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Anti-inflammatory activity of natural dietary flavonoids

Min-Hsiung Pan,*a Ching-Shu Laia and Chi-Tang Ho*b

Published on 13 September 2010. Downloaded on 16/08/2013 20:12:22.

Received 30th July 2010, Accepted 12th August 2010

DOI: 10.1039/c0fo00103a
Over the past few decades, inflammation has been recognized as a major risk factor for various human
diseases. Acute inflammation is short-term, self-limiting and its easy for host defenses to return the
body to homeostasis. Chronic inflammatory responses are predispose to a pathological progression of
chronic illnesses characterized by infiltration of inflammatory cells, excessive production of cytokines,
dysregulation of cellular signaling and loss of barrier function. Targeting reduction of chronic
inflammation is a beneficial strategy to combat several human diseases. Flavonoids are widely present
in the average diet in such foods as fruits and vegetables, and have been demonstrated to exhibit
a broad spectrum of biological activities for human health including an anti-inflammatory property.
Numerous studies have proposed that flavonoids act through a variety mechanisms to prevent and
attenuate inflammatory responses and serve as possible cardioprotective, neuroprotective and
chemopreventive agents. In this review, we summarize current knowledge and underlying mechanisms
on anti-inflammatory activities of flavonoids and their implicated effects in the development of various
chronic inflammatory diseases.

Introduction
Inflammation is a normal biological process in response to tissue
injury, microbial pathogen infection and chemical irritation. This
biological process also involves the innate and adaptive immune
systems. At a damaged site, inflammation is initiated by migration of immune cells from blood vessels and release of mediators,
followed by recruitment of inflammatory cells and release of
reactive oxygen species (ROS), reactive nitrogen species (RNS)
and proinflammatory cytokines to eliminate foreign pathogens,
resolving infection and repairing injured tissues.1,2 Thus, the
main function of inflammation is beneficial for a hosts defense.
In general, normal inflammation is rapid and self-limiting, but
aberrant resolution and prolonged inflammation causes various
chronic disorders.3
Chronic inflammation can inflict more serious damage to
a host tissue than bacterial infection. Diverse ROS and RNS such
as O2 (superoxide anion), OH (hydroxyl radical), H2O2
(hydrogen peroxide), nitric oxide (NO), and 1O2 (singlet oxygen)
generated by inflammatory cells injure cellular biomolecules
including nucleic acids, proteins and lipids, causing cellular and
tissue damage, which in turn augments the state of inflammation.4 These also trigger a series of signaling molecules, inflammatory gene expression and activation of enzymes involved in
chronic inflammation. Inflammatory chemicals produced by
inflamed and immune cells also attack normal tissues
surrounding the infected tissue, causing oxidative damage and
extensive tissue inflammation.1,4

a
Department of Seafood Science, National Kaohsiung Marine University,
No.142, Haijhuan Rd., Nanzih District, Kaohsiung, 81143, Taiwan.
E-mail: mhpan@mail.nkmu.edu.tw; Fax: (+886)-7-361-1261; Tel:
(+886)-7-361-7141 Ext 3623
b
Department of Food Science, Rutgers University, 65 Dudley Road, New
Brunswick, New Jersey, 08901-8520, USA. E-mail: ho@aesop.rutgers.
edu; Fax: +1-732-932-6776

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Studies show that chronic inflammation is linked to a wide

range of progressive diseases, including cancer, neurological
disease, metabolic disorder and cardiovascular disease.3,4
Numbers of studies suggest elimination of chronic inflammation
as a major way to prevent various chronic diseases.1,3 Epidemiological studies provide convincing evidence that natural dietary
compounds that humans consume as food possess many biological activities. Among these natural bioactive compounds,
flavonoids are widely recognized for their biological and pharmacological effects, including antiviral, anti-carcinogenic, antioxidant, antimicrobial, anti-inflammatory, anti-angiogenic and
anti-thrombogenic properties.1,5 Epidemiologic studies indicate
that the incidence of chronic disease and cancer is inversely
correlated with the consumption of fruits and vegetables rich in
flavonoids,5,6 and this is attributed to their possible anti-inflammatory activities. This review forcuses on the molecular basis of
the anti-inflammatory potential of flavonoids, with special
emphasis on their effect on molecular mechanisms and signaling
pathways involved in inflammation, as agents in reducing or
eliminating different chronic inflammation-associated human
diseases.

The role of inflammation in human disease

Inflammation is a complicated process, driven by preexisting
conditions (infection or injury) or genetic changes, that results in
triggering signaling cascades, activation of transcription factors,
gene expression, increased of levels of inflammatory enzymes,
and release of various oxidants and proinflammatory molecules
in immune or inflammatory cells.2 In this condition, excessive
oxidants and inflammatory mediators have a harmful effect on
normal tissue, including toxicity, loss of barrier function,
abnormal cell proliferation, inhibiting normal function of tissues
and organs, and finally leading to systemic disorders.1,2 Over the
past few decades, many studies reveal that chronic inflammation
is a critical component in many human diseases and conditions,
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Fig. 1 Chronic inflammation is linked to human diseases.

including obesity, cardiovascular diseases, neurodegenerative

diseases, diabetes, aging, and cancers2,4 (Fig. 1).
Cardiovascular diseases
Cardiovascular disease (CVD) is becoming the leading cause of
death in the world. Chronic inflammation, such as atherosclerosis, coronary diseases, cerebrovascular disorder, heart failure
and cardiomyopathy is common in CVD.7 In the past,
researchers suggested a number of traditional risk factors
implicated in the pathogenesis of CVD including age, hypertension, dyslipidemia, hypercholesterolemia, glucose tolerance
and metabolic symptoms. However, recent studies focus on the
relationship between endothelial dysfunction and inflammatory
condition.7,8 Vascular endothelium is very important in regulation of vascular homeostasis, and inhibition of leukocyte adhesion and platelet aggregation by release of mediators such as
nitric oxide (NO).8 Increase of NO production, damage of
endothelial cells, increase of oxidative stress and an enhanced
proinflammatory state lead to the alteration of vascular integrity,
the reduction of vasodilator capacity and the appearance of
endothelial dysfunction.
Atherosclerosis is a chronic inflammatory disease and a major
cause of CVD. Recent studies demonstrate that vascular inflammation is the earliest event in the development of atherosclerosis.7,9 The process involves stimulation of cholesterol, oxidized
low-density-lipoprotein (ox-LDL) and oxidative free radicals,
which initiate activation of vascular endothelial cells and enhance
their adhesive property with monocytes by expression of adhesion
molecules selectins, vascular cell adhesion molecule-1 (VCAM-1)
and intracellular adhesion molecule-1 (ICAM-1).10 Once monocytes firmly attach on the surface of endothelium, they transmigrate into the arterial intima and differentiate to macrophages.
This transmigration is triggered by chemoattractant molecules
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such as monocyte chemoattractant protein-1 (MCP-1), proinflammatory cytokines (TNF-a and ILs) as well as growth factors
(PDGF and TGF-b) produced by activated T cells and macrophage.11 Among these, studies indicate that MCP-1 is important
for recruitment of monocytes into intima. Differentiated macrophages that expresse scavenger receptors become foam cells via
uptake of ox-LDL generated in the intima resulting in formation
of fatty streaks.12 The molecules secreted by monocytes, macrophages and arterial cells maintain an inflammatory response
within the artery and promote proliferation and migration of
vascular smooth muscle cells.9,11 Proliferative smooth muscle cells
release fibrogenic mediators and build a dense extracellular matrix
around foam cells and monocytes, finally causingfatty streaks to
progress into fibrous plaque.13
In pathogenesis and progression of atherosclerosis, chronic
inflammation is involved in every stage that is characterized by
infiltration of monocytes/macrophages and production of
proinflammatory cytokines9,11 (Fig. 2). Hence, the modulation or
regulation of the interaction between endothelial and inflammatory cells and the transformation of macrophages to foam
cells could be the basis for the beneficial effects that prevent or
slow down the progression of this disease. This diversity of
cytokine expression and function might also lead to the identification of selective therapeutic targets for the prevention and
treatment of atherosclerosis.10,11
Moreover, clinical research shows that elevated levels of
systemic inflammatory molecules including IL-6, ICAM-1,
P-selectin, E-selectin and C-reactive protein (CRP), are classic
acute-phase markers occurring in patients with coronary disease,
and, therefore that might be a predictor of cardiovascular
risk.14,15 Different treatments of atherosclerosis are associated
with reduction of these inflammatory markers, providing a new
target for blockage or therapy of atherosclerosis by inhibition of
inflammation.9,16
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Neurological disorders

