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146 Flavonoids as Nutraceuticals
7.2.2 FLAVONOLS
Flavonols have the 3-hydroxy flavone backbone and hydroxyl group in the
C-3 position. Quercetin, kaempferol, fisetin, and myricetin are the most
prevalent plant flavonols in fruits, vegetables, and herbs. Flavonols are the
building blocks of proanthocyanins (Panche et al., 2016).
7.2.3 Isoflavonoids
The flavones and isoflavones are isomers with a heterocyclic ring attached
in the C-2 and C-3 positions. The principal source of isoflavonoids like
daidzein and genistein includes the plants of Leguminosae family (Tandon
& Das, 2018).
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147 Bioactive Flavonoids from Natural Sources: Potential Immune-Boosters
7.2.4 FLAVANOLS, FLAVAN-3-OLS, OR CATECHINS
Flavanols and flavan-3-ols with a hydroxyl group bound to the third position
of the carbon ring, and there is no double bond between the second and third
positions (Panche et al., 2016). The polyphenolic flavonoids like epicatechin,
epigallocatechin, epicatechin-3-gallate, and epigallocatechin-3-gallate are
present in Green tea made from the unfermented leaves of Camellia sinensis
(Chakrawarti et al., 2016).
7.2.5 FLAVANONOLS
In flavonols, the hydroxyl group is situated in the third carbon, and the
oxygen atom is attached to the fourth carbon of the ring (Kumar & Pandey,
2013). The phytocompounds silibinin, astilbin, and taxifolin are examples of
flavanonols (Hua et al., 2018).
7.2.6 ANTHOCYANINS
Anthocyanins are the pigments responsible for most of the blue, purple,
and red-colored flowers, fruits, and vegetables (D’Archivio et al., 2007).
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148 Flavonoids as Nutraceuticals
Anthocyanidins are water-soluble aglycon forms of anthocyanins. Proantho-
cyanidins (PACs) are mainly present in grapes. There are multiple forms
of flavonoids, dimers, or oligomers of catechin and epicatechin and their
gallic acid esters. A condensed tannin or polymeric flavanol is known as
PAC. PAC-type compounds are namely malvidin, pelargonidin, peonidin,
cyaniding, delphinidin, and petunidin (Stalikas et al., 2007).
7.2.7 CHALCONES
Chalcones are important compounds in the flavonoid biosynthesis because it
represents the precursor for a broad range of flavonoids (Raffa et al., 2017).
Chalcones consist of phloridzin, arbutin, phloretin, and chalconaringenin.
Major examples of Chalcones occur in significant amounts in tomatoes,
pears, strawberries, bearberries, and certain wheat products. As previously
mentioned, chalcones have a broad spectrum of biological properties, such
as antioxidant, antimicrobial, and anti-inflammatory activities. Isoliquiriti
-
genin, also known as 2′,4,4′-trihydroxychalcone or 6′-deoxychalcone, is a
member of the class of compounds known as 2′-hydroxychalcones (Sahu et
al., 2012).
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149 Bioactive Flavonoids from Natural Sources: Potential Immune-Boosters
7.2.8 FLAVANONES
Flavanones, also known as dihydroxyflavones, have a bitter taste. The juice
and peel of citrus fruits contain flavanones. Examples of flavanones are
naringin, naringenin, and hesperidin. They differ from flavone in structure
doesn't have instaurations between C-2 and C3. These compounds exhibited
pharmacological properties such as anti-inflammatory, antioxidant, anti
-
hypercholesterolemic effects (Panche et al., 2016).
7.2.9 BIS AND BIOFLAVONOIDS
Bis and Bioflavonoids joined in a symmetrical or unsymmetrical manner,
where the moieties are linked by a C-C or C-O-C bond (Mercader & Pomilio,
2013). When the units are doubled, they are called bis-flavonoids, but when
the structural units are not the same, they are called biflavonoids. The
common examples are amentoflavone (dimer of two apigenins), ginkgetin,
moreloflavone, isoginkgetine, hinokiflavone, robustaflavone, and ochnafla
-
vone. They have a basic structural framework of 4,5,7-trihydroxyflavon
flavonoid (Silva et al., 2017).
