Food Chemistry 299 (2019) 125124

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Food Chemistry
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Review

Anti-inflammatory effects of flavonoids T

a b b,c,⁎
Soheila J. Maleki , Jesus F. Crespo , Beatriz Cabanillas
a
U.S. Department of Agriculture, Agriculture Research Service, Southern Regional Research Center, New Orleans, LA, USA
b
Servicio de Alergia, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
c
Department of Dermatology and Allergy, University of Bonn Medical Center, Sigmund- Freud-Str., 25, 53127 Bonn, Germany

A R T I C LE I N FO A B S T R A C T

Keywords: Inflammation plays a key role in diseases such as diabetes, asthma, cardiovascular diseases and cancer. Diet can
Allergy influence different stages of inflammation and can have an important impact on several inflammatory diseases.
Antioxidant Increasing scientific evidence has shown that polyphenolic compounds, such as flavonoids, which are found in
Cancer fruits, vegetables, legumes, or cocoa, can have anti-inflammatory properties. Recent studies have demonstrated
Cardiovascular diseases
that flavonoids can inhibit regulatory enzymes or transcription factors important for controlling mediators in-
Flavonoids
volved in inflammation. Flavonoids are also known as potent antioxidants with the potential to attenuate tissue
Inflammation
damage or fibrosis. Consequently, numerous studies in vitro and in animal models have found that flavonoids
have the potential to inhibit the onset and development of inflammatory diseases. In the present review, we
focused in flavonoids, the most abundant polyphenols in the diet, to give an overview of the most recent sci-
entific knowledge about their impact on different inflammatory diseases.

1. Introduction (Shen, Kreisel, & Goldstein, 2013).

Inflammation is a complex and crucial defensive host response ty-
pically induced by microbial infections. Inflammation can also be
triggered by tissue injury or trauma that occurs without the interven-
tion of pathogens which is referred to as sterile inflammation (Behnia,
Sheller, & Menon, 2016; Chen & Nuñez, 2010). In most cases, in-
flammation is a specific, self-controlled immune response that is
orchestrated in order to resolve infections or to repair tissue and
wounds. However, inflammation can produce a dysregulated response
or can be associated with a disruption in the homeostasis of physiolo-
gical processes without a direct connection to classical inflammation
triggers. When the triggering factors are not contained, a dysregulated
inflammatory response can be elicited, and it can cause chronic sys-
temic damage that results in inflammatory disorders (Franceschi &
Campisi, 2014; Kotas & Medzhitov, 2015). Inflammation involves the
recruitment of innate immune cells, with phagocytic properties, by
specific signals induced by inflammatory triggering factors. These in-
nate immune cells produce pro-inflammatory cytokines and chemo-
kines that attract lymphocytes and trigger an adaptive immune re-
sponse. During the inflammatory immune response, reactive oxygen
species (ROS), reactive nitrogen species (RNS) and different proteases,
are produced and they can lead to tissue damage, fibrosis, cell pro-
liferation, all of which can contribute to the chronicity of inflammation
Inflammation is involved in several stages of diseases such as
asthma, diabetes, CVD, neurodegenerative diseases or cancer. Genetic
but also environmental factors, such as diet, play an important role in
inflammation. A high consumption of red, processed meat, saturated or
trans-fat, ultra-processed food based on refined ingredients or alcohol
has been associated with pro-inflammatory processes (Bouvard et al.,
2015; Ganguly & Pierce, 2015; Grivennikov, Greten, & Karin, 2010;
Moodie et al., 2013;). However, a healthy and active life style, which
includes a diet rich in fruits, vegetables, whole grains, non-ultra-
processed, non-sugared foods, seems to be associated with a higher
prevention of inflammatory diseases (Schwingshackl et al., 2018; van
Breda & de Kok, 2018). Scientific evidence has demonstrated that the
numerous bioactive constituents of fruit and vegetables, such as fla-
vonoids, carotenoids, vitamins, minerals and fiber, can act individually
and in a synergistic way to provide a high nutritional value and health
benefits for consumers (Liu, 2013; Slavin & Lloyd, 2012). In this con-
text, flavonoids have gained increased attention in recent years, with an
important number of studies that have analyzed their potential benefits
in human health. This review summarizes the latest scientific evidence
of the impact that flavonoids, the most abundant polyphenols in the
diet, have on inflammatory diseases.

⁎
Corresponding author at: Department of Dermatology and Allergy, University of Bonn Medical Center, Sigmund- Freud-Str., 25, 53127 Bonn, Germany.
E-mail address: beatriz.cabanillas@salud.madrid.org (B. Cabanillas).

https://doi.org/10.1016/j.foodchem.2019.125124
Received 6 March 2019; Received in revised form 1 July 2019; Accepted 2 July 2019
Available online 03 July 2019
0308-8146/ © 2019 Elsevier Ltd. All rights reserved.
S.J. Maleki, et al. Food Chemistry 299 (2019) 125124

Table 1
Flavonoids subclasses, structure and food source.
Subclass Structure Type Food

Flavonol Quercetin, Apples, cherries,

kaempferol, berries, onions,
galandin, tomatoes, broccoli,
myricetin tea, read wine
Flavone Luteolin, Fruits, vegetables,
apigenin, chysin cereals