Fig. 2 Induction of inflammatory responses by ox-LDL in development

of atherosclerosis. Stimulated ox-LDL increases chemoattractant
concentration and induces monocyte transmigrating into intima then
transforming to macrophage. Differentiated macrophage that specific to
uptake ox-LDL becomes foam cell and leads to the formation of fatty
streak in intima.

Many neurodegenerative diseases, including Alzheimers disease,

Parkinsons disease, multiple sclerosis, amyotrophic lateral
sclerosis and other nervous system pathologies are associated
with inflammatory injury (Fig. 3). This complex inflammatory
process involves different cellular components in the central
nervous system, such as microglial cells, astrocytes, ependymal
cells, macrophages and mast cells.17 Microglial cells are macrophages in the brain and the central nervous system that are the
first response to a neuronal injury.18 In the case of Alzheimers
disease, a cleavage product of amyloid precursor protein (APP),
an integral membrane protein, and the aggregation of amyloid
b peptides (Ab1-42 and Ab1-40) trigger activation of microglials
and astrocytes, following activation of transcription factors such
as nuclear factor-kappa B (NF-kB) and activator protein (AP)-1
that induce production of ROS and various proinflammatory
mediators including NO, PGE2, ILs and TNF-a.17,18 These
proinflammatory cytokines and ROS produced by activated
microglial and astrocytes may cause neuronal damage or
neurotoxicity resulting in apoptosis and necrosis.17 Moreover,
proinflammatory mediators released from microglials and
astrocytes can activate each other to amplify inflammatory
signals to neurons.
Parkinsons disease is a neurodegenerative disorder in the
central nervous system with a pathology similar to Alzheimers
disease. Aggregation and accumulation of a-synuclein protein of
Lewy bodies and loss of dopaminergic neurons are major neuropathological alterations in Parkinsons disease.19 Lewy bodies and

Fig. 3 Neuroinflammation in Alzheimers disease. During the development of Alzheimers disease, b amyloid peptide is produced by cleavage of
amyloid precursor protein (APP), aggregates and accumulates as b amyloid plaques. Both aggregates and plaques cause neurotoxicity or activation of
microglia through up-regulating NF-kB and AP-1 transcription factors, which in turn release ROS and pro-inflammatory cytokines such as NO, PGE2,
IL-1, IL-6, and TNF-a that damage cholinergic neuron. These pro-inflammatory cytokines also directly activate astrocytes that also produce cytokines
to amplify inflammatory signals and result in neuroinflammation and neurodegeneration. Flavonoids act through avoiding b amyloid induced-neuron
injury and death, modulation of pro-inflammatory cytokines and ROS production as well as inhibiting the activation of microglia and astrocyte as
neuroprotective mechanisms.

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intracellular and/or extracellular a-synuclein protein aggregates

released from neurons lead to the activation of microglial cells,20,21
resulting in the activation of transcription factor NF-kB, gene
expression of iNOS, COX-2 and NAPDH oxidase, and production of inflammatory mediators.22 Proinflammatory cytokines
such as TNF-a and ILs derived from activated microglial cells also
trigger activation of astrocytes. Studies show that released factors
from activated microglials and astrocytes have a combinational
effect in promoting neurotoxicity.17,22
In neurodegenerative diseases, the activation of immune cells
such as microglials and astrocytes is a critical step in neuropathology. Oxidative stress is also important in neurodegenerative
diseases, both in Alzheimers disease and Parkinsons
disease.17,18,22 Several therapeutic approaches that target
inflammatory responses demonstrate the ability to interfere with
activation of transcription factor and inhibit function of
inflammatory enzymes and production of ROS.23,24
Obesity
Obesity, resulting from excessive fat sorted in adipose tissue is
a highly prevalent condition that is related to many metabolic
disorders throughout the world. Numerous studies indicate the
high risk of obesity in the development of cardiovascular disease,
type 2 diabetes, hypertension, fatty liver disease and cancer.25 It is
now clear that the function of adipose tissue is not only as fat
storage, but also as a major endocrine and secretary organ that
produces adipokines such as leptin and adiponectin.26 Leptin is an
important hormone in the regulation of energy expenditure and
caloric intake for maintaining energy balance.27 Clinical and
animal studies show that leptin deficiency results in body weight
increase and a high risk for the development of type 2 diabetes.27,28

In recent years, many studies document that obesity is significantly associated with a chronic low-grade inflammation29
(Fig. 4). The first connection between obesity and inflammation
is evidenced by the release of TNF-a from adipocytes. As the
lipid content increases in adipose tissue, adipocytes synthesize
TNF-a and several cytokines (IL-1b and IL-6) that change the
number and size of cells, influencing lipoprotein lipase and
increasing the inflammatory state.30 TNF-a also induces insulin
resistance by downregulation of insulin receptor phosphorylation, decrease of glucose uptake and expression of GLUT4
transporter.29,31 Another important inflammatory feature in
adipose tissue is recruitment of immune and inflammatory cells
such as neutrophils, eosinophils and macrophages.32 Studies in
both mice and humans show that while in an obese state,
macrophage infiltration is increased in adipose tissue.32 Large
adipocytes secret chemotactic signals, such as monocyte chemoattractant protein-1 (MCP-1), to trigger infiltration of
macrophages, that then leads to the creation of a chronic, lowgrade inflammation in obesity.32,33 Increased levels of acute phase
protein CRP are found in many obese individuals,34 and circulating CRP concentrations are related to the development of
cardiovascular disease,14 indicating the association of obesity
and cardiovascular disease. Some lines of evidence also suggest
that obesity is linked to fat storage in the liver that can lead to the
development of fatty liver diseases.25 It is suggested that IL-6
derived from adipocytes may drive the production of CRP in the
liver.35 Overexpression of MCP-1 in adipose tissue leads to
increase of hepatic triglyceride content.33 In addition, elevated
levels of circulating TNF-a in an obese state is often associated
with an increase in insulin resistance.31,36 These observations
emphasize the correlation among obesity, inflammation and
metabolic disorders.

Fig. 4 Obesity in the induction of inflammation. Adipose tissue of visceral obesity induced chronic low-grade inflammation through macrophage
infiltration by MCP-1 and secretion of pro-inflammatory factors. However, obesity may cause the high risk in development of several diseases.