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150 Flavonoids as Nutraceuticals
7.3 IMMUNOSTIMULATORY EFFECTS OF FLAVONOIDS OF
PLANT ORIGIN
Immune boosters enhance the nonspecific humoral and cellular immune
responses. The immunomodulatory activity is related to the structural char
-
acterization of phytosterols. The sugar moiety of the phytophagous forms the
key point for different types of immune responses (Cherng et al., 2008). The
size and molecular weights of polyphenols influence the immunomodulatory
responses, particularly of T-cell cytokine secretion. The polyphenols interact
with immune system components and cells like lymphocytes, dendritic
cells (DCs), neutrophils, and macrophages. The stimulation of the immune
system is regulated by T-lymphocytes by TH-1 (CD4
+
), causing an increase
in the protective effects producing activated macrophages and cytokines.
Macrophages play an important role and act as antigen-presenting cells in
the generation of immune response and trigger phagocytosis.
Masad et al. (2021) reported that quercetin, one of the avonoid
compounds present in honey, differentially activated Th1 cells providing a
crucial mechanism for antitumor activity. Sutoyoto et al. (2018) reported
the immunostimulant activity of kaempferol isolated from acetone extract
of Pityrogramma calomelanos (Silver fern) in a carbon clearance assay.
The phagocytic index of the compound-treated group was high compared
to the normal control group. Kaempferol increased the percentage of CD8
+
cells. There was an increase in B-cells and lymphocytic T-cell proliferation,
the release of cytokines such as IL-4, TNF-α, and IFN-γ. The compound
stimulated the phagocytic property of macrophages, lysosomal enzyme
activity, and NO release by macrophages. Talmale et al. (2014) studied the
immunostimulatory effect of avonoids extracted from Zizyphus mauritiana
stem bark. It stimulated lysosomal degranulation, phagocytic index, and
proliferation of lymphocytic splenocytes. Abdelsalam et al. (2017) evaluated
the immune stimulant effect of avonoids isolated Alcea rosea on hepatocel-
lular carcinoma HepG2 cell line.
Flavonoids exhibited immune booster activity by stimulating mononu-
clear cells to secrete TNF-α, IL-1β, and IFN-γ. The avonoids consisting of
phyllantidine, quercetin, isoquercetin, and astragaline isolated from the roots
and leaves of Phyllanthus niruri water extract increased peripheral blood
mononuclear cell (PBMC) proliferation, increased the release of NO from
macrophages, improved phagocytic index and increased antibody response
and gallocatechin extracted from the leaves of Psidium guajava stimulated
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151 Bioactive Flavonoids from Natural Sources: Potential Immune-Boosters
humoral and cellular immune response in mice. It showed increased expres-
sion of the IL-8 gene, indicating immune-boosting action (Laily et al.,
2015). Nair et al. (2002) carried out the evaluation of avonoid quercetin in
regulating Th-1 and Th-2 cytokine gene expression. The compound signi
-
cantly induced the gene expression and production of Th-1 derived IFN-γ by
normal PBMC. Quercetin treatment increased the phenotypic expression of
IFN-γ cells suggesting the immunopotentiating effects mediated through the
induction of Th-1 derived IFN-γ.
Jung et al. (2012) reported the efcacy of quercetin on impaired immune
function in irradiation-induced inammatory mice. Irradiation exposed
animals showed diminished splenocyte proliferation. The treatment with
quercetin (10 and 40 mg/kg) signicantly enhanced splenocyte proliferation
after 30 days and exhibited a protective effect against irradiation-induced
inammation. Quercetin exhibited in vivo immunostimulatory activity in
ovalbumin-immunized Balb/c mice with increased ovalbumin-specic
serum IgG antibody titers. The compound stimulated Th-2 immune response
and increased CD11c
+
dendritic cell inltration in the peritoneal cavity.
The expression of GATA-3, Tbx-21, and Oct-2 proteins enhanced in mice
splenocytes treated with quercetin, suggesting the immunostimulatory and
adjuvant effect of quercetin (Singh et al., 2017). The in vivo adjuvant effect
of kaempferol was studied by Singh et al. (2018) with ovalbumin antigen in
Balb/c mice. The kaempferol-treated group showed a signicant increase in
IgG, IgG1, and IgG2a antibody titers. The increased expression of Tbx21
and GATA-3 transcription factors (TFs) in splenocytes supported the stimu
-
lation of Th1 and Th2 immune response in the treated group. Kaempferol
treatment also increased the inltration of CD11c
+
, MHCII
+
DCs suggesting
the adjuvant effect and immunostimulatory activity.