Isoflavone Genistein, Legumes such as

daidzein, soybean
glycitein

Flavanone Naringenin, Citrus fruits

hesperetin,
eriodictyol

Flavanol Catechin, Apples, red grapes,

epicatechin, tea
gallocatechin

Anthocyanidin Cyanidin Fruits

2. Flavonoids in the diet: classification, metabolism, and
bioavailability
Flavonoids are polyphenolic compounds that are extensively pre-
sent in the kingdom of plants (Singh, Kumar, & Malik, 2017). The
structure of flavonoids is composed of two benzene rings (A and B)
which are linked by a heterocyclic ring containing oxygen (C). Flavo-
noids can be divided into different subclasses depending on the con-
nection between the rings B and C, the structure of the B ring and the
hydroxylation and glycosylation patterns of the three rings (Table 1)
(Wang, Li, & Bi, 2018). The subclasses include: flavanols, flavanones,
flavones, isoflavones, flavonols and anthocyanidins (Table 1) (Kumar &
Pandey, 2013).
Flavonoids can be found in the human diet in fruits, vegetables,
legumes, tea, dark chocolate, etc. Some specific parts of those foods are
richer in flavonoids than others, such as the peel of certain fruits (Li
et al., 2014) (Table 1). The intake of flavonoid containing foods can
vary depending on the culinary habits of different countries. For in-
stance, soybean consumption has been historically associated with or-
iental cultures or tea consumption is higher in countries such as United
Kingdom, Ireland or Turkey, among others (Sanlier, Atik, & Atik, 2018;
Shukla et al., 2016).
Flavonoids are extensively metabolized in the intestine and conse-
quently their metabolites are transported to the liver where they un-
dergo further metabolization. Metabolites formed in the liver can be
transported to target cells, can re-enter enterohepatic circulation by
means of bile excretion being hydrolyzed to aglycones by the micro-
biota, or can be excreted through urine or faeces. Flavonoid metabolites
that do not undergo absorption in the intestine and reach the colon can
be degraded by colonic microbiota and be reabsorbed (Thilakarathna &
Rupasinghe, 2013). The bioavailability of flavonoids depends on the
specific subclass, but in general, it has been described to be low (Hu,
Wu, & Liu, 2017). Several studies have focused on the improvement of
the bioavailability of flavonoids by different approaches, such as in-
hibition of enzymes that limit their bioavailability (Ravisankar et al.,
Fig. 1. Diagram of the main steps for the extraction and detection of flavonoids
in foods and biological sources. Abbreviations: HPLC, high-performance liquid
chromatography; UHPLC, Ultra-high-pressure liquid chromatography; MS,
mass spectrometry; NMR, nuclear magnetic resonance; EC, electrochemical
detection; FL, fluorescence.
2019), changes in the composition of food matrices (Oliveira, Perez-
Gregório, de Freitas, Mateus, & Fernandes, 2019), or increasing dis-
solution rate (Khan, Kotta, Ansari, Sharma, & Ali, 2015).
3. Flavonoids analysis and detection in food samples
The analysis of flavonoids in foods has gained greater attention in
the last few decades due to the increased recognition of flavonoids as
key bioactive compounds with important physiological effects in
human health. Moreover, the development and improvement of several
analytical techniques and methods used for flavonoid analysis have also
contributed to improving the detection and characterization of flavo-
noids in foods (de Villiers, Venter, & Pasch, 2016). However, the fre-
quent complexity of foods and biological sources that contain flavo-
noids requires you to choose an adequate and source-specific procedure
for sample preparation and extraction. The precise extraction method
depends on the flavonoids-containing source, however, in many cases,
after the homogenization of the biological source, liquid extraction
constitutes the initial phase of extraction. Pretreatment steps such as
filtering, or centrifugation, may be also necessary (de Rijke et al.,
2006). Afterward, a clean-up step usually follows the extraction phase
(Fig. 1). The separation of flavonoids from complex biological extracts
frequently requires techniques such as high-performance liquid chro-
matography (HPLC) that can be coupled to methodologies for detection,
identification and/or characterization such as electrochemical detec-
tion, fluorescence, UV–vis, mass spectrometry (MS) and nuclear mag-
netic resonance (NMR). NMR is important in order to characterize the
structure of flavonoids in complex matrices, although it presents dis-
advantages such as a high cost and that it may not be suitable for all
applications. However, MS is the most common method used for the
identification and characterization of flavonoids nowadays. Ultra-high-

2
S.J. Maleki, et al. Food Chemistry 299 (2019) 125124

Table 2
Anti-inflammatory properties and mechanisms of flavonoids.
Flavonoids properties Mechanism Consequences

Inhibition of regulatory enzymes
Antioxidant properties
Impact on arachidonic acid
metabolism
Modulation of gene expression
Modulation of immune cells
Inhibition of protein kinases, phosphodiesterases
Scavenger activity, inhibition of free radicals production
Inhibition of PLA2, COX, LOX
Modulation of transcription factors: NF-κB, GATA-3, STAT-6
Inhibition of cell activation, maturation, signaling
transduction, secretory processes
Decreased signal transduction, decreased cell activation
Decreased in oxidative stress
Decreased release of proinflammatory mediators such as prostaglandins,
thromboxanes, leukotrienes, etc.
Decreased transcription of proinflammatory genes
Immature cell stage (i.e: DCs), decreased cell proliferation, decreased
release of proinflammatory cytokines

COX, cyclooxygenase; DCs, dendritic cells; LOX, lipoxygenase; PLA2, phospholipase A2; STAT-6, signal transducer and activator of transcription 6.

pressure liquid chromatography (UHPLC) coupled to MS is also fre-
quently utilized for the separation, detection, and identification of fla-
vonoids (Fig. 1) (de Villiers et al., 2016).
4. Anti-inflammatory effects of flavonoids: Mechanisms of action
4.1. General
Flavonoids have anti-inflammatory properties through different
mechanisms such as inhibition of regulatory enzymes and transcription
factors that have an important role in the control of mediators involved
in inflammation. Flavonoids are also potent antioxidants able to sca-
venge free radicals and to decrease their formation. Consequently,
flavonoids have a deep impact on several immune cells and immune
mechanisms that are important in the inflammatory processes
(Table 2).
4.2. Inhibition of protein kinases and transcription factors
4.4. Antioxidant activity
Tissue injury during inflammation produces free radicals such as
oxygen-derived radicals (or reactive oxygen species, ROS), nitrogen-
derived radicals (or reactive nitrogen species, RNS), that have detri-
mental effects in cell function (Mittal, Siddiqui, Tran, Reddy, & Malik,
2014). Free radicals have unpaired electrons that make them highly
reactive and detrimental for lipids, proteins, and DNA. Free radicals
impact on cellular membranes by lipid peroxidation and on proteins
and nucleic acids by oxidative damage. High production of free radicals
together with low sequestration of transition metal ions and low free
radical scavenging activity result in oxidative stress (Nimse & Pal,
2015). Flavonoids have antioxidant activity due to their inhibitory ef-
fects on the production of free radicals and their scavenger activity for
ROS, RNS, and other reactive species. The antioxidant properties of
flavonoids are derived from their chemical structure, the specific sub-
stitution patterns within the structures and the phenolic hydrogens that
enable them to act as hydrogen-donating molecules (Chen, Fan, Wu, Li,
& Guo, 2019; Li, Jiang, Wang, Liu, & Chen, 2016).