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Metabolic disorders
Extensive research reveals that inflammation is a characteristic
feature of metabolic disorders, including fatty liver disease, type
2 diabetes, chronic kidney disease and heart disease (Fig. 5).
Inflammatory responses are considered to be a critical stage of
metabolic dysfunction characterized by abnormal proinflammatory cytokine production, increased acute phase protein
and activation of inflammatory signaling pathways.37 In addition, obesity correlates with an increase in inflammatory conditions and metabolic syndromes.29 Type 2 diabetes is the most
prevalent and serious metabolic disease caused by insulin resistance derived from pancreatic beta cell dysfunction. Both
experimental and clinical studies demonstrate that several
inflammatory cytokines are closely related to pathogenesis of
insulin resistance.38 Increased levels of IL-1b in plasma are
shown to have detrimental effects on the function of IL-1
receptor antagonist proteins (IL-1ra) that promote beta cell
destruction and alter insulin sensitivity.39 Moreover, IL-6 acts on
activation of tyrosine phosphatase and interferes with the interaction between insulin receptor and suppressor of cytokine
signaling (SOCS) proteins that result in insulin resistance.40 In
patients with chronic kidney disease, elevated levels of serum
acute phase proteins such as C reactive protein (CRP), TNF-a
and ILs are associated with an increase in chronic inflammatory
states and insulin resistance.41 In addition to insulin resistance
and Type 2 diabetes, an elevated concentration of CRP and

various cytokines also occur in chronic heart failure with fluid

overload and cardiovascular disease.34,41
Non-alcoholic fatty liver disease (NAFLD) is a common liver
disorder associated with obesity and insulin resistance that
results from abnormal adipokine and cytokine production.42 In
liver tissue, these mediators, such as leptin, TNF-a and ILs
decrease insulin signaling to hepatocytes by the activation of
several signaling molecules and kinases. This results in hepatic
insulin resistance, hyperglycemia and fatty liver development
caused by increased fatty acid uptake and VLDL production.37,42
Hepatic insulin resistance also stimulates the production of CRP
and cytokines that promote atherosclerosis by the inhibition of
NO production, an increase in the adhesion property in endothelial cells, and increasing macrophage uptake ox-LDL.40 This
information indicates that hepatic insulin resistance is related to
the induction of metabolic syndromes and the acceleration of
cardiovascular disease progression.

Bone, muscular and skeletal diseases

Rheumatoid arthritis is an autoimmune disease that causes joint
destruction and functional disability, often characterized by
chronic inflammatory responses primarily affecting the synovium of diarthrodial joints (Fig. 6). Besides infections and genetic
factors, rheumatoid arthritis is indicated in the interaction
between immune cells, such as T cells, B cells, macrophages,

Fig. 5 Proinflammatory cytokines in insulin resistance and metabolic disorders. Insulin synthesized and secreted from b cells in pancreas acts as normal
function in different organs and tissues, includes reducing glucose production and output in liver, facilitating glucose uptake in skeletal muscle, and
decreasing lipolysis in adipose tissue. Excessive pro-inflammatory cytokines (CRP, IL-1, IL-6, and TNF-a) cause dysfunction of b cell or recruit of
inflammatory cells (monocytes and macrophages) that affect both insulin secretion and insulin action, promote pathogenesis of insulin resistance and
subsequently reducing insulin-dependent signalling. This local insulin resistance also contributes to its target tissues such as increase concentration of
glucose and fatty acids in skeletal muscle, liver and adipose tissue that lead to various metabolic disorders. Flavonoids act through interfering with proinflammatory cytokines-induced b cells dysfunction and cell death, decreasing cytokines production, up-regulation of insulin-dependent signaling and
improving glucose uptake in different cell types.

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Fig. 6 Mechanisms of inflammation-associated pathogenesis in rheumatoid arthritis and osteoporosis. In inflamed rheumatoid synovium and bone
tissue, pro-inflammatory cytokines produced by recruited inflammatory cells (macrophages, T cells and B cells), endothelial cells and synovial fibroblasts
are central to the inflammatory process in rheumatoid arthritis and osteoporosis. This pathological process also involves in innate and adaptive
immunity responses. These pro-inflammatory cytokines result in activation of synovial fibroblasts and produce proteases that lead to tissue destruction.
In addition, cytokines-trigger activation and differentiation of osteoclasts are important in bone loss. Flavonoids act through reducing recruitment of
inflammatory cells, cytokines production, MMPs expression, and activation or differentiation of osteoclasts.

dendritic cells and fibroblasts and as such plays an important role

in the pathogenesis of this disease.43 In patients with rheumatoid
arthritis, large numbers of activated T cells are present in
inflamed joints. Recruited T cells develop a lymphoid structure in
synovium with B cells, macrophages and fibroblast-like synoviocytes that create a complex network between cells through
secreting various cytokines, such as TNF-a, IL-1 and IL-6.44
Among these cell types in synovium, fibroblast-like synoviocytes
is known to produce prostaglandins and proteases that destroy
bone and cartilage.45 Moreover, activated B cells and macrophage continuously secrete IL-1 and TNF-a that maintain the
synovial fibroblast in an inflamed state.44,45 Enrichment of these
immune cells and derived-proinflammatory cytokines in synovium causes varying degrees of joint destruction and also extraarticular organ involvement.
Osteoporosis is also a chronic inflammation condition that is
characterized by the loss of bone density (Fig. 6). Studies identify
proinflammatory cytokines TNF-a, IL-1 and IL-6 as important
mediators of bone resorption through increased expression of
20 | Food Funct., 2010, 1, 1531

receptor activator of NF-kB (RANK), activation and differentiation of osteoclast, and decreased osteoblast survival.46 Despite
several in vitro and in vivo studies indicating that proinflammatory cytokines contribute to osteoporosis, and increased
levels of IL-1b, IL-6 and TNF-a in whole blood culture from
patients with osteoporosis, the mechanism involved in bone loss
is still unclear. In addition, recent studies also reveal that elevated
systemic CRP is associated with poor bone health.46,47
Chronic inflammatory diseases
A continued chronic inflammatory state in different organs and
tissues leads to a various chronic inflammatory diseases such as
chronic obstructive pulmonary disease (COPD), psoriasis,
rheumatoid arthritis, chronic pancreatitis and inflammatory
bowel disease (IBD) all of which are frequently associated with
infiltration of immune and inflammatory cells. For example,
inflammatory bowel disease leads to ulcerative colitis (UC) and
Crohns disease (CD), based on clinical features and
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Fig. 7 Underlying mechanisms in inflammatory bowel disease. As bacteria infection or environmental factors that cause colonic endothelium damage
result in recruitment of inflammatory and immune cells from bloodstream. Accumulated inflammatory cells produce pro-inflammatory mediators that
trigger proliferation and activation of T cells, lead to differentiate to Th1 and Th2 cells that result in amplification of inflammatory cascade and cause
tissue injury. Flavonoids act through decreasing inflammatory cytokines production, reducing recruitment of inflammatory cells and modulation of
differentiation and proliferation of T cells.

