 49–51, 54–57, 291, 307, Ganglioside GM1, 36
344, 458–459, 469–470, 482–483, Garlic, 3, 33, 327, 355, 417–418, 420–434,
486–488, 496, 539, 561–567, 576, 441–449, 645
581, 584, 648–649, 663 Gas Chromatography (GC), 54, 92, 126,
Isoflavone, 3, 7, 49, 54, 60–62, 67, 104, 129, 158, 176–177, 182–186, 195,
145, 291, 307, 459, 470, 595–617, 346, 484– 488, 581
620–626, 648 Gas chromatography–mass spectrometry
Flavonoid skeleton. See Diphenylpropanes (GC–MS), 129, 176–177, 184–186,
Flaxseed, 14, 15, 66–67, 145 195
Foam cells, 357, 501, 610 Gastric emptying, 214, 379
Food for Specified Health Uses (FOSHU), 2, Gastritis, 111, 211, 530
8–11 Gastrointestinal tract (GI), 19, 20, 24, 31, 34,
Forkhead box, class O (FOXO), 20–206 95, 104, 292, 373, 566, 577, 661, 664,
Fourier transformation (FT), 186 699
Fourier transform infrared spectroscopy Gastrointestinal disorders, 89, 90, 94, 327,
(FTIR), 186 652
Fractionation, 156 Microbial load, 20–19
Fragaria spp. Structure, 19
F. ananassa, 561 Gel electrophoresis, 137, 144–146
Free radicals 51, 60, 99–104, 115, 253–254, Difference gel electrophoresis (DIGE),
258–259, 272, 280, 287–290, 293–295, 137
309–311, 329–331, 336, 349–352, 380, Gene expression, 5, 30, 96, 136, 145, 203,
402–403, 408, 462, 534, 538, 568, 576, 258, 288, 356, 359, 440, 447, 503–506,
579, 582, 657, 694. See also Reactive 510–512, 570, 582–584, 622, 722
oxygen species (ROS) Generally recognized as safe (GRAS), 295,
French Paradox, 280 311, 497, 512, 740–741
Fructans, 33–37 Genetic engineering, 572, 667–668
 Index 807

Genistein (GEN), 54, 62, 67–68, 104, 388, Glutamate–cysteine ligase, 289
483, 511, 596–604, 610–615, 620–625 Glutamate dehydrogenase, 141
6′-hydroxy-O-desmethylangolensin, 599 Glutathione (GSH), 68, 104, 141, 146,
Genistin, 596, 610, 622 208–209, 225, 232, 258, 280–282, 289,
Genomics, 5–9, 135, 147, 206, 573, 586 293, ,314–315, 337, 355, 360, 381, 387,
Genotoxicity, 430, 652 401–403, 418,–421, 431, 432, 435, 438,
Gentisic, 99 441, 444, 446–447, 498, 503, 538, 540,
Geraniol, 71 570, 610, 652, 660–661, 701
Ghrelin, 214, 386 Glutathione peroxidase (GPx), 68, 146, 225,
Ginger, 332–333, 373, 397, 400, 408–411 289, 314, 355, 381, 387, 401, 432, 446,
Gingerol, 333, 411 498, 503, 610
Ginkgo, 51 Glutathione reductase (GR or GSR), 208, 225,
Ginseng, 159, 205 355, 498
Ginsenosides, 159 Glutathione-S-transferase (GST), 104, 141,
Glucagon, 34, 205 206, 225, 232, 431–435, 570, 571,
Glucagon-like Peptide-1 (GLP-1), 34, 35 652–653, 661
β-Glucans, 14, 686–688, 693, 694, 697, 702, Glutathione synthetase, 225, 289
705–708, 724 Glycated hemoglobin (HbA1c), 145, 378, 379,
Ganopoly, 694 774, 775
Schizophyllan, 694 Glycitein, 596–598, 622
Glucokinase, 535 Glycitin, 596–598
Gluconeogenesis, 138, 201–202, 210, 232 Glycogen biosynthesis, 378
Glucophage, 205 Glycogen synthase kinase-3 (GSK-3), 235,
Glucosamine, 15, 737–738 238, 256, 260, 280, 378
Glucose intolerance, 377 Glycolysis, 138–139, 201–202
Glucose transporter 4 (GLUT-4), 202–203, Glycosides, 49–52, 58–61, 65–66, 388, 459,
214, 378, 445 472, 484–485, 490, 525, 534–536, 563,
α-Glucosidase, 100, 105–111, 528, 533, 567, 575, 596–598, 649, 657, 662–663
542–543, 552, 571, 730 C–glycosides, 459, 536
β-Glucosidase, 110, 597–598, 663–664 O–glycosides, 51, 459, 484–486, 536, 663
Glucosinolates (GSLs), 645–655, 659–662, Glycosylated, 30, 49, 52–54, 483, 650
667–672 Glycosylation, 291, 307, 428, 467, 650, 656
Glucobrassicanapin (4-pentenyl), 646, 669 Glyzcyrrhiza spp.
Glucobrassicin (3-indolylmethyl), G. uralensis. See also Licorice
646–647, 654, 668–669 Goitrogenic, 623
Glucoerucin (4-methylthiobutyl), 646, 654 G–protein coupled receptor 41 (Gpr41), 34, 35
Glucohirsutin (8-methylsulfinyloctyl), 646 Grains, 12, 15, 64–66, 94–95, 99, 207,
Glucoiberin (3-methylsulfinilpropyl), 646, 290–292, 430, 562, 708
654, 668 Grapefruit, 3, 52, 64, 165, 528
Gluconapin (3-butenyl), 646, 668–669 Grapes, 5, 57–59, 64–68, 99, 130, 141, 157,
Gluconapoleiferin (2-hydroxy-4-pentenyl), 167, 280, 291, 481–502, 504, 507–514,
646 545, 561, 564, 578, 581, 584
Gluconasturtiin (2-phenylethyl), 646, 654 Raisins, 68, 481
Glucoraphanin (4-methylsulfinylbutyl), Red, 130, 167, 498, 578
646, 653, 668–671 Grape seed, 5, 499–501
Neoglucobrassicin (1-methoxy-3- Grape seed extract (GSE), 499–502, 513
indolylmethyl), 646 Graviola (Annona muricata), 551
Progoitrin (2-hydroxy-3-butenyl), 646, Growth factors (GF), 47, 62, 68, 70–71, 83,
655, 669 201, 213, 235, 382, 465, 509
Sinigrin (2–propenyl) 646, 653–656, 668 Guaijaverin, 533, 543
Glutamate, 141, 255, 258–259, 265, 266, 693, Guava, 7, 526, 531–533, 543, 548
698–699 Gut associated lymphoid tissues (GALT), 26
808 Index