Oral administration (12.5–100 mg/kg) of the avonoid daidzein stimu-
lated IgM and IgG titer in vivo and dose-dependently increased delayed-type
hypersensitivity reaction implicating the immune stimulatory effect of the
compound in Balb/c mice (Dhiman et al., 2013). Epigallocatechin-3-gallate,
an active ingredient of green tea, was found to induce T-cell activation,
proliferation, differentiation, and production of cytokines, and it prevented
and ameliorated T-cell-mediated autoimmune diseases (Pae & Wu, 2013).
Epicatechin isolated from the chloroform extract of Rhododendron spic-
iferum signicantly stimulated splenocyte proliferation when treated with
concanavalin-A. It enhanced the cytotoxicity of NK cells and the phagocytic
function of macrophages. The compound signicantly increased Th1 cyto-
kines (Liu et al., 2015).
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152 Flavonoids as Nutraceuticals
Some of the avonoids, like ugonin U, a avonoid isolated from
Helminthostachys zeylanica, induced activation of NLRP3 (NOD-, LRR-,
and pyrin domain-containing protein-3) inammasome. It also induced
caspase-1 activation and IL-1β secretion in human monocytes pre-stimu
-
lated with lipopolysaccharide (LPS) (Chen et al., 2017). Flavonoids chrysin
and hesperetin signicantly increased the activity of NK cells in K562 cells
(Sassi et al., 2018). Luteolin (1.5 and 10 µM) and apigenin (5, 10, and 25
µM) increased NK cell activity in mouse splenocytes. Naringenin (25 µM)
stimulated the expression of ULBP-1, ULBP-2, and MIC-A/B in Raji cells
(Kilani-Jaziri et al., 2016). The treatment of avonoids on various in vivo
models of tumors in mice stimulated NK cell activity and increased the
survival time of animals (Kilani-Jaziri et al., 2016). Quercetin signicantly
increased the NK cell activity in a mouse leukemia model in vivo (Bae et
al., 2010). Genistein increased the activity of cytotoxic T-cells and NK
cells, secretion of IFN-γ, and activation of STAT-1 and STAT-4 (Guo et
al., 2007). PAC signicantly elevated the T-cell differentiation to CD8
+
cells in mice splenic cells (Guo et al., 2007). Flavonoids apigenin, icariin,
and gallotannin differentially stimulated CD8 cells along with decreasing
tumor growth by apoptosis. The avonoids quercetin and bilclain showed
modulation of B-cell proliferation and antibody production (Zhang et al.,
2018).
Curcumin can act as a potent therapeutic adjuvant for DCs-related acute
and chronic disorders, and it is very efcient at antigen capture via mannose
receptor-mediated endocytosis (Kim et al., 2005). Activation of cell-mediated
immune response is one of the most studied properties of plant avonoids and
polyphenolic compounds. A polyphenol oenothein B extracted from Epilo
-
bium angustifolium activated myeloid cells and stimulated innate lympho-
cytes and natural killer cells resulting in the increased expression of CD25
and CD69 (Ramstead et al., 2012). It enhanced IFN-γ production by human
and bovine T-cells and NK cells (Ramstead et al., 2015). The administration
of biavone di-C-glucoside, 6,6′′-di-C-beta-D-glucopyranoside-methylene-
(8,8′′)-biapigenin (0.25 mg/kg) resulted in the stimulation of both humoral
and cell-mediated zero response in chicks (Abd-Alla et al., 2009). Flavonoid
daidzein potentiated the proliferation of splenocyte cultures activated with
LPS or concanavalin A and the secretion of IL-2 and IL-3 (Wang et al.,
1997). Genistein increased the number of splenic B-cells, T-cells, cytotoxic
T-cells, and macrophages (Guo et al., 2002). Epigallocatechin gallate, gallic
acid, and tannic acid enhanced the mitogenic activity of B-lymphocytes (Hu
et al., 1992).