Protein kinases are involved in signal transduction during cell ac-
tivation in inflammation. In that respect, certain flavonoids can target
multiple central kinases that are involved in multiple signaling path-
ways (Hou & Kumamoto, 2010). The inhibition of kinases such as
phosphoinositol kinase, protein kinase C, phosphatidylinositol kinase,
tyrosine kinase or cyclin-dependent kinase-4 by different types of fla-
vonoids have been reported (Lolli et al., 2012; Yokoyama, Kosaka, &
Mizuguchi, 2015).
Flavonoids can also modulate protein kinases by the inhibition of
transcription factors, such as NF-κB (Peng, Huang, Cheng, & Liou,
2018). This transcription factor regulates several cytokines, chemokines
and cell adhesion molecules involved in inflammation. IκB acts as an
inhibitory molecule of NF-κB, however, during the course of in-
flammation, IκB is phosphorylated and degraded. Consequently, NF-κB
is translocated from the cytoplasm to the nucleus where it induces the
expression of different pro-inflammatory genes (Lin, Bai, Chen, & Xu,
2010). Flavonoids have been reported to regulate the activity of IκB and
NF-κB, with a direct impact on cell activation (Chen et al., 2017).
Flavonoids can also regulate master regulatory transcription factors for
CD4 + T helper 2 (Th2) cytokines such as GATA-3, and signal trans-
ducer and activator of transcription 6 (STAT-6) (Gao et al., 2012; Liu
et al., 2015).
4.3. Inhibition of phosphodiesterases
Flavonoids can inhibit phosphodiesterases such as cAMP phospho-
diesterase. cAMP is a second messenger molecule key in the regulation
of different cell functions during inflammation. High levels of cAMP
have been associated with anti-inflammatory functions. The enzymes
phosphodiesterases can hydrolyze cAMP to keep normal levels. The
inhibitory effects of flavonoids on phosphodiesterases have the poten-
tial to block cAMP degradation and prolong cAMP signaling (Guo et al.,
2018; Wahlang, McClain, Barve, & Gobejishvili, 2018).
4.5. Impact on arachidonic acid metabolism
Arachidonic acid is released during inflammation from phospholi-
pids contained in the plasma membranes by the enzyme phospholipase
A2 (PLA2). Arachidonic acid is then metabolized by different oxyge-
nases, such as cyclooxygenase (COX) and lipoxygenase (LOX), in order
to produce prostaglandins, thromboxanes, leukotrienes and other in-
flammatory mediators (Yahfoufi, Alsadi, Jambi, & Matar, 2018).
Flavonoids have the potential to inhibit the enzymes involved in the
metabolism of arachidonic acid decreasing the release of the in-
flammatory mediators derived from this pathway. For example, flavo-
noids can inhibit the biosynthesis of prostaglandins, thromboxanes,
leukotrienes by inhibition of the enzymes PLA2 (Kumar, Caruso, Ullah,
Cornelio, & Fossey, 2017; Novo Belchor et al., 2017), COX (González
Mosquera et al., 2018) or LOX (Hanáková et al., 2017).
4.6. Effects in immune cells
The different properties and activities of flavonoids have an impact
on cell activation, maturation, signaling transduction, cytokine pro-
duction, or secretory processes in several immune cells (Fig. 2). For
instance, flavonoids have been shown to inhibit maturation of dendritic
cells (DCs) by suppression of maturation markers such as CD80, CD86,
which are molecules essential for CD4 + T cell activation and they are
upregulated during the maturation of DCs. This would translate into an
inhibitory effect in the secretion of cytokines and proliferative response
of CD4 + T cells (Li et al., 2017; Lin, Wang, Wang, & Ling, 2017;
Masilamani et al., 2011). Flavonoids also have an influence on the in-
flammatory response of DCs by means of modulation of iron metabo-
lism (Galleggiante et al., 2017). Several studies have found that certain
flavonoids can decrease the release of histamine or prostaglandin from
mast cells or inhibit the production of pro-inflammatory cytokines or
chemokines in mast cells, neutrophils and other immune cells (Gong,