histopathology, which result from abnormal regulation of the

immune system in the intestine.48 In IBD, damage of epithelium
in the colon increases recruitment of immune cells such as activated T lymphocytes and leucocytes that are mediated by the
expression of adhesion molecules.49 This is thought to be a key
step of inflammatory process involved in IBD (Fig. 7).
A number of studies indicate that an increased level of
proinflammatory cytokines is important for pathogenesis of
IBD.48 In general, epithelial cells, paneth cells, enterocytes and
immune cells of colon form a complex barrier by the expression
of cytokines, chemokines and metabolite from microbes or hosts
in order to fight pathogens and to maintain intestinal homeostasis. Also, an alteration of the immune system toward luminal
antigens is thought to play a crucial role in pathogenesis in
IBD.48 In an immune response, T helper (Th) cells recognize selfantigens (from food consumption or intestinal bacteria) that
present from lymphocytes and phagocytes, and then start to
produce cytokines. As the specific-antigen occurs, it enhances
production of various cytokines in colonic epithelium that
promote CD4 and CD8 cells which then differentiate to Th1 and
Th2 cells. These two Th cells produce a dramatic amount of
proinflammatory cytokines that affect colon mucosa and intestinal cells.50 Studies show that Crohns disease is mediated by
Th1 cells that are characterized by the production of IL-1, IL-6,
interferon-g (IFN-g) and TNF-a, whereas ulcerative colitis is
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thought to be a Th2 cell mediated response by the secretion of

IL-4, IL-5 and IL-10.48,50 Overexpression of these proinflammatory cytokines is found in the intestinal mucosa from IBD
patients and is related to the alteration of intestinal homeostasis
and results in an abnormal inflammatory response in the intestinal mucosa. Indeed, increased proinflammatory cytokines in
colon mucosa are also linked to the enhanced expression of antiapoptotic molecules, leading to apoptotic resistance and
promotion of accumulation of T cells.48,50

Cancers
Several lines of evidence indicate that cancer development in
humans is a multistep and long-term process which requires six
properties, including limitless replication potential, evasion of
apoptosis, self-sufficiency in growth signals, insensitivity to antigrowth signals, sustained angiogenesis, and tissue invasion and
metastasis.51 Since Virchow observed in 18th century, that
cancers frequently occur at sites of chronic irritation, much
research confirms the concept that chronic inflammation is
a critical component of tumor promotion and progression,
including colorectal, gastric, pancreatic, pulmonary, cystic,
hepatocellular, ovarian, skin and esophageal cancers.4,52 In view
of inflammation involved in different cancers, increasing
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evidence suggests that inflammation should be the seventh hallmarker in cancer development.53
The pathological mechanism of inflammation involved in
tumorigenesis is very complicated.54 In tissue injury or inflammatory stimulation, inflammatory cells are recruited and
production of pro-inflammatory cytokines and diverse ROS and
RNS that induce genetic change which enhances malignant
transformation and proliferation of initiated cells. Subsequently,
as tumor tissue forms, inflammation continues to promote
development of cancer by creating an inflammatory microenvironment, which consists of stromal cells, inflammatory cells and
the extracellular matrix from surrounding tissues. The inflammatory and immuosuppressive cytokines and chemokines
secreted from these cells not only promotes proliferation,
angiogenesis, invasion and metastasis but also suppresses the
hosts immune system and facilitates tumor growth and development54,55 (Fig. 8).
There are many key molecules that link inflammation and
cancer, including transcription factors, signal transducers and
activators of transcription 3 (STAT3), nuclear factor-kB (NFkB), nuclear factor of activated T-cells (NFAT), activator
protein-1 (AP-1), CCAAT enhancer binding protein (C/EBP),
cAMP response element binding protein/p300 (CBP/p300),

activator transcription factor (ATF), downstream genes iNOS,

COX-2, interleukin-6 (IL-6), IL-1b, tumor necrosis factor-R
(TNF-R), 5-lipoxygenase (5-LOX), hypoxia inducible factor-1a
(HIF-1a), and vascular endothelial growth factor (VEGF),
resulting in inflammation and tumorigenesis.54,56 Besides the
above, inflammatory signaling is regulated by upstream kinases,
such as NFkB-inducing kinase (NIK), IkB kinase (PKC),
mitogen-activated protein kinase (MAPK), phosphoinositide-3
kinase (PI3K)/Akt and protein kinase C (PKC), also important
in inflammation linked tumorigenesis. These critical molecules
can be considered important in the modulation of an inflammatory response, and thus could block or prevent inflammationassociated carcinogenesis.54,56

Chemoprevention: inflammation as potential target

The term chemoprevention was coined by Sporn in the mid1970s and is defined as the use of a chemical substance of either
natural or synthetic origin to prevent, hamper, arrest, or reverse
a disease.57 It is suggested that inflammation is a multifaceted
and complicated process implicated in infiltration and activation
of various immune and inflammatory cells, cytokine production,
signal transduction and molecular mechanism that results in

Fig. 8 Role of inflammation in cancer development. Chronic inflammation is a critical component of tumor promotion and progression, including
colorectal, gastric, pancreas, lung, bladder, hepatocellular, ovary, skin and esophageal cancers. In colonic tumorigenesis, inflammatory stimulation,
inflammatory cells are recruited and production of pro-inflammatory cytokines and diverse ROS and RNS that induction of genetic change, enhanced
malignant transformation and proliferation of initiated cells. Subsequently, as tumor tissue formation, inflammation also promotes development of
cancer by creating an inflammatory microenvironment. The inflammatory and immuosuppressive cytokines and chemokines secreted from these cells
not only promote proliferation, angiogenesis, invasion and metastasis but also suppress the hosts immune system and facilitates tumor growth and
development.

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a widespread physiological state in organ and tissue. There are

many clinical drugs and dietary natural compounds that are
demonstrated to be able to exert protective action by different
mechanisms, on a number of pathological aspects through targeting interference with chronic inflammatory response. For
example, anti-inflammatory drugs, including nonsteroidal antiinflammatory drugs (NSAID), are found to have some neuroprotective effects.58 Resveratrol and curcumin are found to
prevent cell damage and death through their antioxidative
activities that reveal potential neuroprotective activities.59,60
Anti-a4 integrin monoclonal antibody acts by disrupting adhesion and migration of immune cells that attenuate cytokine
release in Crohns disease individuals.61 Using monoclonal
antibodies against B cells function, TNF-a and IL-6 signaling are
beneficial for autoimmune diseases, including rheumatoid
arthritis and inflammatory bowel disease.62 In patients with type
2 diabetes, treatment with an IL-1 receptor antagonist may
restore the function of pancreatic b cells and improve insulinresistance.39 Kinase Inhibitors such as SB203580, a p38 MAPK
inhibitor, are found to decrease IL-1b production and reduce
rheumatoid arthritis in mice.63 Oral intake of tyrosine kinase
inhibitor showed a reduction of inflammatory markers and
improved quality in rheumatoid arthritis and psoriasis patients.62
In an in vivo study, PPARg agonist reduced the expression of
proinflammatory cytokines that then decreased immune complex
deposition and renal inflammation, and lowered atherosclerotic
lesions.64 PPARg agonist also lowered plasma glucose and serum
CRP and TNF-a, and increased the production of adiponectin in
adipose tissue, thus improving insulin resistance in humans with
type 2 diabetes.62
The relationship between inflammation and cancer is established.54,55 Numerous evidence demonstrates that inflammatory
pathways are critical targets in cancer treatment and prevention.65 Many natural bioactive compounds are reported to
interfere with the initiation, promotion/progression, and invasion/metastasis of cancer through the control of intracellular
signaling cascades as the process of inflammation progresses.
These bioactive compounds include flavonoids, flavonolignans,
isothiocyanates, proanthocyanidins, terpenoids, and other
polyphenolic compounds.1,56 These bioactive compounds act by
avoiding the causes of tissue damage, inhibiting signaling pathways and the activation of transcription factors, inhibiting
oxidant-generating enzymes and mediators of inflammation,
scavenging reactive oxygen and nitrogen species generated by
inflammatory cells, and modulating angiogenesis and metastasis.