Haber–Weiss reaction, 289 Redox, 102, 254, 282, 498, 568

Heat shock factor-1 (HSF-1), 233–234 Homofermentation, 91–92
Heat shock Protein (HSP), 138, 206, 231–234 Homofermenters, 91
HSP-16.2, 206 Homogenization, 155, 426
HSP70, 231, 233, 234, 240 Homorientin, 546
HSP90, 203, 231, 233 Horminone, 210
Helicobacter pylori, 89, 91, 94, 101–102, Human immunodeficiency virus (HIV), 78,
111–114, 116, 294, 334, 383–384, 530, 295, 510, 536, 730
540, 543, 566, 652 Huntington’s disease, 204–206, 511
Hemeoxygenase-1 (HO-1), 225, 232, 239 Hydrogen peroxide (H2O2) 25, 96, 115, 276,
Hemoglobin A1C, 214 287–289, 294, 308, 311, 314–316, 351–
Hepatic steatosis, 146–147, 512 353, 405–406, 436, 441, 504, 510, 701
Hepatotoxicity, 262, 405 Hydrogen sulfide (H2S), 260, 444–445
Herbacetin, 66 Hydrophilic, 157, 168, 528
Herbs, 52, 74–75, 99, 104, 115, 159, 162, 175, Hydrophobic, 168, 183, 738
205, 206–211, 292–295, 301–317, 327– 8-hydroxy-2′-deoxyguanosine (8–ODG), 547
329, 332, 335, 373 3-hydroxy-3-methylglutaryl CoA (HMG-
Hericium spp. CoA), 317, 699
H. erinaceus, 686–688, 700 Hydroxybenzoic acids, 63, 64, 305, 540,
Hesperetin, 52–54, 291, 461–463, 471 562–566
Hesperidin, 52, 209, 291, 309, 461–465, Hydroxycinammic Acids (HCA), 64, 65, 305,
470–472 482–483, 496, 551, 564–566, 649–651,
Hesperitin, 462 666
Heterofermentation, 91–93 Hydroxycinnamic alcohols, 66
Heterofermenters, 92 6-hydroxydopamine (6–OHDA), 352–353
Heteronuclear multiple–bond correlation Hydroxyflavone, 49
(HMBC), 177, 193–194 3-hydroxykynurenine (3-HK), 352–353
Heteronuclear multiple–quantum correlation 7-Hydroxylase, 66
(HMQC), 177, 192–194 Hydroxylation, 74, 307
Hexanoate, 550–551, 580 Hydroxyl radical, 287–289, 310, 352, 498
Hexokinase, 535 4-Hydroxynonenal (HNE), 141, 237, 255
Hexose, 27, 92 3-(2-hydroxyphenyl)-propanoic acid, 384
High Density Lipoprotein (HDL), 142, Hypercholesterolemia, 3, 255, 315–316, 447,
315–316, 379, 399, 410, 447, 586, 469–697
604–608, 623–625, 697–699, 729–731, Hypercholesterolemic, 398–400, 403,
763–771, 786–787 500, 697
HDL2, 142 Hyperglycemia, 105–106, 109–110, 377, 381,
HDL cholesterol, 399, 586, 607–608, 623, 401, 404, 512, 542
698, 729–731, 767–770 Hyperin, 533–543
High–pressure liquic chromatography Hyperinsulinemia, 255
(HPLC), 163, 176, 195, 484–486, 492, Hyperlipidemia, 315–316, 399, 469, 686, 719,
496, 528, 671, 725 738
High voltage electrical charge (HVEC), 495 Hyperlipidemic, 316, 500
Hippocampus, 238, 252, 257, 261 Hypertension, 1, 3, 39, 84, 100–107, 110, 116,
Hippuric acid, 130 236, 255, 267, 275, 315, 373, 445, 469–
Hispidulin, 210, 293 470, 503, 542, 686, 696, 698–701, 727,
Histone deacetylase (HDAC), 203, 281, 442. 734–735
See also Sirtuins Hypertriglyceridemia, 542
Homeostasis, 22, 96, 99–104, 145, 204, 208, Hypochlorous acid, 288, 701
214, 227, 236, 254, 279, 282, 400, 436, Hypocholesterolemia, 39, 738
447, 498, 508, 568, 777–778 Hypocholesterolemic, 316, 398–401,
Iron, 227 607–608, 694, 697, 708, 735, 739
 Index 809

Hypoglycemic, 292, 401, 410, 443, 694, Inhibitor of kappa kinase (IKK), 294, 509
702–704 Insulin, 10, 35, 105, 131, 138, 145, 201–214,
Hypotension, 269–272, 275–278 233, 237–238, 255, 279, 374, 377–381,
Hypotensive, 542, 694, 698–700 386, 401, 447–448, 506, 512, 534, 537,
Hypoxia, 204, 226–228, 382 702–705, 739, 750, 772–778, 786–787
Hypoxia-inducible factor 1 (HIF-1), 226–228, Secretagogues, 205
382 Sensitivity, 778
Factor inhibiting HIF (FIH), 227 Insulin–like growth factor receptors (IGFR),
HIF-1α, 204, 226–228 201, 206
HIF-1β, 226–228 Insulin–like growth factors (IGF), 201–205,
Hypoxia responsive element (HRE), 226–228 227, 233, 237
Insulin like growth factors signaling (ILS),
Ilimaquinone, 78 201–204, 210–211, 216
Illudins, 78–79 Insulin receptor substrate (IRS-1), 202–204
Immune system, 26, 31, 38, 55, 101, 288, Insulin resistance (IR), 131, 138, 145, 203,
329–334, 345, 358, 387, 696, 741, 779 214, 255, 374, 378–381, 447, 702–705,
Innate immune system, 329–335 772–778
Immunity, 15, 16, 31–32, 95, 235, 329, 388, Insulin signaling, 201–202, 206–208, 211,
695–696, 715, 735, 778 238, 279, 506
Immunoglobulins, 31, 94, 388 International Life Sciences Institute (ILSI), 5,
IgA, 31 8, 9, 10
Immunomodulation, 30–31, 39, 333–335 Inulin, 33–36
Immunomodulatory, 327, 695 Invasion, 31, 68, 71, 468, 566, 583
Immunoprotective, 537, 543 Ion–exchange chromatography, 163
Immunostimulants, 332, 683, 687, 695 β-Ionone, 491
Indoles Irofulven, 79
Indole-3-carbinol (I3C), 647, 654–655, Iron-sulfur center, 288
660, 672 Ischemia, 405, 445, 473, 499, 658
Indomethacin, 384 Ischemic stroke, 53, 357
Infectious disease, 77, 100–101, 374–375, Isoalliin, 418, 422
388, 686 Isobaric Tag Relative Absolute Protein
Inflammation, 15–16, 31–32, 38, 51, 57, Quantitation (iTRAQ), 137
59, 63, 70–71, 82, 131, 144, 145, 203, Isogonic, 2
212, 228, 235, 239, 240, 253–255, Isolation, 7, 153–163, 167–168, 737
258–260, 315, 331, 345, 351, 358–360, Isoprenaline, 399
373, 380–381, 403, 411, 464–468, 473, Isoprenoid, 3
482, 501–512, 568–570, 584–586, 604, Isoprostanes, 145, 611, 782–783
612–613, 619, 622, 657, 720–722, Isorhamnetin, 52, 54, 485–486, 581, 649–650,
779–780 657, 663
Chronic, 51, 82, 358–360, 657 Isothiocyanates (ITCs), 3, 647, 651–655,
Inflammatory bowel disease, 30–31, 89, 94, 659–662, 668, 672
358, 384 Allyl isothiocyanate (AITC), 653
Inflammatory bowel disorders (IBD), 30 Benzyl isothiocyanate (BITC), 653–654
Inflammatory bowel syndrome (IBS), 32 Erucin (4-methylthiobutyl isothiocyanate,
Inflammatory diseases, 48, 50, 211, 358, 376, MTBITC), 653–654
384, 401, 406, 501, 512, 656, 721 Iberin (4-methylsulfinilpropyl
Inflammatory pathways, 138, 146 isothiocyanate, MSPITC), 653–654
Inflammatory response, 55, 279, 281, Phenethyl isothiocyanate (PEITC),
464–465, 584, 721 653–654
Infrared Absorption Spectroscopy, 181 Sulforaphane (SFN), 652–656, 671–672
Infrared (IR), 145, 176–177, 181, 186, 195, Isotope–Coded Affinity Tags (ICAT), 137
378, 405, 776 Isovitexin, 546
810 Index