3
S.J. Maleki, et al.
Fig. 2. Effects of flavonoids in immune cells. Flavonoids can inhibit maturation of DCs by suppressing the expression of maturation markers (such as CD80/CD86),
with a decreased proliferative response of CD4 + T cells (A). Flavonoids can decrease the release of histamine, prostaglandin and cytokines from mast cells (B).
Flavonoids can also bind to cytokine receptors or FcεRI and decrease signaling (C).
Shin, Han, Kim, & Kang, 2011; Weng et al., 2012; Weng, Patel,
Panagiotidou, & Theoharides, 2015). The impact of flavonoids in cell
signaling is supported by studies that demonstrate that they can bind to
cytokine receptors such as IL-17RA subunit of the IL-17 receptor,
causing attenuation in its signaling. Flavonoids can also inhibit down-
stream signaling from receptors such the high affinity receptor for IgE
(FcεRI) and other receptors at the site of inflammation (Kim, Jung,
et al., 2014; Liu, Zhu, et al., 2017) (Fig. 2). Flavonoids can have in-
hibitory effects on monocyte adhesion function or decrease the acti-
vation and proliferative response or certain immune cells implicated in
chronic inflammation (Del Bo' et al., 2016; Zhang et al., 2018).
5. Flavonoids and asthma
Asthma is a heterogenous chronic respiratory disease characterized
by airway inflammation, obstruction, and bronchial hyperresponsive-
ness. The pathophysiology of asthma is complex, and several immune
responses can be involved in the disease. For instance, allergic asthma is
induced by allergens and mediated by Th2 cell-related immune re-
sponses. Th2 cells produce cytokines essential for IgE class switching in
B cells and recruitment of mast cells or eosinophils (Schatz &
Rosenwasser, 2014). In that respect, flavonoids, such as anthocyani-
dins, flavones, flavonols and isoflavones, have shown to possess bene-
ficial properties in asthma (Table 3).
A recent study provided evidence that the flavonoid polymer oli-
gomeric proanthocyanidins (OPCs), reduced airway inflammation, in-
flammatory cells infiltration, Th2 cytokines, and allergen specific IgE in
a murine model of asthma. OPCs were found to inhibit the maturation
of pulmonary CD11c+ DCs by decreasing the expression of the co-sti-
mulatory molecule CD86, affecting in that way the promotion of pro-
liferative responses in CD4 + T cells (Li et al., 2017). Mast cells are key
players in the induction and progression of asthma due to their ability
to release mediators that promote the interaction with distinctive cell
4
Food Chemistry 299 (2019) 125124
types important in asthma (Komi & Bjermer, 2018). Early studies found
that certain flavones, such as luteolin, were able to decrease the release
of histamine and prostaglandin D2 from human mast cells in culture
(Kimata et al., 2000). More recently, the novel flavone tetra-
methoxyluteolin (methlut), which is a structural analog of luteolin, was
shown to have a higher inhibition potential than luteolin over a human
mast cell line in the release of mediators implicated in asthma. Both
luteolin and its analog inhibited the release of histamine, β-hex-
osaminidase and TNF. Moreover, they decreased the release of CCL2, an
important stimulus for the recruitment of different inflammatory cells,
in mast cells derived from human cord blood. The inhibitory effects of
luteolin and its analog over mast cells would involve the blocking of
essential mechanisms for the production of proinflammatory mediators
and degranulation, such as blocking of intracellular calcium or inhibi-
tion of NF-κB at gene and protein levels (Weng et al., 2015). Other
flavonoids such as flavonols have also been found to have inhibitory
effects on the release of cytokines by mast cells or basophils and they
have been demonstrated to be anti-inflammatory agents (Gong et al.,
2011; Rogerio et al., 2010; Weng et al., 2012). The flavonol quercetin
that can be found in onions, broccoli or apples showed anti-in-
flammatory properties in a murine model of airways allergic in-
flammation when administrated orally in microemulsion. Quercetin
decreased the recruitment of eosinophils to the bronchoalveolar fluid
and reduced the levels of the cytokines IL-5 and IL-4 (Rogerio et al.,
2010). Other flavonols such as kaempferol administrated orally in a
murine model of allergic airway inflammation decrease the infiltration
of eosinophils in the airways and block their degranulation in the lung
tissue (Gong et al., 2011). In all the aforementioned studies using fla-
vonols, the decrease in the release of cytokines and the reduction of
allergic inflammation were mediated through mechanisms involving
the blockade of NF-κB (Gong et al., 2011).
Isoflavones have also shown anti-inflammatory properties in a
guinea pig model of asthma. In that respect, genistein, an isoflavone
 Table 3
Summary of the anti-inflammatory effects of flavonoids in asthma, food allergy, CVD, and cancer.
Subclass Type Disease Effect Reference
S.J. Maleki, et al.

Flavonol Quercetin Asthma Anti-inflammatory properties in a murine model of airways allergic inflammation Rogerio et al. (2010)

Food Suppression of IgE-mediated allergic inflammation in intestinal cell models; reduction of Lee et al. (2010); Kim, Jung, et al. (2014), Plundrich et al. (2017)
allergy histamine release from mast cells; decrease of peanut allergenicity through covalent binding

CVD Anti-atherosclerotic activity; reduction in oxidative stress; inhibition of DCs maturation in mice; Kamada et al. (2005), Xiao et al. (2017), Lin, Wang, et al. (2017),
cardio-protective properties against heart injury in rats Bartekova et al. (2018), Kumar, Kasala, et al. (2017); Roslan et al. (2017)

Cancer Target telomeric sequences with an impact in cancer cell replication Tawani and Kumar (2015)

Isoquercitrin Asthma Improvement of ocular symptoms caused by pollinosis Hirano et al. (2009) and Kawai et al. (2009)

Kaempferol Asthma Decrease in the infiltration of eosinophils in the airways of a murine model Gong et al. (2011)

Food Inhibition of chemokines production by neutrophils Devi et al. (2015)

allergy

Flavone Luteolin Asthma Decrease in the release of histamine and prostaglandin from human mast cells in culture Kimata et al. (2000)

Food Inhibitory effects over RBL degranulation Yamashita et al. (2016)

allergy

CVD Improvement of systolic/diastolic function in rat hearts after ischemia/reperfusion Zhu et al. (2017)

Baicalein Food Activation of regulatory T cells and enhancement of intestinal barrier function in a murine food Bae et al. (2016)

5
allergy allergic model

CVD Protection against cardiac hypertrophy induced by pressure overload in mice Zhang et al. (2017)

Tetramethoxyluteolin (methlut) Asthma Inhibition of the release of mediators implicated in asthma in human mast cell line Weng et al. (2015)

Chrysin CVD Inhibition of platelet function in vitro Ravishankar et al. (2017)

Ruthenium-conjugated chrysin CVD Inhibition of the platelets function and thrombus formation in vitro Ravishankar et al. (2018)

Isoflavone Genistein Asthma Reduction in airway hyperresponsiveness in guinea pig and murine asthmatic models; Duan et al. (2003), Kim et al. (2014), Gao et al. (2012)
stabilization of mast cells; inhibition of pro-inflammatory cytokines in mast cells; inhibition of
GATA-3, STAT-6

Food Ex vivo suppression of basophils degranulation from allergic subjects Masilamani et al. (2017)
allergy

Ipriflavone Food Ex vivo suppression of basophils degranulation from allergic subjects Masilamani et al. (2017)
allergy

Puerarin CVD Decrease in inflammatory responses and NF-kB activation in an experimental model in rabbits Ji et al. (2016)

Isoflavone Food Inhibition of maturation of human DCs by suppressing the expression of CD83 and CD80. Masilamani et al. (2011)
allergy

Cancer Association to a decreased risk of ovarian, breast, colorectal, endometrial and lung cancers Grosso et al. (2017)

(continued on next page)

