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Anti-inflammatory activity of natural dietary flavonoids

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

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 humandiseases. 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 migra-

tion 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 inflamma-

tion.4 These also trigger a series of signaling molecules, inflam-

matory 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

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 Epidemi-

ological studies provide convincing evidence that natural dietary

compounds that humans consume as food possess many bio-

logical activities. Among these natural bioactive compounds,

flavonoids are widely recognized for their biological and phar-

macological effects, including antiviral, anti-carcinogenic, anti-

oxidant, antimicrobial, anti-inflammatory, anti-angiogenic and

anti-thrombogenic properties.1,5

Epidemiologic studies indicatethat 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-inflam-

matory 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 preexistingconditions (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,

aDepartment of Seafood Science, National Kaohsiung Marine University,No.142, Haijhuan Rd., Nanzih District, Kaohsiung, 81143, Taiwan.E-mail: [email protected]; Fax: (+886)-7-361-1261; Tel:(+886)-7-361-7141 Ext 3623bDepartment of Food Science, Rutgers University, 65 Dudley Road, NewBrunswick, New Jersey, 08901-8520, USA. E-mail: [email protected]; Fax: +1-732-932-6776

This journal is The Royal Society of Chemistry 2010 Food Funct., 2010, 1, 1531 | 15

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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 atheroscle-

rosis, coronary diseases, cerebrovascular disorder, heart failure

and cardiomyopathy is common in CVD.7 In the past,

researchers suggested a number of traditional risk factorsimplicated in the pathogenesis of CVD including age, hyper-

tension, 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 regula-

tion of vascular homeostasis, and inhibition of leukocyte adhe-

sion 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 majorcause of CVD. Recent studies demonstrate that vascular inflam-

mation is the earliest event in the development of atheroscle-

rosis.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 expressionof adhesion

molecules selectins, vascular cell adhesion molecule-1 (VCAM-1)

and intracellular adhesion molecule-1 (ICAM-1).10 Once mono-

cytes firmly attach on the surface of endothelium, they trans-

migrate into the arterial intima and differentiate to macrophages.

This transmigration is triggered by chemoattractant molecules

such as monocyte chemoattractant protein-1 (MCP-1), proin-

flammatory cytokines (TNF-aand ILs) as well as growth factors

(PDGF and TGF-b) produced by activated T cells and macro-

phage.11 Among these, studies indicate that MCP-1 is important

for recruitment of monocytes into intima. Differentiated macro-

phages 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, macro-

phages and arterial cells maintain an inflammatory response

within the artery and promote proliferation and migration ofvascular smooth muscle cells.9,11 Proliferative smooth muscle cells

release fibrogenicmediators and build a denseextracellular 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 inflam-

matory 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 identi-fication 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

Fig. 1 Chronic inflammation is linked to human diseases.

16 | Food Funct., 2010, 1, 1531 This journal is The Royal Society of Chemistry 2010

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intracellular and/or extracellular a-synuclein protein aggregates

released fromneurons 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 produc-

tion of inflammatory mediators.22 Proinflammatory cytokines

such as TNF-aand ILs derived fromactivated microglial cellsalso

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 neuropa-

thology. 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 metabolicdisorders 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 Itis

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 Leptinis 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 anda high risk forthe developmentof type 2 diabetes.27,28

In recent years, many studies document that obesity is signif-

icantly 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 phosphoryla-tion, 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 che-

moattractant protein-1 (MCP-1), to trigger infiltration of

macrophages, that then leads to the creation of a chronic, low-

grade inflammation in obesity.32,33 Increased levels of acute phase

protein CRP are found in many obese individuals,34 and circu-

lating CRP concentrations are related to the development of

cardiovascular disease,14 indicating the association of obesityand 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 proin-

flammatory cytokine production, increased acute phase protein

and activation of inflammatory signaling pathways.