Jambolan (Jamun), 533–535 Lactose, 27, 33, 89, 94–95

Japanese knotweed, 280 Lactose intolerance, 89, 94–95
Jerusalem artichoke, 33 Lamiaceae, 208– 210, 287, 292–294,
c-Jun N-terminal kinase (JNK), 71, 233–236, 301–319, 334–336
240, 260, 437, 445, 504, 509–510 Laminarin, 724, 727
Lavender, 157, 160
Kaempferol, 51–54, 160–161, 291, 313, 335, LDL cholesterol, 62, 357, 472, 502, 568, 607,
461–463, 483–488, 530–536, 542–543, 622, 697, 767–769
549–553, 563, 580–581, 649–650, 657, LDL/HDL ratio, 316, 763, 768–770
663 Leeks, 33, 417
Kale, 291, 644, 649–655, 668, 671–672 Legumes, 49, 99
Kefir, 93–95, 102–110 Lemons, 52, 66, 75, 291
Kelch-like ECH-associated protein-1 Lentinus spp.
(Keap-1), 225 L. edodes, 579, 691, 694, 699–701
Kidney bean, 3 Leptin, 386, 759–761
Kiwi, 57 Leucotrienes
Klebsiella spp. Leucotriene B4, 82
K. oxytoca, 567 Leukocyte, 57, 357
Kovats indices, 176, 183–185 Levodopa, 268–278. See also
Krill, 716– 723, 732, 737 3,4-dihydroxyphenylalanine (DOPA)
Oil, 719–723 Lewy bodies, 234, 240, 257
Licorice, 167, 205, 373
Lactase phloridzin hydrolase (LPH), 664 Liebermann-Burchard Reaction, 178
Lactic acid bacteria (LAB), 6, 26–27, Lifespan, 202, 205–206, 215, 281, 507, See
35–37, 89–96, 101–106, 111–116, also Aging
319, 708 Lignans, 3, 48, 65–68, 291, 562–566
Lactic acid (Lactate), 25–27, 34–35, 89–95, Enterodiol, 66
101–116, 319, 708 Enterolactone, 66, 291
Lactitol, 37 Lariciresinol, 66
Lactobacillus spp., 6, 14, 26–34, 37, 89–95, Matairesinol, 66
130, 311, 566–567, 672, 705 Pinoresinol, 65–66
L. acidophilus, 6, 29–32, 95–96, 107–108, Secoisolariciresinol, 65–66, 563
111 Syringaresinol, 65–66
L. acidophilus, CK92 6 Lignins, 65–66, 645, 685
L. brevis, 93 Limonene, 71, 75–76, 374, 547
L. bulgaricus, 107–108, 111 Limonins, 156, 165, 190–194
L. casei, 6, 14–16, 32, 93, 95, 111 Limonoids, 160–161, 164–166, 178
L. casei, LC1 6 Linalool, 5, 209, 335, 551
L. casei NY1301, 6 Lingonberries, 562, 567, 582
L. casei Shirota, 6 Linoleic acid, 697, 764
L. curvatus, 93 α-Linolenic acid (ALA), 15, 697
L. delbrueckii, 6, 32 Lipase, 398, 409, 763
L. delbrueckii subsp. bulgaricus, 6, 32 Lipids, 100–104, 125, 131, 162, 237, 258,
L. fermentum, 29, 93 288, 313, 331, 351, 379–380, 449, 502,
L. gasseri, 93 526, 545, 656–657, 693, 696, 701, 706,
L. helveticus, 6, 93, 108 718–719, 722, 727–729, 735, 738–739,
L. helveticus CK60, 6 750, 759, 762–763, 770–771, 779–780,
L. johnsonii, 93 786–787
L. plantarum, 32, 95, 111 Biosynthesis, 201, 214
L. rhamnosus, 31, 93 Desaturase, 749, 763
Lactococcus spp. 26, 92–93 Hydroperoxides (LPO), 289, 307, 311,
L. lactis, 26, 93 381, 472, 499, 538
 Index 811

Oxidation, 201–202, 307, 318, 513, 569, Lymphocytes

717, 732 B lymphocytes, 465
Peroxidation, 141, 145, 209, 237, 254– CD4+ T cells, 333, 388
255, 281, 316, 352, 358, 380–381, CD8+ T cells, 333, 359, 382
387, 399–408, 434, 473, 512–513, Natural killer cells (NK), 31, 336, 686,
538, 584, 604, 610, 611, 697, 701, 696, 779
781, 786 T helper, 333
Peroxides, 360, 399, 403–405, 500 T lymphocytes (T Cells), 333, 779
Plasma, 131, 762 Lyophyllum spp.
Lipogenesis, 35, 139 L. decastes, 685, 686, 687
Lipoic acid, 141 Lysosome, 233, 240
Lipophilic, 157, 459
Lipopolysaccharide (LPS), 54, 212, 239, 386, Macrophages, 31, 54, 57–59, 145, 227, 239,
466 314, 329, 333–336, 357, 402, 411, 464,
Lipoxygenase (LOX), 51, 307, 465–466, 472, 472, 500–503, 512, 537, 568, 584,
538 610–611, 721
5–lipoxygenase, 465 Malic acid, 161, 649
Liquid Chromatography (LC), 126–128, Malignant, 70, 75, 428, 505, 661
163–164, 167, 177, 182, 496, 581 Malondialdehyde (MDA), 315–317, 380–381,
Liquid chromatography–mass spectrometry 387, 463, 467, 502, 506, 735
(LC–MS), 126–128, 167, 177, 496 Malpighia spp.
Listeria spp., 567 M. emarginata, 527, 534, 543
L. grayi, 335 M. glabra, 527
L. innocua ,312, 319, 335 M. punicifolia, 527
L. ivanovii, 335, 376 Maltitol, 7, 37
L. monocytogenes, 91, 312, 335, 376, 566, Malvidin, 58, 60, 484, 534, 563, 650
579, 580 Mammalian target of rampamycin (mTOR),
Lisuride, 273 202–204
Liver disease, 359, 405 Maná-cubiu (Solanum sessiliflorum) 545,
Liver X receptor (LXR), 96 551
Longevity, 206, 281, 329, 482, 507. See Mangaba (Hancornia speciosa), 552
also Lifespan Mangifera spp.
Loquat, 57 Mangifera indica, 535, 537, 543
Low–density lipoprotein (LDL), 55, 58, Mangiferin, 536–538, 543
62–66, 100, 214, 293, 315–317, Mango, 57, 526, 535–538, 543
356–360, 379–380, 398–402, 410, Mannitol, 27, 693, 700
445–447, 470–472, 481–482, 498–502, Manno-oligosaccharide, 3
568–569, 604–612, 622, 626, 657, Marine, 76–78, 81–83, 153, 164, 175,
697–699, 708, 721, 763–770, 777, 715–717, 723–742
782–786 Hydrolysates, 731–736
LDL cholesterol, 62, 357, 472, 502, 568, Marine Peptides, 734
607, 622, 697, 767, 769 Sea sponge, 78, 81–82
LDL oxidation, 100, 293, 315, 357, 360, Marjoram, 157, 162, 308, 318
399, 482, 499, 568, 569, 611 Mass Spectrometry (MS), 125–129, 135–137,
Low–pressure LC (LPLC), 163–166 146, 158, 167, 176–177, 182–185, 186,
Lupeol, 71 195, 496, 513, 581, 736
Lutein, 3, 71, 165, 528, 530, 542, 547, 564, Mass spectra, 176–177, 184–186, 195
645, 725 Mass spectrometers 136, 185
Luteolin, 49, 50, 160, 208–209, 308, 336, Matrix–assisted laser desorption ionization
461–463, 468, 483, 488 (MALDI), 137
Luteoxanthin, 528, 547 Matrix metalloproteinases (MMP), 51, 68,
Lycopene, 3, 71, 542, 564, 728 360, 383, 468
812 Index