Flavonoids: new approach in chronic inflammatory

diseases
Flavonoids are plant secondary metabolites that are ubiquitous
in fruits, vegetables, nuts, seeds and plants. These polyphenolic
compounds are a subgroup of chemically related polyphenols
that possess a basic 15-carbon skeleton and can be represented as
C6-C3-C6, consisting of two benzene rings (C6) joined by a linear
three carbon chain (C3).1 Based on the differences in the structure of the aglycones C ring, flavonoids can be classified into
seven groups: flavones, flavanones, flavonols, flavanonols, isoflavones, flavanols (catechins) and anthocyanidins (Table 1). The
structural variation of flavonoids may come from various
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patterns of substitution through enzymatic reactions including

hydroxylation, methoxylation, sulfonation, acylation, prenylation, or glycosylation. Flavonoids are most frequently
present as conjugates in glycosides and polymers that are water
soluble and degraded to variable extents in the digestive system.66
There are also a wide variety of types of naturally occurring
flavonoidsat least 2000. Some of them exhibit a broad spectrum of pharmacological properties such as antioxidant, free
radical-scavenging, anti-inflammatory, anti-carcinogenic, antiviral, anti-bacterial, anti-thrombogenic and anti-atherogenic
activities. It is reported that human intake of all flavonoids is
a few hundred milligrams to 650 mg per day in our diet.66
Significant scientific evidence shows that flavonoids have many
beneficial health effects for human beings. Many studies show
that flavonoid intake improves health and fights off chronic
diseases.67 Among the biological properties of flavonoids, antiinflammatory activity is attracting growing interest in managing
chronic inflammatory diseases. The biochemical and molecular
mechanisms, as well as the signaling pathways, of flavonoids
implicated in chronic inflammatory diseases are described below.
Flavones
Apigenin, a flavonoid present in parsley and celery (Fig. 9), is
found to inhibit HIF-1a and VEGF expression by blocking
PI3K/Akt signaling or LPS-induced pro-inflammatory cytokines
expression by inactivating NF-kB through the suppression of
p65 phosphorylation.1 Lupus is autoimmune disease, characterized by production of autoantibodies to attack nuclear antigens
and immune complex deposition in organs.68 In an in vivo study,
apigenin decreased response of Th1 and Th17 cells to major
lupus autoantigen, and subsequently suppressed the ability of
lupus B cells to produce pathogenic autoantibodies that limit the
inflammatory state in SFN-1 mice. Apigenin also downregulated
the expression of COX-2 and cellular FLICE-like inhibitory
protein (c-FLIP) in immune cells as well as causing activated
immune cells to undergo apoptosis, thus suppressing inflammation in lupus.69 In the pathogenesis of rheumatoid arthritis, it is
reported that inflammatory cytokines produced by fibroblastlike synoviocytes are involved in joint destruction. Apigenin is
known to induce ROS production and cause apoptosis through
oxidative stress-activated ERK1/2 pathway in fibroblast-like
synoviocytes.70 Moreover, intake of apigenin also showed
immunomodulating effects triggered by TNF-a in a mouse
model of rheumatoid arthritis.71
Luteolin is prevalent in thyme and also exists in beets, brussels
sprouts, cabbage and cauliflower, and is shown to possess great
antioxidative activity. It is known that the activation of microglia
and cytokine production is important in neurodegenerative
diseases. Treatment with luteolin strongly suppressed IFNginduced CD40 expression and the production of TNF-a and IL-6
through downregulated phosphorylation of STAT-1 in microglia.72 Also, luteolin significantly inhibited LPS-induced activation of microglia by inhibiting JNK phosphorylation and
activation of AP-1, increasing dopamine uptake and decreasing
excessive TNF-a, NO and superoxide production in microglia,73,74 suggesting the neuroprotective effect of luteolin against
brain injury. In addition, luteolin was found to regulate MAPK
and NF-kB signaling that inhibits TNF-a induced IL-8
Food Funct., 2010, 1, 1531 | 23

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Table 1 Backbone structures of the different classes of flavonoids

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Groups

Structure

Examples

Flavones

Apigenin, luteolin, tangeretin,

nobiletin, 5-hydroxy3,6,7,8,30 ,40 hexamethoxyflavone

Flavonols

Kaempferol, myricetin, quercetin,

isorhamnetin

Flavanols

Catechin, gallocatechin,
epicatechin, epigallocatechin-3gallate

Flavanones

Naringenin, hesperetin, eriodictyol

Isoflavones

Daidzein, genistein, glycitein

Anthocyanidins

Cyanidin, delphinidin,
pelargonidin

production, which is an important inflammatory cytokine

involved in maintaining the inflammatory state in inflammatory
bowel diseases.75 Luteolin also decreases TNF-a, IL-1 and MCP1 gene expression and increases adiponectin and leptin levels
through the enhancement of transcriptional activity of PPARg in
3T3-L1 adipocytes that might improve obesity-driven insulin
resistance.76
Citrus peel is a rich source of polymethoxyflavones, such as
tangeretin and nobiletin, and exhibits a broad spectrum of biological activities, including modulation of inflammatory-derived
cancer development.77 It is shown that tangeretin suppresses IL1b-induced COX-2 expression through inhibiting activation of
MAPK and Akt.1 In an in vivo study, nobiletin was found to lower
levels of eotaxin, a potent eosinophil chemoattractant cytokine
24 | Food Funct., 2010, 1, 1531

that relieves the infiltration of eosinophils and airway inflammation in asthmatic rats.78 It is suggested that the inhibition of foam
cells forming macrophage and ox-LDL uptake is one of the targets
for atherosclerosis. Nobiletin inhibited macrophage foam-cell
formation through reducing metabolism of b-VLDL, is primarily
taken up by macrophages via the LDL receptor in cultured murine
J774A.1 macrophages.79 Several studies demonstrate that nobiletin can improve arthritic diseases as evidenced by decreasing
proinflammatory cytokine production in human synovial cells
and downregulating gene expression of MMPs in human synovial
fibroblasts,80 as well as in collagen-induced arthritic (CIA) mice.81
Nobiletin can also inhibit leukocyte infiltration, protein expression of iNOS and COX-2 as well as tumorigenesis in mouse skin.1
In our previous studies, we reported that a metabolite of nobiletin
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Fig. 9 Representative natural flavonoids and their dietary sources. (A) flavones, (B) flavonols, (C) flavanols, (D) flavanones, (F) isoflavones, (G)
anthocyanidins.