Food Chemistry 299 (2019) 125124
S.J. Maleki, et al. Food Chemistry 299 (2019) 125124

with the function of tyrosine kinase inhibitor, decreased acute

bronchoconstriction induced by the allergen ovalbumin (OVA) and
reduced airway hyperresponsiveness in the guinea pig asthmatic model.
The mechanism would involve the stabilization of mast cells through
the inhibitory activity of genistein on protein tyrosine kinases (Duan
et al., 2003). It is known that protein tyrosine kinases are essential in
different steps of inflammation, therefore the use of inhibitors, such as
genistein, has the potential to attenuate airway inflammation asso-
ciated to asthma (Duan et al., 2003). In line with this assumption, an-
other study demonstrated that genistein inhibits the production of pro-
inflammatory cytokines in activated mast cells through the extracellular
signal-regulated kinase (ERK) pathway (Kim, Lim, Kang, Um, & Nho,
2014). Furthermore, genistein decreased airway inflammation asso-
ciated with Th2-type cytokines in a murine asthmatic model, through
the inhibition of the master regulatory transcription factors, GATA-3,
Liu, Zhu, et al. (2017)
Masuda et al. (2014)

Del Bo' et al. (2016)

Singh et al. (2014)

and STAT-6 (Gao et al., 2012).

Asthma can be associated with other responses different from the
ones produced by the Th2 immune response. Interferon-γ, IL-17 and
Reference

neutrophils, which are not associated with a Th2 response, are found in
the lungs of certain patients with asthma. IL-17 is an important proin-
flammatory cytokine implicated in local tissue inflammation in asthma
Attenuation of Th17 cell-induced inflammation with a decrease in airway hyperreactivity in a

(Halwani et al., 2017). Cyanidin, a type of anthocyanidin that is found

in red berries, apples or plums, among other, attenuates the signaling of
IL-17A, by binding to the IL-17RA subunit of the IL-17 receptor. The
interaction of cyanidin with IL-17RA prevents IL-17A from binding to
the receptor affecting its signaling. In mouse models of severe asthma,
cyanidin attenuated Th17 cell-induced inflammation with a decrease in
airway hyperreactivity (Liu, Zhu, et al., 2017).
At a clinical level, most studies have focused on the influence of the
intake of fruits and vegetables containing flavonoids on asthma, and
only a limited number of studies have focused on individual flavonoids.
In that regard, a recent systemic review and meta-analysis was carried
out considering 58 articles published up to June 2016, that investigated
Reduction in symptoms of Japanese cedar pollinosis

Anti-allergic effects in a mice model of food allergy

Decrease in monocyte adhesion to endothelial cells

the effects of vegetables and fruits consumption on risk of asthma and

wheeze. Vegetable and fruit intake was found to reduce the risk of
asthma and/or wheeze in most of the studies (n = 30). However, 8
studies did not find any association and 20 studies had mixed results.
The meta-analysis showed that fruit consumption did not have any
association with the risk of prevalent asthma, but it had a beneficial
mouse model of severe asthma

effect (inverse association) on asthma severity. The consumption of

vegetables had an inverse association with risk of prevalent asthma, but
a non-significant relationship with wheeze prevalence. Studies that
evaluated immune responses found beneficial effects of fruits and ve-
getables intake on systemic or airway inflammation (Hosseini, Berthon,
Wark, & Wood, 2017). In the case of individual flavonoids, a study
Effect

found that isoflavone supplements do not improve clinical outcomes in

patients with poorly controlled asthma (Smith et al., 2015), however,
others have demonstrated that consumption of soy isoflavones improve
lung function in patients with asthma compared to those who do not
Asthma

Asthma
Disease

allergy

consume them (Bime, Wei, Holbrook, Smith, & Wise, 2012; Smith et al.,
Food

CVD

2004).
Asthma is frequently associated with allergic rhinitis and pollinosis.
In that respect, clinical studies have also focused on the effects of fla-
vonoids in these two conditions. In a randomized, double-blind, pla-
cebo-controlled trial, a green tea containing high concentrations of
methylated catechin, a flavonoid, showed a reduction in symptoms of
Japanese cedar pollinosis (Masuda, Maeda-Yamamoto, Usui, &
Anthocyanidin

Fujisawa, 2014). Pycnogenol® is an extract from the bark of French

Epicatechin

Cyanidin
Catechin

maritime pine (Pinus pinaster) which contains a mix of water-soluble

flavonoids. In a small randomized, double-blind, placebo-controlled
Type
Table 3 (continued)

study the efficacy of Pycnogenol® in the improvement of allergic rhi-

nitis symptoms was evaluated. The study found that the treatment with
Anthocyanidin

Pycnogenol® at least five weeks before the beginning of the allergy

Flavanol
Subclass

season improved the symptoms of allergic rhinitis (Wilson et al., 2010).

In another study, an enzymatically modified isoquercitrin was found to
relieve ocular symptoms caused by pollinosis in a double-blind,