Tissue inhibitor of metalloproteinases Microflora, 14–16, 21–24, 291, 578, 600–601,

(TIMP), 68 659–663, 666, 708
Medicinal herbs, 175 Microglia, 239, 255, 258–260, 279–281, 386,
Medicinal plants, 76, 175, 377, 541 466
Medium polar solvents, 155 Microtubule, 81, 215, 238, 253, 437–440
Medium-pressure LC (MPLC), 163, 166 Microwave–assisted extraction (MAE),
Medlar, 64 158–159
Melatonin, 481, 492 Milk, 3, 6–7, 15, 22, 93–95, 101–102,
Memantine, 261, 265–267 106–115, 596–601, 619, 622, 671, 693,
Membrane 718, 749, 756–757, 767–768–776, 777,
Blebbing 315, 463 784–787
Fluidity, 254, 701, 722 Mint, 74, 159
Membranes Miso, 596–597, 617
Neuronal, 261 Mitochondria, 102, 139, 203, 228, 238, 254,
Memory, 58, 142, 252–253, 261, 265–266, 259, 315, 437, 512, 729
330, 336, 620 Cytochrome C, 229, 315, 353, 383, 442
Menopausal hot flashes (MHF), 620–621, 626 Dysfunction, 139, 253, 256–260
Metabolic stress, 145 Mitochondrial stress, 228
Metabolic syndrome 213–214, 374, 377–379, Mitogen-activated protein kinase (MAPK),
502, 538, 751–753, 757, 760, 764–765, 50, 71, 226–227, 232–236, 240, 260,
768, 772–773, 777, 778, 780, 782, 787 288, 509
Metabolism MAPK signaling, 50, 227, 233–236, 260
Dopamine, 258, 268 Mitogenic, 201–202, 382, 510, 613
Energy, 38, 103, 139, 226–227, 254–256, Mitogens, 70
376, 735 Mobile phase, 164
Iron, 227 Molecular oxygen, 287–289
Metabolomics, 35, 37, 125–132, 135, 143, Molisch test, 178
147, 154, 573, 578, 581, 586 Monoamine oxidase (MAO), 268
Metainflammation, 380 MAO–A, 275
Metallothioneins, 206 MAO–B, 268, 275–277
Metformin, 205 MAO–B inhibitors, 276–277
Methiin, 418 Monocyte chemoattractant protein-1 (MCP-1),
Methionine, 141, 146, 270, 420, 645, 670 510–512, 612, 626, 783
Methoxylation, 307 Monocytes, 145, 335, 357, 503, 568, 604,
1-Methyl-4-phenyl–pyridinium (MPP+) 240, 612–613, 626, 696
259 Monolignol, 66
Microbiome, 20, 21, 22, 37, 38, 39 Monoterpenes, 71, 74–76, 162, 176, 211, 293,
16S rRNA 21 304–305, 309, 313, 316, 552
Actinobacteria, 20 Morphine, 328, 385
Bacteroidetes, 20 Mucin, 27, 30, 35, 398
Betaproteobacteria, 20 Mucosa, 19, 20, 36, 375, 409
Colonization, 20–21, 24–25, 566 Mulberries, 280, 490
Resistance, 24 Multidimensional protein identification
Commensal, 21, 24–26 technology (MudPIT), 137
Firmicutes, 20 Multidrug-resistant (MDR), 77–78, 529
Fluorescent in situ hybridization (FISH), Mushrooms, 14, 16, 328, 691– 702, 705–709
21 Almond (Agaricus subrufescens), 702
Gammaproteobacteria, 20 Basidiomycete, 78
Gut microbiota, 22–26, 31–38, 127, 130, Blushing wood (Agaricus sylvaticus), 705
600–601, 739 Hedgehog (Hydnum repandum), 697–699
Phyla, 20, 683, 691 Jelly ear (Auricularia auricula-judae),
Verrucomicrobia, 20 691–693, 704
 Index 813

King bolete (Boletus edulis), 694 Neohesperidoside, 459–461

Maitake (Grifola frondosa), 698, 705 Neoxanthin, 528, 565, 725, 728
Meadow (Agaricus campestris), 703 Nephropathy, 214
Morel (Morchella esculenta), 691 Nephrotoxicity, 404
Oyster (Pleurotus ostreatus), 328, 691, Neural networks, 128
699, 705–707 Neurodegenerative diseases (NDG), 15–16,
Paddy straw (Volvariella volvacea), 691 204–216, 234, 235–240, 251, 252–267,
Parasol (Marcolepiota procera), 697 278–282, 328, 336, 385–388, 619, 652
Poplar (Agrocybe aegerita), 697 Neurofibrillary tangles (NFTs), 215, 234, 238,
Reishi (Ganoderma lucidum), 691 252–254, 260–262
Shiitake (Lentinus edodes), 685, 691, 694, Neuroinflammation, 279, 386
699, 706–707 Neuronal injury, 236, 240
Snow (Tremella fuciformis), 703 Neuropathy, 214, 378
Trumpet (Craterellus cornucopioides), 697 Neuroprotection, 225, 265, 276–282, 511
Velvet stem (Flammulina velutipes), 691 Neuroprotective, 209, 261, 279–280, 405,
Winter truffle (Tuber brumale), 691 511, 586
Mustard, 644, 653, 657, 667 Neurotoxicity, 233, 238–240, 385, 405
Mutagenesis, 100–102, 406, 430, 530 Neurotransmission, 262, 265, 722
Mutagenic, 466, 658 Neurotransmitters, 252, 257–258, 261–262,
Mutagenicity, 431–432 266
Mutations, 204–206, 209, 256–257, 260, 458, Neurotrophic, 386
706 Neutrophils, 330, 336, 359, 465, 500, 537,
Mutatoxanthin, 528 778
Mycobacterium spp., 313, 376, 579 Nuclear factor kappa-light-chain-enhancer of
Myocardial infarction (MI), 399, 445, 449, activated B cells (NF-κB), 48, 53–71,
472, 500, 720–721, 772, 780 138, 203, 212–213, 226–227, 240, 260,
Myricetin, 51–52, 160, 463, 468, 482–485, 279, 281, 294, 359, 381–383, 386, 445,
530, 533, 542–543, 563, 576, 581 503–512, 570, 612
Myristic acid, 335 N-g-L-glutamyl-S-sinapyl-L-cysteine, 540
Myrosinase (thioglucoside glucohydrolase), Nicotinic acetylcholine receptors (nAChRs),
646–647, 659–662, 669, 672 238, 255, 265
Niemann–Pick C1–like (NPC1L1), 96
N-acetyl-D-glucosamine, 737 Nitric oxide (NO) 54–57, 63, 260, 281, 294,
N-acetyl-S-cysteine, 442, 661 314, 333–334, 351–352, 359, 381–382,
NADPH oxidase, 288, 331 386,
NAD(P)H quinone oxidoreductase 1 (NQO1), 402–403, 408, 411, 445, 466, 470–471, 497,
225, 472, 511, 652 502–504, 569, 604, 609–610, 625–626,
Naringenin, 52–54, 461–463, 471, 483 727, 730
Naringin, 3, 165, 291, 462–463, 472, 580 Nitric oxide synthase (NOS), 57, 502
Narirutin, 165, 461 Endothelial nitric oxide synthase (eNOS),
Natural products 445–446, 471, 497, 502–504, 511,
91, 101, 153–158, 164–168, 175, 186–187, 610, 625
190, 206, 292, 302, 327, 328, 332, 355, Inducible nitric oxide synthase (iNOS),
375, 464, 468, 530, 658 54–58, 281, 333, 466
Nausea, 263–265, 269, 270–272, 373, 408, Nitriles, 181, 647, 651, 655–659, 661
738 Allyl nitrile, 656
Necrosis, 82, 103, 232, 281, 288, 353, 380, Nitrile crambene, 655
466, 501, 570, 612, 626, 658, 696, 778 Sulforaphane nitrile, 655
Negative ion chemical ionisation, 185 3-Nitrotyrosine (3-NT), 141
Neochrome, 528 N-methyl-D-aspartate (NMDA) 255, 265–266
Neohesperidin, 461 N-methyl-D-aspartate receptor (NMDAR),
Neohesperidose, 52, 460–461 238
814 Index