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(30 ,40 -didemethylnobiletin) and 5-hydroxy-3,6,7,8,30 ,40 -hexamethoxyflavone, a hydroxylated PMF in citrus peel, inhibited
12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced skin
inflammation and tumor promotion by suppressing MAPK and
PI3K/Akt signaling pathways.82,83
Recently, two new flavones isolated from Cirsium japonicum
DC, pectolinarin and 5,7-dihydroxy-6,40 -dimethoxyflavone were
found to reduce high-carbohydrate/high-fat diet-induced diabetes in rat through decreasing plasma glucose and increasing
adiponectin levels that may improve glucose and lipid homeostasis.84

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Flavonols
Quercetin, an ubiquitous plant secondary metabolite, is found
abundant in onions, broccoli, apples, grapes, wine, tea, and leafy
green vegetables, is well known as a potent antioxidant and antiinflammatory agent. Recently, it was shown to possess good antiatherosclerotic activity. In human umbilical vein endothelial cells
(HUVECs), quercetin treatment strongly attenuated the inflammation-induced upregulated expression of VCAM-1, ICAM-1
and monocyte chemoattractant protein-1 (MCP-1), which may
contribute to its interference with the interaction between
monocytes and vascular endothelial cells during the early stages
of atherosclerosis.85 Oral feeding of quercetin (64-mg/kg body
weight daily) significantly inhibited atherosclerotic lesion size in
the aortic sinus and thoracic aorta through reducing superoxide
production, improving endothelial NO synthase (eNOS) function and decreasing plasma-sP-selectin levels in the apolipoprotein E (ApoE)(-/-) gene-knockout mouse.86 Quercetin also
decreased circulating inflammatory markers, including IFNg,
IL-1a and IL-4 in high fat diet animal models and therefore may
improve inflammation or obesity-associated disorder.87 In addition, consumption of quercetin is found to decrease systolic
blood pressure and plasma oxidised LDL in obese subjects (aged
2565 years) without affecting liver and kidney functions.88
When rats were fed a diet of rutin, a quercetin glycoside, there
was markedly attenuated dextran sulfate sodium (DSS) induced
gene expression of IL-1b and IL-6 in colonic mucosa and
decreased intestinal colitis.89 Quercetin was found to inhibit
2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of rats
possibly through downregulation of TNF-a-induced NF-kB
activation.90
Kaempferol, another flavonol-type flavonoid present in broccoli, tea and various vegetables, is considered to improve osteoporosis. For example, treatment with kaempferol stimulated
differentiation and mineralization of murine pre-osteoblastic cell
lines that may contribute to the prevention of bone loss.91 In the
pathology of osteoporosis, proinflammatory cytokines TNF-a is
important for bone disruption and osteoclastogenic cytokine
production. Kaempferol was reported to antagonize TNF-ainduced p65 translocation and production of IL-6 and MCP-1as
well as RANKL-triggered osteoclast precursor cell differentiation. These data indicate that kaempferol exerted a profound
anti-osteoclastogenic effect.92 Advanced glycation end products
(AGE) are oxidative products formed from nonenzymatic reaction of reducing sugars with free amino groups of proteins. AGE
is reported to be involved in diabetic complications and various
age/inflammation-related chronic diseases through generation of
26 | Food Funct., 2010, 1, 1531

ROS and activation of inflammatory signaling cascades.93

Studies show that supplementation of kaempferol in mice
reduced AGE-induced activation of NADPH oxidase and
proinflammatory gene expression through modulating the NFkB signaling cascade.94 When aged Sprague-Dawley rats were fed
with a diet containing kaempferol, the activation of T cell was
inhibited and COX-2, iNOS and MCP-1 gene expressions of
kidney through modulation of NIK/IKK and MAPK signalings
were reduced possibly reducing kidney disease.95 In addition,
both kaempferol and quercetin could significantly improve
insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes
by acting as agonists of PPARg that may exert a beneficial effect
on hyperglycemia and insulin resistance.96
Flavanols
Tea is a popular beverage worldwide. It is produced from the
leaves of Camellia sinensis. There are more than 300 different
kinds of tea made by different manufacturing processes. Among
these, green tea has attracted attention for its health benefits
contributed by catechin compounds including epigallocatechin3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate
(ECG), and epicatechin (EC). Numerous studies demonstrate the
potential of green tea in iron-chelating, radical-scavenging, antiinflammatory and brain-permeable activities thus preventing
cardiovascular, chronic and neurodegenerative diseases.97,98
In vivo study shows that pretreatment with ()-catechin
protected dopaminergic neurons in the substantia nigra against
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced
toxicity through modulation of the phosphorylation of c-Jun Nterminal kinase (JNK) and GSK-3b.99 Pretreatment with epicatechin also attenuated ox-LDL induced neurotoxicity in
mouse-derived striatal neurons.100
EGCG is the most abundant polyphenolic compound in green
tea. EGCG is found to inhibit LPS-induced microglial activation, NO and TNF-a production as well as subsequent neuronal
injury both in the human dopaminergic cell line SH-SY5Y and in
primary rat mesencephalic culture, suggesting the neuroprotective activity of EGCG may be inhibition of microglial
activation.101 Neuronal damage and death caused by excessive
NO is one of the pathological mechanisms in neurodegeneration.
EGCG was found to inhibit NO-induced PC12 cell death by
scavenging ROS.102
Obesity is a low-grade inflammatory state and is predisposed
to an increased incidence of diabetes and CVD. A number line of
evidence shows that EGCG possesses excellent activity against
obesity-associated pathogenesis and metabolic disorders. In high
fat diet-induced obesity animal models, supplementation with
dietary EGCG reduced body weight gain and body fat, plasma
cholesterol and MCP-1 levels, and decreased lipid accumulation
in hepatocytes as well as attenuated insulin resistance.103 In
addition, feeding EGCG improved high fat diet-induced nonalcoholic steatohepatitis in mice by decreasing triglyceride and
cholesterol levels, lipid peroxidation, and expression of a-smooth
muscle actin (a-SMA) in liver tissue. The liver protective effect of
EGCG in mice on obesitywas further evidenced by expressions of
insulin receptor substrate-1 (IRS-1) and phosphorylated IRS-1
(pIRS-1), and decreasing TNF-a and NF-kB signaling in liver
tissues thus improving nonalcoholic steatohepatitis and insulin
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resistance.104 Treatment with EGCG on regulatory T cells from