37

In addi-tion, obesity correlates with an increase in inflammatory condi-

tions and metabolic syndromes.29 Type 2 diabetes is the most

prevalent and serious metabolic disease caused by insulin resis-

tance 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 inter-

action between insulin receptor and suppressor of cytokine

signaling (SOCS) proteins that result in insulin resistance.

40

Inpatients 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 developmentcaused 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 endo-

thelial 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 jointdestruction and functional disability, often characterized by

chronic inflammatory responses primarily affecting the syno-

vium 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 fromb 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 ofb 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 pro-

inflammatory cytokines-inducedb 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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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 syno-

viocytes 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 synoviocytesis known to produce prostaglandins and proteases that destroy

bone and cartilage.45 Moreover, activated B cells and macro-

phage 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 syno-

vium causes varying degrees of joint destruction and also extra-

articular 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

receptor activator of NF-kB (RANK), activation and differen-

tiation of osteoclast, and decreased osteoblast survival.46 Despite

several in vitro and in vivo studies indicating that proin-

flammatory 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

Fig. 6 Mechanisms of inflammation-associated pathogenesis in rheumatoid arthritis and osteoporosis. In inflamed rheumatoid synovium and bone

tissue, pro-inflammatory cytokines producedby recruited inflammatory cells (macrophages, T cellsand 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.


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histopathology, which result from abnormal regulation of theimmune system in the intestine.48 In IBD, damage of epithelium

in the colon increases recruitment of immune cells such as acti-

vated 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 homeo-

stasis. Also, an alteration of the immune system toward luminal

antigens is thought to play a crucial role in pathogenesis inIBD.48 In an immune response, T helper (Th) cells recognize self-

antigens (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 intes-

tinal 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

thought to be a Th2 cell mediated response by the secretion ofIL-4, IL-5 and IL-10.48,50 Overexpression of these proin-

flammatory 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 intes-

tinal mucosa. Indeed, increased proinflammatory cytokines in

colon mucosa are also linked to the enhanced expression of anti-

apoptotic molecules, leading to apoptotic resistance and

promotion of accumulation of T cells.48,50

Cancers

Several lines of evidence indicate that cancer development inhumans 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 anti-

growth 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

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.


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evidence suggests that inflammation should be the seventh hall-

marker in cancer development.53

The pathological mechanism of inflammation involved in

tumorigenesis is very complicated.54 In tissue injury or inflam-

matory 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 promotedevelopment of cancer by creating an inflammatory microenvi-

ronment, which consists of stromal cells, inflammatory cells and

the extracellular matrix from surrounding tissues. The inflam-

matory 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 devel-

opment54,55 (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 (NF-

kB), 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 importantin inflammation linked tumorigenesis. These critical molecules

can be considered important in the modulation of an inflam-

matory response, and thus could block or prevent inflammation-

associated carcinogenesis.54,56

Chemoprevention: inflammation as potential target

The term chemoprevention was coined by Sporn in the mid-

1970s 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 tar-

geting interference with chronic inflammatory response. For

example, anti-inflammatory drugs, including nonsteroidal anti-

inflammatory drugs (NSAID), are found to have some neuro-

protective effects.58 Resveratrol and curcumin are found to

prevent cell damage and death through their antioxidativeactivities that reveal potential neuroprotective activities.59,60

Anti-a4 integrin monoclonal antibody acts by disrupting adhe-

sion 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 insulin-

resistance.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 andimproved 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 estab-

lished.54,55 Numerous evidence demonstrates that inflammatory

pathways are critical targets in cancer treatment and preven-

tion.65 Many natural bioactive compounds are reported to

interfere with the initiation, promotion/progression, and inva-sion/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 path-

ways 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 struc-

ture of the aglycones C ring, flavonoids can be classified into

seven groups: flavones, flavanones, flavonols, flavanonols, iso-

flavones, flavanols (catechins) and anthocyanidins (Table 1). The

structural variation of flavonoids may come from various

patterns of substitution through enzymatic reactions including

hydroxylation, methoxylation, sulfonation, acylation, pre-

nylation, 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 spec-

trum of pharmacological properties such as antioxidant, free

radical-scavenging, anti-inflammatory, anti-carcinogenic, anti-viral, 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, anti-