6
S.J. Maleki, et al.
parallel-group, placebo-controlled trial (Hirano et al., 2009; Kawai
et al., 2009). Furthermore, a cross-sectional study in Japanese women
found that a high intake of soybean and isoflavones might be correlated
with a reduction in the prevalence of allergic rhinitis (Miyake et al.,
2005).
Although these results seem to be promising and the studies at a
molecular and cellular level importantly indicate that flavonoid con-
sumption has a protective effect on asthma, further scientific evidence
should be provided in order to stablish the clinical implications of in-
dividual flavonoid consumption on specific inflammatory diseases like
asthma.
6. Flavonoids and food allergy
Food allergy is defined as adverse reactions to a food mediated by
the immune system. The best characterized food allergy is the one
mediated by IgE, in which Th2 cells play an essential role in the in-
duction of IgE in the sensitization phase. After a new exposure to the
offending food, IgE antibodies bound to FcεRI on effectors cells of al-
lergy, such as basophils and mast cells, recognize specific allergenic
epitopes with a consequent cell activation and release of inflammatory
and vasoactive mediators. As a result, an allergic inflammation that can
affect several organs is elicited (Tordesillas, Berin, & Sampson, 2017).
Different types of flavonoids have shown to have a suppressive ef-
fect on the Th2 response, which may translate into a protective me-
chanism against allergic reactions to foods (Mlcek, Jurikova,
Skrovankova, & Sochor, 2016) (Table 3). In this context it has been
demonstrated that dietary isoflavones inhibited sensitization to peanut
and had protective effects against allergy to this legume in a murine
model of peanut allergy. The mechanism involves regulation of DCs
function. Isoflavones inhibit the maturation of human DCs by sup-
pressing the expression of CD83 and CD80. This suppression would
alter the secretion of cytokines that are involved in CD4 + T cells
regulation (Masilamani et al., 2011). Experiments with the flavone
baicalein showed a decrease in food allergy response induced by OVA
by means of activation of regulatory T cells (Treg) and enhancement of
intestinal barrier function in a murine food allergic model (Bae et al.,
2016). In another model of food allergy in rats, baicalein reduced OVA-
specific IgE, mast cells degranulation and improved pathological dis-
turbances in the intestinal tract (Yan et al., 2017). In line with these
results, the flavonols quercetin and kaempferol have shown suppression
of IgE-mediated allergic inflammation in intestinal cell models (Lee, Ji,
& Sung, 2010). Other flavonoids have also been shown to participate in
the regulation of intestinal barrier integrity by means of modification of
cytoskeletal association, increased expression of tight junctions and
other mechanisms (Oteiza, Fraga, Mills, & Taft, 2018; Tomlinson,
Butelli, Martin, & Carding, 2017). Further studies with Quercetin and
kaempferol contained in extracts from the perennial herb Aceriphyllum
rossii have shown a reduction of β-hexosaminidase and histamine re-
lease from mast cells. The compounds also inhibited downstream sig-
naling from the FcεRI receptor by means of decreasing the phosphor-
ylation of different kinases such as Syk, PKC, and MAPK (Kim, Jung,
et al., 2014). Interestingly, kaempferol inhibited chemokines produc-
tion by neutrophils, in which the MAPK pathway is involved. This effect
is an indication of the anti-inflammatory properties of kaempferol (Devi
et al., 2015). Moreover, kaempferol was the most active compound
from citrus fruits such as Citrus tachibana in reducing allergic symptoms
in a mouse model of OVA-induced food allergy. In that study, the citrus
fruit extract reduced the release of the Th2 cytokines IL-4, IL-5, and IL-
13 and this effect was accompanied by a reduction of allergic symp-
toms, such as diarrhea or risk of anaphylaxis (Chung, Shin, Choi, &
Shon, 2016).
Another interesting connection between flavonoids and food allergy
arises from studies that demonstrated that certain flavonoids can in-
teract directly with food allergens and have an impact on their aller-
genicity. For instance, quercetin present in polyphenols extracted from
7
Food Chemistry 299 (2019) 125124
cranberry or blueberry covalently binds to peanut proteins decreasing
their allergenic capacity (Plundrich, Bansode, Foegeding, Williams, &
Lila, 2017). In that regard, another study showed that polyphenol ex-
tracts containing flavonoids from cranberries reduced the allergenic
potential of gliadins from wheat. The polyphenolic extracts seem to
interact with gliadins making them insoluble and perhaps masking their
epitopes. The extracts also reduced degranulation in experiments with
passively sensitized rat basophilic leukemia (RBL) cell line upon gliadin
exposure (Pérot et al., 2017).
Other foods, such as cocoa, have been found to be a healthy food
rich in flavonoids with the capacity to inhibit Th2 immune responses
and decreased mast cell degranulation and functionality in rat models
of food allergy (Massot-Cladera, Franch, Castell, & Pérez-Cano, 2017).
In that respect, the flavanol epicatechin contained in cocoa, and other
foods, such as certain apples and green tea, showed anti-allergic effects
in a mouse model of food allergy. The study proposed that the effect
may be triggered by epicatechin modulation of host receptors at the
local site of inflammation or at systemic level (Singh et al., 2014).
Several in vivo and in vitro models of food allergies have been de-
veloped for the analysis of the effects of flavonoids on food allergies.
For instance, passively sensitized RBL cell lines have been widely uti-
lized to determine the allergenic potential of different compounds
(Castell, Perez-Cano, Abril-Gil, & Franch, 2014; Falcone, Wan, Barwary,
& Sagi-Eisenberg, 2018). However, under physiological conditions,
food components reach and interact with allergic effector cells after
transferring through different membranes, such as epithelial mem-
branes. Therefore, new in vitro models with a higher physiological re-
levance have been proposed by Yamashita et al. They have proposed an
in vitro model using transwell inserts in which intestinal epithelial
CACO-2 cells are cultured in the apical side and RBL cells in the ba-
solateral side. With this model the inhibitory effects of the flavonoids
luteolin and kaempferol over RBL degranulation was stablished in a
more physiologically relevant environment (Yamashita, Yokoyama,
Hashimoto, & Mizuno, 2016).
At a clinical level, studies with peanut or milk-allergic human
subjects have showed that the isoflavones genistein and ipriflavone had
a synergetic effect in suppressing degranulation ex vivo of basophils
from these subjects. However, the study showed that supplementation
with short-term over-the counter genistein and ipriflavone had no effect
in the suppression of effector cells of allergies (Masilamani et al., 2017).
Therefore, although in vitro studies have largely demonstrated protec-
tive effects of flavonoids in the development or severity of food aller-
gies, further clinical studies would be necessary to support these find-