N,N, Dimethyl animobenzaldehyde, See Oncogenes, 70, 458

also Ehrlich’s reagent BRCA1, 615
Nobiletin, 3, 462–463, 467–468, 471 p21, 50, 69–70, 79, 463, 509
Nomilinic acid, 165 p27, 69, 203, 463, 509
Nonergolines, 272 p38, 50, 71, 232–236, 240, 254, 260,
Nonpolar solvents, 154, 157 509–510
Nonsteroidal anti–inflammatory drugs p53, 50, 60, 70, 79, 281, 463–464,
(NSAID), 51, 70, 293, 384, 735 505–510
Aspirin, 207, 383, 385 Onion, 33, 417–418, 421–434, 441–443,
Ibuprofen, 240, 410 448–449
Nonvolatile, 157–158, 175–176, 181, Orange, 52, 75, 481
333 Oregano, 99, 162, 208–210, 291, 294, 301,
Norepinephrine, 274–275 308–311, 314, 318–319, 334, 337, 736
Normoxia, 227–228 Organosulfur compounds, 428–429, 443,
Nosocomial, 28, 37, 375 446
Nuclear factor-erythroid-2 related factor-2 Orientin, 546
(Nrf-2), 225–226, 232, 445, 507, 511, Origanum spp.
652 O. acutidens, 312
Nuclear Magnetic Resonance Spectroscopy O. compactum, 312
(NMR), 125–130, 176–177, 182, O. rotundifolium, 312
185–191, 195, 581 O. vulgare, 208, 334
1H NMR, 125, 187, 188 Ornithine decarboxylase (ODC), 482, 505
2D NMR, 186–187 Osteoarthritis, 15, 384–385, 411
13C NMR, 189–191 Osteoclast, 359
Nuclear Overhauser Effect (NOE), 187 Osteoporosis, 3, 358–359, 595, 606, 617, 626,
Nucleus basalis of Meynert, 261 707
Nutraceuticals, 71, 162, 175, 484, 538, 565, Overhauser enhancement, 177, 187, 190
573–574, 715–716, 720, 723–731, Oxazolindine-2-thione, 647
740–742 Oxidation, 56, 66, 74, 91, 92, 99–104, 115,
Nutrigenetics, 578, 582, 586 138–139, 145–146, 180, 201–202,
Nutrigenomics, 5, 143, 147, 578, 582–585 210–211, 253–255, 287, 293–295,
307–308, 315–318, 343, 344–360,
Obesity, 1, 3, 13, 22, 38, 135, 328–329, 378–382, 399–402, 419, 446, 467, 472,
380–381, 386–388, 501, 512, 542, 552, 481–482, 498–501, 513, 526, 568–569,
696, 702, 728–729, 738 610, 611, 652, 657, 701, 717, 722–723,
Ocium basilium, 316, 334, See also Basil 729, 732–735, 762– 768
Olea europaea, See Olives Oxidative damage, 51, 141–142, 209,
Oleanic acid, 71 254–255, 258, 281, 351–352, 381, 401,
Oleic acid, 697 404, 466, 473, 499, 506, 513, 526, 530,
Oleoresin, 333, 410 538, 568, 694, 701, 707
Oligofructose, See also Fructo-oligosaccharide Oxidative stress, 3, 48, 66, 99, 102, 137–147,
(FOS) 202–206, 225–240, 251–260, 278–281,
Oligopeptide, 3 288, 314–315, 351–352, 356, 359, 381,
Oligosaccharides, 3–7, 23, 33–37, 112–114, 399–405, 458, 469–470, 498–507,
388, 617, 693, 702, 737 510–512, 526, 537–538, 547, 568, 571,
Olives, 64, 138, 146–147, 533, 697, 752–755, 656–658, 701, 709
760, 772, 778–783
Oil, 64, 138, 146, 697, 752–755, 760, 772, Paclitaxel, 80–81, 382
778–783 Palmitic acid, 335
Omega-3 Fatty Acids, 14–16, 388, 716–723, Panax ginseng. See also Ginseng Paraquat
741–742 240, 352, 402
Omega-6 Fatty Acids 15 Parkin, 240, 260
 Index 815