obese individuals significantly enhanced the function of regulatory T cells by the production of anti-inflammatory cytokine IL10.105 Moreover, EGCG is reported to inhibit TNF-a stimulated
activation of activator protein-1 (AP-1) and secretion of MCP-1
porcine aortic endothelial cells that work against vascular
endothelial inflammation and atherosclerosis.106
EGCG also protects against bone, muscular and skeletal
diseases. In synoviocytes and chondrocytes, upregulation of
MAPK is critical for proinflammatory cytokine-induced
signaling that causes production of several mediators of cartilage
damage in an arthritic joint. EGCG was reported to modulate
IL-1b-induced activation of MAPKs and DNA binding activity
of AP-1 in osteoarthritis chondrocytes.107 Synovial fibroblasts
produce metalloproteinases (MMPs) induced by proinflammatory cytokine TNF-a, which are involved in destroying
cartilage and bone in Rheumatoid arthritis. Treatment with
EGCG suppresses TNF-a-induced production of MMP-1 and
MMP-3 through downregulating phosphorylation of MAPKs,
such as ERK1/2, p38, JNK and the activation of AP-1 transcription factor in RA synovial fibroblasts.108 Furthermore,
EGCG suppresses osteoclast differentiation through downregulating expression of nuclear factor activated T cells c1 (NFATc1) and reduces histologic scores in experimental arthritis in
mice that may improve osteoporosis and rheumatoid arthritis.109
Flavanones
Much of the activity of flavanones from citrus peels appears to
have an impact on vascular endothelial cells that reveal protective effect against atherosclerosis and cardiovascular diseases. In
high cholesterol-fed New Zealand white rabbits, diet supplemented with naringenin were shown to reduce gene expression of
vascular cell adhesion molecule-1 (VCAM-1), intercellular
adhesion molecule-1 (ICAM-1) and MCP-1 in endothelial cells.
Plasma lipoprotein levels, total cholesterol, triglyceride, and
high-density lipoprotein (HDL) were also decreased by naringenin feeding.110,111 These findings suggest that naringenin can
prevent hypercholesterolemia caused fatty liver and acts on
interfering immune cells and vascular endothelial cells as well as
macrophage infiltration against atherosclerosis. Naringin is
shown to inhibit TNF-a-induced expression of MMP-9 in
vascular smooth muscle cells (VSMC) through modulation of the
PI3K/AKT/mTOR/p70S6K pathway and suppression of the
transcriptional activity of AP-1 and NF-kB.112 Emerging studies
demonstrate that obesity is a major risk factor for atherosclerosis
and cardiovascular disease. Adiponectin secreted from adipocytes was found to suppress atherogenesis by inhibiting monocyte adhesion, reducing macrophage uptake ox-LDL and
suppressing the accumulation of ox-LDL in vascular wall.113
Studies show that naringin and hesperetin, other flavanones
found in large quantity in citrus peel, enhanced adiponectin
transcription in differentiated 3T3-L1 adipocytes through activation of PPARg.114 Naringin is also reported to inhibit high fat
diet-induced atherosclerosis and normalize hyperinsulinemia and
obesity in low-density lipoprotein receptor-null mice.115
Cytokines promote proliferation and migration of vascular
smooth muscle cells and play an important role in atherosclerosis. Hesperetin is found to inhibit platelet-derived growth
This journal is The Royal Society of Chemistry 2010

factor (PDGF)-BB induced proliferation of primary cultured rat

aortic vascular smooth muscle cells through regulation of Akt
and MAPKs signaling that results in cell cycle arrest.116 Moreover, hesperetin also increased NO releases from human umbilical vein endothelial cells through up-regulation eNOS
expression that may improve function of vascular endothelial
cells.117 In addition to the anti-atherosclerosis effect, studies also
demonstrate the protective activity of naringin and hesperetin
against neuroinflammatory injury. Both naringin and hesperetin
attenuated LPS/IFNg-induced TNF-a production through glial
cells, while naringin showed a greater effect as evidenced by
inhibition of iNOS expression by modulation of p38 MAPK and
STAT-1 signaling.118
Isoflavonoids
The health benefits of isoflavonoids from soybeans was recognized in recent years, especially about its anti-atherosclerotic
functions. Consumption of soy-based diets is associated with
a lower risk of cardiovascular disease in humans and reduced
atherosclerosis in several experimental animals.119 These effects
are related to their antioxidant, anti-inflammatory and antithrombogenic properties through inhibition of endothelial and
inflammatory cell activation and reduction in recruitment of
leukocytes, as well as foam cell formation. Genistein, the major
isoflavone abundantly present in soybean, is known for its role in
the regulation of vascular function and protection against
atherosclerosis.120 Treatment with genistein markedly inhibited
TNF-a-induced cell adhesion molecule CD62E and CD106
expression and subsequent monocyte adhesion in HUVECs and
human brain microvascular endothelial cells.121 Genistein also
decreased the interaction between monocyte and endothelial cells
through the activation of PPARg that inhibits of monocyte
adhesion in culture cells and animals.122,123 In an in vitro study,
genistein inhibited LPS-induced MCP-1 secretion from macrophages that contribute to reduced monocyte migration.124 In vivo
administration of genistein inhibits LPS-induced expression of
iNOS and nitrotyrosine protein in vascular tissue that prevents
hypotension and vascular alterations.125
Genistein is also known to have a potential effect on rheumatoid arthritis, diabetes, metabolic disorders, neurodegenerative diseases and chronic colitis by modulation of inflammatory
response. For instance, genistein inhibits production of proinflammatory molecules NO, IL-1b, and HC gp-39, known as
markers of cartilage catabolism in LPS-stimulated human
chondrocytes.126 In a collagen-induced rheumatoid arthritis rat,
genistein modulated Th1-predominant immune response by
suppressing the secretion of IFNg and increasing IL-4 production that balances the inflammatory state.127 NAFLD is an
obesity-related fatty liver disease caused by proinflammatory
cytokine TNF-a and ILs and leads to the dysfunction of hepatocytes and increase fatty acid uptake. Genistein is reported to
reduce high fat diet-induced steatohepatitis through decreasing
plasma TNF-a levels and improved liver function in rat.128
Supplementation with genistein and daidzein also decreases
mRNA levels of TNF-a, IL-1b and MCP-1 in plasma and liver
tissue in obese Zucker rats, suggesting a preventive effect of
dietary genistein on steatohepatitis through its anti-inflammatory activity.129 Furthermore, intake of high-dose isoflavones
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(genistein, daidzein, and glycitein) significantly reduced serum

TNF-a and increased adiponectin levels in women, indicating
that isoflavonids could regulate inflammatory conditions and
improve metabolic parameters.130
In addition, genistein attenuated LPS-induced loss of dopamine uptake in rat mesencephalic neuron-glia cultures through
reducing microglia activation and production of NO and TNFa131 may protect dopaminergic neuron injury-caused pathogenesis of Parkinsons disease. In Alzheimers disease, accumulation
of astrocytes at sites of Ab deposition is the earliest neuropathological changes that initiate the inflammatory response.
Treatment with genistein reduced Ab-induced production of
inflammatory mediator iNOS, COX-2, TNF-a and IL-1b in
astrocytes, possibly through activation of PPARs.132 Also, oral
treatment with genistein reduced TNBS-induced chronic colitis
by inhibiting expression of COX-2 mRNA and protein as well as
the myeloperoxidase (MPO) activity in rat colon that exerts
beneficial anti-inflammatory effects against inflammatory bowel
disease.133 Genistein is a well-known tyrosine kinase inhibitor. In
an in vitro study, genistein was found to prevent IL-1b/IFNginduced expression of COX-2 and iNOS as well as produce PGE2
and NO in human islets that may improve insulin resistance and
prevent pathogenesis of diabetes.134
Anthocyanidins
Anthocyanidins are common plant pigments that give the red
and blue colors in some fruits and vegetables such as blueberries
and grapes. Epidemiological investigations and animal experiments indicate that anthocyanins may contribute to chemopreventive activities of various chronic inflammatory
diseases.135,136 Anthocyanins-rich berries were demonstrated to
possess a broad spectrum of biological properties, including
antioxidant, cadioprotective, neuroprotective, anti-inflammatory and anticancer.137 In an animal study, cyanidin was reported
to reduce PGE2 levels in paw tissues and TNF-a levels in serum
in adjuvant-induced arthritis.138 Damage and apoptosis of
vascular endothelial cells is frequently observed in atheromatous
plaques and contributes to pathology of atherosclerosis. It has
been shown that cyanidin inhibited TNF-a-induced endothelial
cell apoptosis, elevated expression of eNOS and thioredoxin may
improve vascular endothelial cell function and vasculopathy.139
VEGF is known as a major pro-angiogenic and pro-atherosclerotic factor. Both cyanidin and delphinidin, other major anthocyanidins present in pigmented fruits and vegetables, inhibit
PDGF-induced VEGF expression through down-regulation of
p38 MAPK and JNK signalings in vascular smooth muscle
cells.140
Delphinidin also shows protective effects against cardiovascular disease. It is suggested that proliferation of vascular
endothelial cells is important in the pathogenesis of atherosclerosis.141 Delphinidin treatment inhibits serum and VEGFinduced bovine aortic endothelial cell proliferation through
modulation of ERK and also results in cell cycle arrest.142 Also,
delphinidin increased eNOS expression by mediating the MAP
kinase pathway, thus preventing bovine aortic endothelial cell
apoptosis.143 In addition, delphinidin was found to fight against
ox-LDL-induced damage in HUVECs and regulate apoptotic
molecule expression.144 These studies suggest delphinidin may be
28 | Food Funct., 2010, 1, 1531

important in preventing both plaque development and atherosclerosis.