ings.
7. Flavonoids and cardiovascular diseases (CVD)
In CVD, vascular disturbance and endothelial dysfunction are as-
sociated with inflammation and oxidative stress, which have a direct
impact on the pathophysiology of hypertension or atherosclerosis (Siti,
Kamisah, & Kamsiah, 2015). Most observational studies have found that
flavonoid consumption may have an important influence in decreasing
the risk of CVD by mechanisms that include: anti-inflammatory, anti-
oxidative, vasodilatory activities, or by increasing HDL (Rees, Dodd, &
Spencer, 2018) (Table 3).
A systematic review of fourteen prospective cohort studies assessed
the association between risk of CVD and the intake of six flavonoids
(flavonols, anthocyanidins, proanthocyanidins, flavones, flavanones
and flavanols). The meta-analysis showed that consumption of the six
types of flavonoids were associated with a significant decrease on CVD
risk. A dose-response analysis demonstrated that a mean increase of
10 mg in the consumption of flavonol per day was linked to a 5% of
lower risk of CVD (Wang, Ouyang, Liu, & Zhao, 2014). A recent sys-
tematic review and meta-analysis of ten studies showed strong evidence
of consumption of flavonoid-rich food in the context of a healthy diet
and reduced risks of mortality from CVD. The lowest risk of all-cause
S.J. Maleki, et al.
mortality was found in individuals that consumed 200 mg of total fla-
vonoids per day (Liu, Liu, et al., 2017). In a randomized, controlled,
cross-over trial the ingestion of apple with skin, which contains high
amount of flavonoids, was compared with ingestion of apple flesh,
which contains low amount of flavonoids. The study found a lower risk
of CVD in the group that consumed apples with skin in comparison to
the group that consumed apple flesh (Bondonno et al., 2018). The im-
pact of flavonoids on endothelial function and vascular oxidative stress
could be key for such observed improvements (Bondonno et al., 2018;
Cicero et al., 2017). In overweight men, the consumption of açai which
is a flavonoid-rich fruit was associated with improvement in vascular
function. The observed improvement would have a positive effect in the
prevention of CVD. The study, however, did not find significant dif-
ferences in blood pressure, heart rate, or postprandial glucose response
(Alqurashi, Galante, Rowland, Spencer, & Commane, 2016).
In vitro and in vivo studies have demonstrated the protective role of
flavonoids on the development and progression of CVD. Experiments
with quercetin using animal models revealed that its intake was asso-
ciated with a decrease in inflammation and atherosclerosis (Guillermo
Gormaz, Quintremil, & Rodrigo, 2015; Lin, Lin, et al., 2017). In this
context it has been also demonstrated in rabbits fed with a diet rich in
cholesterol/quercetin glucoside that quercetin metabolites had anti-
atherosclerotic activity. Cholesterol accumulation significantly de-
creased due to the potential action of quercetin, whose metabolites
were found in the aorta of the rabbits (Kamada, da Silva, Ohnishi-
Kameyama, Moon, & Terao, 2005). The atheroprotective properties of
quercetin would be associated with a reduction in oxidative stress. The
mechanism involves quercetin regulation of subunits of NADPH oxi-
dase, which is key for the formation of ROS in vascular cells (Xiao et al.,
2017). Furthermore, a recent study found that quercetin has the ability
to inhibit the maturation of DCs in mice by downregulation of ma-
turation markers CD80, CD86 or major histocompatibility complex II
(MHC-II). This was shown to influence the capacity of DC to stimulate
CD4 + T cells proliferation in mice and protected against the devel-
opment of atherosclerosis (Lin, Wang, et al., 2017). Activated macro-
phages in inflamed arteries have also been found to be potential targets
of quercetin (Xue et al., 2017). Another interesting connection between
quercetin and CVD arises from studies in rats, in which it was found
that quercetin had cardio-protective properties against heart injury
(Bartekova et al., 2018; Kumar, Kasala, Bodduluru, Kumar, & Lahkar,
2017; Roslan, Giribabu, Karim, & Salleh, 2017). In that respect, a recent
study found that pretreatment with quercetin for 14 days decreased
oxidative stress, improved heart architecture and reduced inflammation
in rats (Kumar, Caruso, et al., 2017). A therapeutic treatment with
quercetin was shown to diminish myocardial injury and hyperthermia
associated with heat stroke (Lin, Lin, et al., 2017). Other flavonoids
have also been demonstrated to have an impact on atherosclerosis or
heart disease. For example, the isoflavone puerarin was found to de-
crease inflammatory responses and NF-kB activation in an experimental
model in rabbits, with a suppression of atherosclerosis (Ji, Du, Li, & Hu,
2016). Anthocyanin and phenolic acid rich fractions of wild blueberry
may also have preventive effects on atherogenesis by decreasing
monocyte adhesion to endothelial cells which is a key step in ather-
ogenesis (Del Bo' et al., 2016). Other types of flavonoids, such as the
flavone luteolin found in fruits, vegetables or herbs, improved systolic/
diastolic function in rat hearts after ischemia/reperfusion. The me-
chanism involved an enhancement of sarcoplasmic reticulum Ca2 + -
ATPase through p38 MAPK signaling (Zhu et al., 2017). Baicalin, a
flavone that can be found in the rhizome of certain herbs, was found to
be protective against atherosclerosis and myocardial ischemic injury in
different animal models. In that regard, oral administration of baicalin
in mice was found to be protective against cardiac hypertrophy induced
by pressure overload. Baicalin improved cardiac dysfunction, myo-
cardial hypertrophy and decreased apoptosis in heart tissue and cardiac
fibrosis (Zhang et al., 2017).
Flavonoids can also function as inhibitors of platelet activation, due
8
Food Chemistry 299 (2019) 125124
to their hydroxyl groups. Excessive activation of platelets can con-
tribute to limiting blood flow to organs such as the heart or brain
(Ravishankar et al., 2018). Experiments with chrysin, a flavonoid found
in honey and passionflower, showed an inhibition of platelet function.
However, a synthetic analogue of chrysin, Ruthenium-conjugated
chrysin, was found to have higher potential for inhibiting the function
of platelets and formation of thrombus under physiological conditions
(Ravishankar et al., 2017).
8. Flavonoids, inflammation and cancer
In the complexity of cancer, inflammation has an important impact
in different stages of tumor development. Several environmental risk
factors for the development of cancer such as chronic infections, to-
bacco use or obesity are associated, to some degree, with chronic in-
flammation (Grivennikov et al., 2010). Diet plays an important role in
cancer. For example, a high consumption of red and processed meat has
been linked to a higher probability of carcinogenesis in humans
(Bouvard et al., 2015). Ultra-processed food or high consumption of
alcohol has an impact on the risk of obesity (Moodie et al., 2013;
Rauber, Campagnolo, Hoffman, & Vitolo, 2015) and indirectly an in-
creased probability of cancer (Grivennikov et al., 2010; Smyth et al.,