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The tea polyphenols stimulated the proliferation and activation of
T-lymphocytes, indicated by the increase in the CD4
+
/CD8
+
ratio (Deng et
al., 2010). Green tea and its bioactive constituent epigallocatechin 3-gallate
improved the symptoms and reduced the pathology in some experimental
animal models of autoimmune disorders. The treated group showed a
signicant increase in the number and frequencies of regulatory T-cells in
the spleen and lymph nodes (Pae et al., 2012). The activation of mononuclear
cells and increase in the phagocytic response are induced by some avo
-
noids and phenolic compounds such as daidzein (20 and 40 mg/kg) (Zhang
et al., 1997), procyanidin A
1
(Liu et al., 2010), procyanidin C
1
(62.5 µg/
mL), procyanidin dimer B
2
(Sung et al., 2013), kaempferitrin (25 µM) (Del
Carmen Juarez-Vazquez et al., 2013), oenothein B (Schepetkin et al., 2009),
geraniin and isocorilagin (Liu et al., 2012) via inuencing MAPK (Mitogen
Activated Protein Kinase) and NF-κB signaling pathways. The humoral
immune response can be quantied by the serum levels of specic immuno
-
globulins by antibody titer assays. Green tea, a rich source of polyphenols,
exhibited a stimulatory effect on IgM and IgG-mediated humoral immune
response (Khan et al., 2016). Polyphenol-rich pomegranate extract increased
IgG response (Oliveira et al., 2010). Immunoglobulin synthesis was induced
by cyanidol (Daniel et al., 1986) and daidzein (Zhang et al., 1997).
The avonoid compounds bilclain, astilbin, and quercetin showed an
impact on B-lymphocytes, their modulation, proliferation, and antibody
production. In B-cell leukemia, wogonin (Lin et al., 2013), chrysin (Xu et
al., 2019), quercetin (Spagnuolo et al., 2012), and epigallocatechin gallate
(EGCG) (Huang et al., 2013) decreased cell burden and induced differentia-
tion on B-cell leukemia (Kawai et al., 2011).
Flavonoids are one of the natural sources of immune boosters and anti-
retroviral for AIDS therapy because of their potent anti-HIV activity and low
toxicity (Saravanan et al., 2015). Epigallocatechin inhibited protease kinetics
and post-adsorption entry of the virus (Yamaguchi et al., 2002). Robust-
aavone and hinokiavone isolated from Garcinia multiora and Rhus
succedanea showed anti-HIV activity against polymerase HIV1 reverse tran-
scriptase enzyme. Quercetin 3-o-(2-galloyl) a-L-arabinopyranose, wikstrol
B, pterocarpans, xanthohumol, 2-methoxy-3-methyl-4,6-dihydroxy-5-(3′
-
hydroxy) cin-namoyl benzaldehyde, lawinal, luteolin, hydroxyl panduratin
A, taxifolin, aromadendrin, apigenin 7-0-beta-D-(4′-caffeoyl) glucuronide,
formosanatin C, 5-hydroxy-7-methoxy avone, baicalin, chrysin, and
kaempferol are some of the avonoids exhibiting potent activity against
human immunodeciency virus (HIV) (Saravanan et al., 2015). Toll-like
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154 Flavonoids as Nutraceuticals
receptors are important in the development of innate immune response, and
their activation stimulates the secretion of inammatory cytokines. Modula
-
tion of toll-like receptors is of pharmaceutical importance. Quercetin can
effectively act as a toll-like receptor modulator and is used for the treatment
of HIV (Chin et al., 2018). The avonoid compound reduced viral replica
-
tion and enhanced the immune response (Thompson, 2016).
Nanotechnology use in medicine is spreading rapidly in the drug devel-
opment eld of developed countries. Various nanomedicines with different
therapeutic effects are developed by pharmaceutical researchers by using the
active principle from the natural products and synthetic materials. There is
a rapid growth in the eld of herbal nanomedicine development due to the
increased use of natural products for the treatment of various ailments. The
factors such as the ability to cross the cell membranes like the blood-brain
barrier, gain access to cells, and translocate around the body through blood
and lymph make nanomedicine a promising tool for drug delivery to the site
of action (Rao et al., 2009).