Parkinson’s diseases (PD), 204, 230, 234, Phenyl lactic acid, 25

239–240, 251, 256–260, 267–272, 276, Phenyl propanoid, 3
278, 279–281, 488 Phloroglucinol, 724, 729
Parsley, 49 Phlorotannins, 726, 729–730
Pathogen associated molecular patterns Phophatidylinositol-3, 4, 5-trisphosphate
(PAMPs), 330 (PIP3), 202
Peach, 57 Phophatidylinositol-4, 5-bisphosphate (PIP2),
Peanuts, 55, 280, 291, 490 202
Pelargonidin, 54, 58–60, 506, 528, 543, 563, Phosphatase and tensin homolog deleted on
650 chromosome 10 (PTEN), 203–205,
Peonidin, 58–60, 484, 534, 563, 650 227
Peppercorn, See Peppers Phosphatidylserine, 314
Peppermint, 162 Phosphodiesterase (PDE), 458, 465, 471–472
Peppers, 334 Phosphoenolpyruvate carboxykinase
Peptides, 6, 15, 24–25, 107, 111, 115–116, (PEPCK), 202, 205
137, 142, 165, 227, 238, 660, 716, 3′-Phosphoinositide dependent kinase-1
733–735 (PDK1), 202–203
Perillyl alcohol, 76 Phospholipase, 78, 81, 465–466, 722
Peripheral blood mononuclear cells (PBMC), Phospholipase A2 (PLA2), 78, 81, 82, 466,
143–145, 611, 778–780 722
Peroxidation, 66, 141, 145, 209, 237, 254– Phospholipase-C (PLC) 315
255, 281, 310, 316, 352, 358, 380,–382, Phosphoprotein phosphatase (PP2A), 203,
387, 399–411, 434, 473, 512–513, 538, 235
584, 604, 610–611, 697, 701, 781, 786 PP2A and its regulatory subunit B56β
Peroxiredoxins, 146 (PPTR-1), 203
Peroxisome proliferator-activated receptor Phylum 38, 683, 691
alpha (PPARδ), 445 Phytoalexin 280, 497
Peroxisome proliferator-activated receptor Phytoalexins 68
alpha (PPARα), 139, 336, 378, 445 Phytochemicals 47–48, 90–91, 95–116, 208,
Peroxisome proliferator-activated receptor 290–294, 329, 334–336, 389, 457, 464,
beta (PPARβ), 378 481–485, 489–514, 526, 562, 568–569,
Peroxisome proliferator-activated receptor 577, 644–645, 651, 672, 716, 729–730
gamma (PPARγ), 240, 336, 378, 613, Phytoestrogens 14–15, 60–62, 68, 332, 497,
626, 703–704, 728, 757 511, 595, 602, 614–615, 624–626
Peroxynitrite radical, 287, 351–352, 411 Phytosterol 3, 6
Petunidin, 58, 60, 484, 534, 563, 650 β–Sitosterol, 3
P-glycoprotein, 529 PI3K-AKT pathway, 60, 202–205, 225–227,
Phagocytosis, 31, 260, 329–333 235–236, 260, 265, 281, 353, 445, 463,
Phagosomes, 331–332 509, 511, 702
Phenolic phytochemicals, 90–91, 95–106, V-akt murine thymoma viral oncogene
110–116, 290–294, 716, 729–730 (AKT), 202–205, 226, 227, 235–238,
Phenolics, 24, 47–49, 63–68, 83–84, 90–116, 260, 265, 281
129–130, 155, 178, 207–212, 274,–280, Pineapple, 526, 539–543
290, 291, 292, 293, 294, 304, 305, 307, Pinene, 161
308, 309, 310, 311, 313, 314, 316, 329, α-Pinene, 336
334, 335–337, 344, 347, 381, 388, 411, β-Pinene, 547
462, 465, 468, 481–513, 525–540, Piper spp.
547–553, 561, 562–586, 611, 645–650, P. nigrum, 334, 373
656–671, 699, 716, 724–730, 736 Piribedil, 273
Acids, 48, 63, 207, 291, 304, 344 Pitanga, 541–543
Phenols, 48–49, 354, 411, 482, 493, 496, Plasma cholesterol, 607, 735, 739
563, 724 Platelet-activating factor (PAF), 66
816 Index

Platelet aggregation, 14, 55, 66, 294, 307, Propionate, 23, 35

357–358, 443–444, 470–471, 481–482, Propionic acid, 6
497–501, 513, 569, 584, 604, 612–613, Prostaglandins, 15, 51, 70, 81–82, 444,
657, 699, 784 465–466, 469
Pleurotus spp. Prostaglandin E2, 82, 778– 779
P. eryngii, 685–688, 701, 705–706 Prostaglandin, F2a 145
Plum, 57 Prostaglandin I2, 444
Polar solvents, 154–157, 162 Prostate specific antigen (PSA), 50, 356, 605,
Poly ADP ribose polymerase (PARP), 315, 616, 626
441, 464 Protein kinase
Polycyclic aromatic hydrocarbons (PAH), 52 Protein kinase-A (PKA), 386
Polydextrose, 6, 37 Protein kinase-B (PKB), 202, 446
Polymerization, 81, 238, 344, 349, 488–490, Protein kinase-C (PKC), 315, 353, 465,
738 471, 503
Polyphenols, 3, 4–7, 130, 281, 316, 344, Proteome, 136–137, 142–145, 578
355, 466, 495, 500–501, 528, 536, 568, Proteomics, 135–147, 573, 586
577–581, 649, 662–664, 694, 719 Proteus spp., 312, 376, 567
Polyphenol oxidase (PPO), 344 P. vulgaris, 567
Polysaccharide, 3, 23, 27, 66, 105, 333, 345, Protocatechuic acid, 99
388, 687–688, 693–697, 701, 704, Pseudomonas spp., 312, 319, 334, 376
707–708, 724–730 P. aeruginosa, 312, 335
Poly unsaturated fatty acids (PUFA), 66, P. fluorescens, 312
254–255, 716, 756, 761, 776 P. pseudoalkaligenes, 312
Trans, 786 Psidium spp.
Polyuronides, 724, 725 P. arboretum, 548
Pomegranate, 57, 291 P. cattleianum, 548
Postmenopausal, 39, 145, 379, 502, 598, 618, P. grandiflorum, 548
626, 696, 756–761, 776, 783 P. guajava, 531–533, 548
Postprandial, 100, 105–106, 110, 201, 214, P. guineensis, 545, 548
542, 552, 608, 704, 736, 740 P. incanescens, 548
Pouchitis, 32 Psyllium husk, 6
Prebiotics, 3, 16, 19, 27, 33–39, 705 Pterostilbene, 68, 490, 506
Preparative planar chromatography, 163 Pulsed electric field (PEF), 494–496
Presenilin, 256 Pumpkin, 99
Pressurized liquid extraction (PLE), 493–494 Puupehenone, 78
Principal component analysis (PCA), Pyrethrins, 76
128–129, 581 Permethrin, 76
Proanthocyanidins, 49, 54–55, 211, 292, Pyrone ring, 457–459
488–490, 493, 497–501, 512, 563–566, Dihydropyrone, 459
571
Type-A, 55–56 Quercetin, 3, 51–54, 99, 139, 160, 208–209,
Type-B, 56, 212, 381, 488, 528 313, 411, 461–472, 482–488, 493, 501,
Probiotics, 3, 14–19, 25–39, 89–90, 94–96, 511, 528–544, 548–553, 563, 576, 580,
115, 388, 566, 602, 692, 705, 708 581, 610, 649, 650, 656, 657, 663, 664,
Procyanidins, 55–58, 212, 381–382, 488, 494, 718
501, 512, 528, 563, 567 Quince, 57
Programmed cell death (PCD), See Apoptosis Quinic acid, 65, 161, 564, 649–651
Proinflammatory, 31, 70–71, 82, 212, 255, Quinine, 78, 434, 435
258, 279–281, 315, 337, 358–359, 388,
466, 507, 510, 584, 652, 701, 721 Raffinose, 6, 27
Prolyl hydroxylases (PHD), 227 Randomized controlled trials (RCTs),
(E)-1-Propene-1-sulfenic acid, 422–424 605–609, 614, 617–620, 625
 Index 817