2015). In contrast, a diet rich in fruit and vegetables, in the context of a
healthy life style, has been associated with a lower risk of different
types of cancer (Aune et al., 2017; Schwingshackl et al., 2018; Turati,
Rossi, Pelucchi, Levi, & La Vecchia, 2015; van Breda & de Kok, 2018)
(Table 3).
In line with these observations, several studies performed in vitro
and in animal models have demonstrated the potential protective
properties of flavonoids against the development and progression of
different types of cancers (George, Dellaire, & Rupasinghe, 2017; Sak,
2014; Srivastava et al., 2016). Clinical studies, however, have not al-
ways supported a strong association between flavonoid intake and a
decreased risk of cancer, although the results depend on the subclass of
flavonoid, the specific cancer analyzed, and the study population re-
cruited.
In the context of in vitro and animal studies it has been recently
demonstrated that three flavonoids (isorhamnetin, genkwanin, and
acacetin) isolated from T. kirilowii, a perennial herb, had inhibitory
effects on the proliferation of human breast cancer cells. The flavonoids
caused cell cycle arrest at G2/M phase, apoptosis, and autophagy in
these cells. It is known that different oncogenes stimulate the activity of
phosphoinositide 3-kinase (PI3K), therefore increased PI3K signaling
has been shown to be important in cancer. The downregulation of
PI3Kγ-p110 and subsequent signaling pathway have been implicated in
the flavonoid-mediated cell cycle arrest, apoptosis, and autophagy as
shown by Zhang et al (Zhang et al., 2018). Another important char-
acteristic in a high proportion of tumors is the overexpression of the
ribonucleoprotein enzyme telomerase. Telomerase maintains telomeres
length by the addition to the 3′ end hexanucleotide repeats. Interest-
ingly, quercetin was found to target the telomeric sequence by the in-
terruption of elongation of telomeric ends, which could impact cancer
cell replication (Tawani & Kumar, 2015). A recent study provided
evidence that total flavonoids from the leaves of persimmon (Diospyros
kaki L.), a plant used as tea infusion in Asia, inhibited the growth of
liver tumors in mice by enhancing immune function. Flavonoids from
persimmon showed increased spleen and thymus indices, monocyte and
macrophage phagocytosis and natural killer cells cytotoxicity (Chen
et al., 2018).
Numerous clinical studies have tried to analyze the correlation be-
tween flavonoid consumption and reduced risk of cancer. In a study
population of 1063 randomly, selected women aged 75 years or more, a
5-year follow-up assessed all-cause, cancer, and cardiovascular mor-
talities. An estimation of flavonoid consumption was carried out
through two comprehensive food composition databases. Twelve per-
cent of deaths were documented during the 5-year period. Women that
S.J. Maleki, et al.
had a high flavonoid intake had lower risk of all-cause mortality than
women with low intake of flavonoids and similar results were found for
cancer and CVD mortality (Ivey, Hodgson, Croft, Lewis, & Prince,
2015). Importantly, different subclasses of flavonoids can have a dif-
ferential effect on the risk of specific cancers. Recently, it has been
demonstrated that among six flavonoid subclasses (flavonols, flavones,
flavanones, flavanols, anthocyanidins, and isoflavones), higher intake
of flavonol and flavanols was associated with decreased risk of color-
ectal cancer in a Korean study. The gen CYP1A1, which encodes a
member of the cytochrome P450 superfamily of enzymes, was also
studied in this association. CYP1A1 genetic variants have been asso-
ciated with colorectal cancer and its activity can be potentially modu-
lated by flavonoids. The study showed that carriers of specific CYP1A1
genetic variants had stronger inverse association between flavonol in-
take and colorectal cancer risk (Cho et al., 2017).
For a wider type of cancers, different meta-analyses have evaluated
the potentially beneficial effects of flavonoids. Data from a meta-ana-
lysis of prospective studies published up to 2016 showed that the intake
of isoflavones is significantly related to a reduced risk of stomach and
lung cancers and somewhat significantly associated with decreased
breast and colorectal cancer. However, total flavonoids intake was not
associated with lower risk of breast cancer. In case-control studies, the
meta-analyses showed an association between total and/or individual
flavonoids and reduced risk of cancer in the digestive track, upper aero
track, colon, rectum and lung. In the case of isoflavones in the case-
control studies, their intake was associated with a decreased risk of
ovarian, breast, colorectal, endometrial and lung cancers. The results
although promising were found to be inconclusive in some cases
(Grosso et al., 2017).
A meta-analysis of 23 studies evaluated the association between the
intake of flavonoids and the risk of digestive tract cancers. The study
found a lack of significant association between flavonoid intake and
colorectal, esophageal and gastric cancer. However, when the geo-
graphic location was taken into account, they found an association
between flavonoid consumption and a lower risk of gastric cancer in the
European population, but not in American or Asian populations. Both in
vitro and animal studies demonstrate that flavonoids can have positive
effects in preventing the development of digestive tract cancer.
However, the lack of association in certain studies with humans may be
due to the lack of effective absorption of flavonoids in the native form,
lack of enough bioavailability or that the doses of flavonoids assessed in
vitro are much higher than the regular intake of flavonoids by humans
(Bo et al., 2016).
9. Conclusions
Dysregulated inflammation has an important implication in chronic
systemic damage that can result in inflammatory disorders such as CVD,
cancer, or allergies. Increasing knowledge has been gained recently
regarding the influence that diet has over chronic inflammatory dis-
orders. In that context, the role of flavonoids as a key component of a
healthy diet, has gained increased consideration due to its anti-in-
flammatory properties. Recent data from in vitro studies have added
new insights into the multiple variables that different subclasses of
flavonoids can modulate in several stages of inflammation.
Furthermore, the use of novel animal experimental models has pro-
vided important steps towards the understanding of the potential health
benefits of flavonoids. These important advances have expanded the
knowledge about the positive impact that a healthy diet rich in flavo-
noids has in the complexity of chronic inflammatory disorders.
However, future approaches and further scientific efforts at a clinical
level and in the area of bioavailability will provide a deeper under-
standing of the anti-inflammatory and anti-oxidant effects of flavonoids
in chronic disorders and in general human health.
9
Food Chemistry 299 (2019) 125124
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
Authors declare no conflict of interest.
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