The nanochemical technology uses various nanocomposites and nanopar-
ticles for biosensing avonoids and their delivery as drugs. The avonoid
quercetin and its derivatives, such as myricetin and rutin, are used for
sensing and delivery. The avonoid-based hybrid nanocomposites exhibited
signicant immunomodulatory activity (Parhi et al., 2020). The nanoparticle
-
encapsulated drugs exhibited a higher rate of proliferation of B-lymphocytes,
T-lymphocytes, and NK cells. Immunotherapeutic nanoparticles become an
effective cancer treatment therapy. Gold nanoparticle-immobilized (GNP)
silymarin and GNP-luteolin had antitumor effects (Dykman & Khlebtsov,
2019). Some avonoids isolated from medicinal plants, such as quercetin
and rutin, are used as reducing or capping agents in the green synthesis of
nanoparticles (Selvakesavan & Franklin, 2021). The polyphenols extracted
from Phyllanthus niruri were formulated into polymeric nanoparticles and
evaluated for immunomodulatory activity. The results of the study showed
that the nanoparticles were signicantly effective compared to the unfor-
mulated extract, as evidenced by the increased phagocytic index in vitro
(Pratiwi et al., 2019).
7.4 FLAVONOIDS AS CHEMOPREVENTIVE AGENTS IN CANCER
TARGETED THERAPY
Natural products rich in flavonoids from fruits and other sources are potent
chemo-preventive agents in cancer-targeted therapy. Naringin, naringenin,
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155 Bioactive Flavonoids from Natural Sources: Potential Immune-Boosters
hesperetin, hesperidin, nobiletin, and tangerine are some examples, and
these compounds possess inhibition of the growth of certain types of cancers
by various mechanisms such as cell cycle modulation, apoptosis induction,
anti-angiogenic property, etc. The antioxidant effects of some Citrus flavo
-
noids like hesperidin, tangerine, and nobiletin have been reported. These
compounds have the ability to interact with and stabilize free radicals and
protect the cells and DNA from damage (Yi et al., 2008). Flavonoids also
suppress the process of carcinogenesis by various mechanisms. Flavonoids
such as nobiletin blocked carcinogenesis by suppressing c-Myc expression.
Flavonoids like tangerine showed the lowest IC
50
value in COLO205 human
colon carcinoma cells and HL-60 human promyelocytic leukemia cells by
triggering apoptosis (Pan et al., 2002).
The pretreatment of avonoids myricetin, apigenin, and hesperidin
increased humoral antibody production levels, macrophage phagocytosis,
antioxidant marker enzymes, natural killer cell cytotoxicity, and splenic
lymphocyte proliferation in cyclophosphamide-induced myeloid-suppressed
animals. The compounds decreased proinammatory cytokine levels,
reduced lipid peroxidation, and decreased tissue damage in the bone marrow
and spleen, indicating the immunostimulatory effects of the compounds.
They can be very useful during cancer chemotherapy to reduce the side
effects (Berkoz et al., 2021).
Polyphenolic compounds isolated from propolis stimulated immune
response in mice bearing Ehrlich Ascites Carcinoma (EAC) tumor. The
increase in ascetic uid induced by EAC was markedly reduced after the
treatment, and the survival time was prolonged. There was a dose-dependent
increase in B-cells, cytotoxic T-cell, and NK cell activity, and the treatment
increased the functional activity of macrophages, indicating increased host
resistance against tumor cells (Orsolic et al., 2005).
Kaempferol augments antioxidant defense against free radicals and
modulates a number of key elements in cellular signal transduction path-
ways linked to inammation, tumor angiogenesis, metastasis, and apoptosis.
Kaempferol-mediated MAPK activation prevented DNA damage leading to
cell transformation and cancer development. The compound directly binds
to the RSK2 protein and paralyzes the RSK2 protein, a key suppressor of
apoptosis. Kaempferol binds to Src at its ATP site preventing its skin cancer-
promoting activity (Chen & Chen, 2013). Kaempferol reduced CDK1 levels
in human breast cancer cell line MDA-MB-453 and inhibited proliferation
by disrupting the G2 checkpoint of the cell cycle (Luo et al., 2009). The
compound impaired cancer angiogenesis through the inhibition of VEGF
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