Rasagiline, 276, 277 (E)-S-1-Propenyl-L-cysteine sulfoxide, 418,

Raspberries, 57–59, 60, 291, 561–571, 576, 422–424
579–585 S-Adenosylhomocysteine (SAH), 141
Reactive nitrogen species (RNS), 287, 351, S-Adenosylmethionine (SAM), 141, 274
411 Sadler indices, 185
Reactive oxygen species (ROS), 15, 70, Sage, 208–210, 291, 293, 308–311, 314, 318,
100–103, 146, 207–209, 225, 238–240, 334–336
260, 287–289, 315, 345, 351–360, Salicylic acid, 139–141, 207
380–383, 403, 407, 436–437, 442, Salidroside, 110
469–470, 500–504, 512, 538–541, S-(+)-Alk(en)yl-L-cysteine sulfoxide, 417,
546–547, 568–570, 611, 626, 652, 420
656–657 S-Allylcysteine (SAC), 434, 446
Quenching, 15, 99, 209, 292, 336, 354, S-Allyl-L-cysteine sulfoxide, 418, 421–427,
402, 513, 656 444
Red currants, 57 Salmonella spp., 29, 294, 312, 334, 376,
Redox signaling, 141, 445 566–579
Reproductive health, 335, 624 S. enteritidis, 312
Resin ducts, 74 S. typhi, 312, 334
Resins, 74, 157, 163, 176 S. typhimurium, 294, 312, 376
Resorcinol, 345 Salvia spp.
Resveratrol (RSV), 68–71, 100, 278–282, 291, S. officinalis, 208, 310, 314, 334
482, 490, 496–513, 564 S. pisidica, 313
Pallidol (dimer), 68 S. tomentosa, 313
Piceid (glycoside), 68, 490, 506 Saponins, 159, 165, 329, 607–608, 617
Retinoic acid, 71, 441 Scavenger receptor, 233, 584
Retinol, 71 Seaweed, 6, 7, 724–731, 742
Retinopathy, 214, 378 Peptides, 6
Reutericyclin, 25 α-Secretase 252
Reuterin, 25 β-secretase 255
Reversed phase, 165–166 γ-secretase 252
Rheumatoid arthritis, 38, 51, 358, 411, 706 Selective estrogen receptor modulators
Rhizopus spp. (SERM), 603
R. oligosporus, 540, 579 Selegiline, 276, 277
Rhodiola, 102, 108–110, 206 Selenium 289, 562, 645, 694, 707–709
Rice, 2, 3, 61, 379, 572, 684 Seminal vesicles 386
Rivastigmine, 262–265 Serotonin 384, 471, 540, 722
RNA interference (RNAi), 669 Serum glucocorticoid–responsive kinase
Ropinirole, 273 (SGK) 203
Rosemary, 159–162, 208, 209–210, 291, 295, Sesame, 3, 6, 65–66
301, 308–309, 314–318, 334–335 Sesamin, 3, 5, 66
Rosmanol, 209, 295, 310 Sesquiterpenes, 76–78, 162, 185–186, 211,
Rosmarinic acid, 208–209, 293–295, 309–314, 293, 304, 549
335–337 Sesterterpenes, 81, 82, 83
Rosmarinus officinalis, See Rosemary Shigella spp., 29, 567, 579
Rotavirus 29, 30, 531–532 Shogaol, 333
Rotenone, 259 Short chain fatty acids (SCFA), 23–25, 34–36,
Rubixanthin, 542 130, 708
Rubus spp. Signaling, 47, 50–54, 61, 68–71, 136–146,
R. idaeus, 561 201–214, 225–240, 252–261, 278–282,
Rutin, 51, 462–463, 470, 528 288, 294, 329, 353–355, 378–383, 436,
Rutinose, 52, 459–461, 563 442–446, 458, 472, 482, 499, 505–513,
Rye, 66–67 570, 583, 616, 619, 622, 652, 702
818 Index

Silica gel, 163, 164, 725 Strawberries, 291, 548, 561–567, 570–573,
Silybin, 718 580–585
Silymarin, 466, 718 Streptococcus spp., 6, 89, 92–95, 312–313,
Sinapic acid, 59, 64–65, 307, 313, 649– 651, 334, 376
666 S. anginosus, 334
Sirtuins, 203, 281, 482 S. faecalis, 312
SIRT1, 281, 482, 497, 506–512 S. intermedius, 334
SIRT2 (Sir2), 203, 507 S. oralis, 334
SIRT3, 281 S. pneumoniae, 313, 376
Size-exclusion chromatography, 163 S. pyogenes, 312
S-methyl-L-cysteine sulfoxide, 418, 422, S. salivarius, 32
426 S. sanguis, 334
Smoking, 383, 502, 547 Streptozotocin, 403, 410, 447–448, 703, 739
Solvent extraction, 156–166, 426, 493 Stress response signaling, 70, 202, 206–209,
Solvent free microwave extraction (SFME), 231–232 Stroke 53, 315, 357, 512, 604,
159 618, 700–701, 720, 780
Sonication, 156–159 Structure-function, 96, 100–101, 513
Sorbitol, 27, 37, 378 Subcritical water extraction (SWE), 493
Soxhlet extraction, 156–159, 168 Sublimation, 156
Soyasaponin, 3 Substantia nigra pars compacta (SNpc), 204,
Soybean 3– 7, 14–15, 37, 60–67, 93–95, 239–240, 257–258
102–113, 157, 165, 291, 388, 538–540, Sucrose, 27, 213, 399
595–626, 752–756, 765–767, 773–776, Sugar alcohols, 37
782–783 Sulfenic acid, 421–424
Soy cheese, 61 Sulfonylureas, 205, 377
Soymilk, 61, 95, 102–115 Sulfoxide, 3
Soy protein (SP), 5, 6, 14, 62, 163, 183, Supercritical fluid extraction (SFE), 158–160,
525, 596, 605–626 168, 492–493
Tempeh, 596–597, 601 Superoxide anion (O2–) 287–289, 310, 336,
Soy foods (SF), 182, 596-626 352, 402, 469, 470
Soy isoflavones (SI), 595–598, 603-626 Superoxide dismutase (SOD), 51, 68, 104,
Soy protein isolates (SPI), 596–598, 609, 614, 141, 146, 202, 206–210, 225, 280–281,
623, 626 289, 314–315, 381, 434, 503, 697
Sperm, 387 Cu/Zn-SOD (cytoplasmic), 141, 289
Spices, 47, 159, 176, 181, 205–211, 292, Dismutation, 289
301–313, 327–333, 371, 373, 381, EC–SOD (extracellular), 289
385–387, 398, 408, 411–412 Iron/manganese superoxide dismutase
Spinach, 141, 645 (SOD–2), 202
Squid, 716–718, 723, 732–737 Mn–SOD (mitochondrial), 289
S-Sinapyl glutathionem 540 Ni–SOD (cytoplasmic), 289
S-Sinapyl-L-cysteinen 540 Synbiotics, 130
Staphylococcus spp. 311, 566 α–Synuclein, 230, 234, 240, 257, 260
S. aureus, 91, 294, 312, 313, 334, 335, Syringic acid, 130
375, 530 Syzygium spp.
S. epidermidis, 335 S. cumini, 533
Star anise, 159, 373 S. jambolanum, 533
Stationary phase, 163–167 S. aromaticum, See Cloves
Sterol regulatory element binding protein
(SREBP), 139 Tacrine, 262–263
Stigmasterol, 210 Tamoxifen, 205
Stilbenes, 48, 68–69, 291, 481–482, 490–491, Tandem mass spectrometry (MS/MS), 182,
506, 562–564, 568, 581, 648 185, 496, 581
 Index 819