Proanthocyanidines and theaflavins
Proanthocyanidins (PAs), also called condensed tannins, are
ubiquitous and present as the second most abundant group of
natural phenolics after lignin. Oligomers and polymers of
proanthocyanidins are widely found in the plant kingdom in
fruits, cereals, berries, beans, nuts, cocoa and wine. The abundance of proanthocyanidins in plants makes them an important
part of the human diet and are reported to exhibit a wide range of
biological effects.145 A recent study demonstrated that dietary
grape seed proanthocyanidins (GSPs) is effective against ultraviolet (UV) radiation-induced skin tumor in mice. Dietary GSPs
inhibited UVB-induced infiltration of proinflammatory leukocytes and the levels of myeloperoxidase, cyclooxygenase-2
(COX-2), prostaglandin (PG) E(2), cyclin D1 and proliferating
cell nuclear antigen (PCNA) in the skin and skin tumors.146 PAs
are shown to mediate several anti-inflammatory mechanisms
involved in the development of cardiovascular disease by
modulation of monocytes adhesion in the inflammatory process
of atherosclerosis.145 PAs also exhibit in vivo hepatoprotective
and anti-fibrogenic effects against dimethylnitrosamine-induced
liver injury.147
Theaflavins, a mixture of theaflavin (TF-1), theaflavin-3gallate (TF-2a), theaflavin-30 -gallate (TF-2b), and theaflavin3,30 -digallate (TF-3) are the major components of black tea. We
previously reported that TF-3 exerts its anti-inflammatory and
cancer chemopreventive actions by suppressing the activation of
NFkB through inhibition of IKK activity.148 We also found that
epicatechins in green tea and theaflavins in black tea are able to
reduce the concentration of methylglyoxal in physiological
phosphate buffer conditions.149 Among these black tea components, TF-3 is generally considered to be the more effective
component for a protective effect against inflammatory
processes.150

Conclusion
Chronic inflammation is linked to numerous human diseases.
Increasingly epidemiological and experimental studies demonstrate that modulation of inflammatory response by natural
phytochemicals plays an important role in the prevention, mitigation, and treatment of many chronic inflammatory diseases.
Flavonoids are a group of natural compounds widely present in
vegetables, fruits and edible plants that possess potent biological
activities. Dietary intake of flavonoids is suggested to prevent
and lower the risk of chronic diseases. In this review, we discussed the possible mechanisms by which flavonoids play a role
in the regulation of the inflammatory processes associated with
atherosclerosis (cardiovascular disease), neurodegenerative
diseases, obesity, metabolic disorders, bone, muscular and skeletal diseases, and chronic inflammatory diseases, as well as
cancers. The anti-inflammatory activity of flavonoids is seen
through several mechanisms involving the modulation of
inflammatory signaling, reduction of inflammatory molecule
production, diminishing recruitment and activation of
inflammatory cells, regulation of cellular function and their
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antioxidative property. Regarding the safety, ability and the antiinflammatory effects of flavonoids, they are likely to have
a potential role in preventive and therapeutic roles in chronic
inflammatory conditions. However, additional, extensive
research of flavonoids in strengthening the network of inflammatory response needs to be studied in the future.

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Abbreviations
Ab
AGE
AP-1
ApoE
APP
a-SMA
ATF
CBP/p300
CD
C/EBP
c-FLIP
CIA
COPD
COX-2
CRP
CVD
DSS
EC
ECG
EGC
EGCG
ERK1/2
eNOS
GLUT4
GSK-3b
HC gp-39
HDL
HIF-1a
H2O2
HUVEC
ICAM-1
IL
IL-1ra
IBD
IFN-g
IKK
iNOS
IRS-1
JNK
5-LOX
LPS
MAPK
MCP-1
MMP
MPO
MPTP
mTOR
NADPH
oxidase

amyloid b peptide
advanced glycation end products
activator protein-1
apolipoprotein E
amyloid precursor protein
a-smooth muscle actin
activator transcription factor
cAMP response element binding protein/p300
Crohns disease
CCAAT enhancer binding protein
cellular FLICE-like inhibitory protein
collagen-induced arthritic
chronic obstructive pulmonary disease
cyclooxygenase-2
c-active protein
cardiovascular disease
dextran sulfate sodium
epicatechin
epicatechin-3-gallate
epigallocatechin
epigallocatechin-3-gallate
external signal regulated kinase 1/2
endothelial NO synthase
glucose transporter type 4
glycogen synthase kinase 3b
human cartilage glycoprotein-39
high-density lipoprotein
hypoxia inducible factor-1a
hydrogen peroxide
human umbilical vein endothelial cell
intercellular adhesion molecule-1
Interleukin
IL-1 receptor antagonist protein
inflammatory bowel disease
interferon-g
IkB kinase
inducible nitric oxide synthase
insulin receptor substrate-1
c-Jun N-terminal kinase
5-lipoxygenase
lipopolysaccharides
mitogen-activated protein kinase
monocyte chemoattractant protein-1
matrix metalloproteinase
myeloperoxidase
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
mammalian target of rapamycin
nicotinamide adenine dinucleotide phosphateoxidase

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NAFLD
NF-ATc1
NF-kB
NFAT
NIK
NO
NSAID
1O2
O2
OH
ox-LDL
p70S6K
PDGF
PGE2
PI3K
pIRS-1
PKC
PPARg
RA
RANKL
ROS
SOCS
STAT
TGF-b
Th cell
TNBS
TNF-a
TPA
UC
VCAM-1
VEGF
VLDL
VSMC

non-alcoholic fatty liver disease

nuclear factor of activated T cells c1
nuclear factor-kappa B
nuclear factor of activated T-cells
NF-kB-inducing kinase
nitric oxide
nonsteroidal anti-inflammatory drugs
singlet oxygen
superoxide anion
hydroxyl radical
oxidized low-density-lipoprotein
p70 ribosomal S6 kinase
platelet-derived growth factor
prostaglandin E2
phosphoinositide-3 kinase
phosphorylated IRS-1
protein kinase C
peroxisome proliferator-activated receptor g
rheumatoid arthritis
receptor activator for nuclear factor kB ligand
reactive oxygen species
suppressor of cytokine signaling
signal transducers and activators of
transcription
transforming growth factor-b
T helper cell
2,4,6-trinitrobenzene sulfonic acid
tumor necrosis factor-a
12-O-tetradecanoyl-phorbol-13-acetate
ulcerative colitis
vascular cell adhension molecule-1
vascular endothelial growth factor
very-low-density lipoprotein
vascular smooth muscle cells

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