Tangeretin, 49, 291, 462, 467–468, 471 Thioredoxin reductase (TR), 146, 225
Tangerines, 52, 291 Thiosulfinates, 421–426
Tannins, 91, 98–101, 211, 292, 305, 334–336, Thrombin, 142, 444
481–483, 488, 526, 530, 534–536, Thrombosis, 294, 443, 471, 699
561–568, 584, 648, 726, 729 Thromboxane
Condensed, 211, 292, 481, 482, 488, 530, Thromboxane A2 (TXA2), 444, 466, 471,
562, 564 503, 612
Ellagitannins, 305, 547, 562–569 Thujone, 210, 335
Gallotannins, 305, 547, 562–564 Thyme, 49, 159–161, 208–210, 294, 301,
Hydrolyzable, 305, 536, 562 308–309, 312–319, 334–337
Tartaric acid, 65, 161 Thymol, 161, 210, 294, 309, 316, 335–337
Tau protein, 215, 237–238, 252–256, Thymus spp.
260–261, 279, 385 T. algeriensis, 308–309
Aggregation, 215, 279, 385 T. atlanticus, 316
Hyperphosphorylation, 69, 233, 238, T. capitatus, 308, 312
253–256, 261, 436–437 T. longicaulis, 312
Taxifolin, 467, 546 T. mastichina, 312
Taxines, 80 T. moroderi, 312
Taxol, 81, 160–161. See also Paclitaxel T. piperella, 312
Taxus spp. T. pulegioides, 312
T. baccata. See Yew T. serpyllum, 308
T. cuspidata. See Yew T. sipyleus, 309
Tea, 3, 6, 7, 49–50, 57–58, 99, 154, 167, T. vulgaris, 208, 308–309, 312, 316, 334
207–210, 291–292, 308, 343–362, T. zygis, 312, 316
371–372, 532–534, 579, 671, 696 Thyroid hormone, 139, 623, 624
Black tea, 167, 344–348, 353–361, 372 Tocopherols, 14, 15, 309, 310, 314, 356, 498,
Flavonoids, 6 645, 701
Green tea, 7, 57–58, 99, 207, 292, Tocotrienols, 3
343–359, 533, 671, 696 Toll-like receptors (TLR), 212, 235, 330, 333
Oolong tea, 344 Tomato, 3, 5, 141
Terpenes, 73–75, 176, 186, 212, 278, 304, Transcription 47, 57, 71, 139, 202, 212,
332–335, 547 225–227, 232–236, 240, 279, 294, 356,
Isoprene, 72 359, 378, 442, 506–511, 570, 585, 602,
Terpenoids, 47–48, 71–74, 79–84, 164, 186, 612, 652
207–210, 290, 304, 536 Transcription factor, 225–226, 232–233,
Terpineol, 335 279, 294, 359, 442, 509, 511, 570,
Testosterone, 386–387 612, 652
Tetraterpenes, 71 Transcriptomics, 135, 139, 143, 147, 586
Texturized vegetable protein (TVP), 597, 601, Transferrin, 227
626 Transforming growth factor (TGF)
Theaflavin–3–gallate, 347 TGF-α, 227
Theaflavins, 344–348, 354–358 TGF-β, 53, 203, 226, 236–237, 260–261,
Thearubigins, 344, 347, 354 382
Theobroma spp. TGF-β signaling, 53, 203, 226, 236,
T. grandiflorum, 545, 549 260–261
Thiazolidinediones (TZD), 205, 377 Trehalose, 693
Thin layer chromatography (TLC), 164 Triacylglycerol (TAG or TG), 7, 35, 138–139,
Thiobarbituric acid reactive substances 146–147, 208–214, 315–316, 377–380,
(TBARS), 141, 209, 309, 317–318, 401, 410, 446–448, 501, 607–608, 626,
404, 501 697–699, 720–721, 735, 739, 753–770,
Thiocyanates, 647, 659 774, 782
Thioredoxin, 141, 146, 225 Trichomes, 74, 304
820 Index

Trimethylamine N–oxide (TMAO), 131 Vibrio spp.

Trimethyllysine, 131 V. parahaemolyticus, 579
Trinitrobenzene sulfonic acid (TNBS), V. labrusca, 484
335 Vinblastine, 382
Triterpenes, 71, 293, 562, 694, 703 Vincristine, 382
Triterpenoids, 3, 71–73, 178 Vinegar, 3, 5
Tuberculosis, 77–78 Viniferin, 68, 490, 581
Mycobacterium tuberculosis, 77–78 Violaxanthin, 528, 542, 547, 565, 725
Plasmodium falciparum, 77 Vitamin C 141, 290, 498–499, 527–529, 532,
Tubulin, 81, 437–438 536, 540, 546–547, 550, 561, 565–567,
Tucumã tucumã (Astrocaryum aculeatum), 584–585, 645, 671, See also Ascorbic
551, 552 acid
Tumorigenesis, 213, 295, 355–356, 433, 506, Vitamin E, 15, 141, 209, 318, 498, 499, See
570, 654 also Tocopherols
Tumor suppressor, 204, 458, 463, 509, 615 Vitis spp.
Turmeric, 3, 157, 164, 332–333, 379, 397, V. labrusca, 484
398,–411, 719 V. vinifera, 64, 68, 484–486, 490–492, 561
Typhimurium spp., 567 Volatile, 76, 160, 175–176, 181–186, 211, 304,
Tyrosine kinase, 202, 205, 465, 510 406, 421, 426, 491, 547–551, 580, 581
Tyrosol, 110, 482, 507
Walnuts, 15
Ubiquinone, 3 Wheat, 6, 7, 379, 684, 706–707
Ulcer, 102, 111, 114, 383 Whey, 6, 15
Ulcerative colitis (UC), 30, 31 White adipose tissue (WAT), 501, 729
Ultra–Violet Absorption Spectroscopy, 178 Wine, 49, 59, 68, 99–100, 130, 167, 280, 291,
Ultraviolet (UV), 90, 98, 101, 177, 181, 229, 388, 481–483, 490–513, 562, 575, 581
235, 280, 490, 496–499, 510, 563, 648, Red, 59, 99, 130, 167, 280, 388, 498–507,
695, 707, 728 575
Ulvans, 725–727 Wogonin, 49
Unfolded protein response (UPR), 231–234
Uric acid, 352, 546 Xanthane oxidase (XO), 352, 402
Ursolic acid, 71, 210, 294, 295, 313, 314 Xenobiotic, 466, 652, 665
Uxi (Endopleura uchi), 551–552 Xenoestrogens, 602
X-ray diffraction, 178
Vaccenic acid, 749, 763, 786 Xylan, 27
Vaccinium spp.
V. corymbosum, 561 Yeasts, 6, 71–72, 313, 670, 708–709
V. macrocarpon, 561, 566 Candida spp., 311–313, 376, 708
V. myrtillus, 561 Cryptococcus spp., 334
V. oxycoccus, 566 Saccharomyces spp., 28, 281, 313, 670,
Vacuum liquid chromatography (VLC), 163, 692, 707–708
164 Yew, 80–81
Vanadium, 704 Yogurt, 3, 61, 89–95, 106, 110–111, 579–757,
Vanilloid, 3 761, 768–769, 771, 777–787
Vascular endothelial growth factor (VEGF),
213, 227, 382, 570 Zeaxanthin, 542, 645, 725
VEGF receptor (VEGFR), 213 Zinc, 139, 142, 229, 409, 552, 562
Vasoconstrictor, 106, 584 Deficiency, 139
Vasodilatation, 609 Zingeron, 333
Vasorelaxation, 470 Zinziber spp.
Very low density lipoprotein (VLDL), Z. officinale, 333, 373, 397, 408–409
764–770 Zoochemicals 15