inflammatory 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, character-

ized by production of autoantibodies to attack nuclear antigens

and immune complex deposition in organs.68 In anin vivostudy,

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 inhibitoryprotein (c-FLIP) in immune cells as well as causing activated

immune cells to undergo apoptosis, thus suppressing inflamma-

tion in lupus.69 In the pathogenesis of rheumatoid arthritis, it is

reported that inflammatory cytokines produced by fibroblast-

like 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 microgliaand cytokine production is important in neurodegenerative

diseases. Treatment with luteolin strongly suppressed IFNg-

induced CD40 expression and the production of TNF-a and IL-6

through downregulated phosphorylation of STAT-1 in micro-

glia.72 Also, luteolin significantly inhibited LPS-induced activa-

tion of microglia by inhibiting JNK phosphorylation and

activation of AP-1, increasing dopamine uptake and decreasing

excessive TNF-a, NO and superoxide production in micro-

glia,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


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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 MCP-1 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 bio-

logical activities, including modulation of inflammatory-derived

cancer development.77 It is shown that tangeretin suppresses IL-

1b-induced COX-2 expression through inhibiting activation of

MAPK andAkt.1 Inan in vivo study,nobiletin was found to lower

levels of eotaxin, a potent eosinophil chemoattractant cytokine

that relieves the infiltration of eosinophils and airway inflamma-

tion in asthmatic rats.78 It is suggested that the inhibition of foam

cells forming macrophage andox-LDLuptake is oneof thetargetsfor atherosclerosis. Nobiletin inhibited macrophage foam-cell

formation through reducing metabolism ofb-VLDL, is primarily

takenup by macrophages via the LDLreceptor in cultured murine

J774A.1 macrophages.79 Several studies demonstrate that nobi-

letin 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 expres-

sion of iNOS and COX-2 as well as tumorigenesis in mouse skin.1

In our previous studies, we reported that a metabolite of nobiletin

Table 1 Backbone structures of the different classes of flavonoids

Groups Structure Examples

Flavones Apigenin, luteolin, tangeretin,nobiletin, 5-hydroxy-3,6,7,8,30,40-hexamethoxyflavone

Flavonols Kaempferol, myricetin, quercetin,isorhamnetin

Flavanols Catechin, gallocatechin,epicatechin, epigallocatechin-3-gallate

Flavanones Naringenin, hesperetin, eriodictyol

Isoflavones Daidzein, genistein, glycitein

Anthocyanidins Cyanidin, delphinidin,pelargonidin


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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-hexame-

thoxyflavone, 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 dia-

betes in rat through decreasing plasma glucose and increasingadiponectin levels that may improve glucose and lipid homeo-

stasis.84

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 anti-

inflammatory agent. Recently, it was shown to possess good anti-

atherosclerotic activity. In human umbilical vein endothelial cells

(HUVECs), quercetin treatment strongly attenuated the inflam-

mation-induced upregulated expression of VCAM-1, ICAM-1

and monocyte chemoattractant protein-1 (MCP-1), which maycontribute 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) func-

tion and decreasing plasma-sP-selectin levels in the apolipopro-

tein E (ApoE)(-/-) gene-knockout mouse.86 Quercetin also

decreased circulating inflammatory markers, including IFNg,

IL-1aand IL-4 in high fat diet animal models and therefore may

improve inflammation or obesity-associated disorder.87 In addi-

tion, consumption of quercetin is found to decrease systolic

blood pressure and plasma oxidised LDL in obese subjects (aged2565 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 broc-

coli, tea and various vegetables, is considered to improve oste-

oporosis. 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 thepathology of osteoporosis, proinflammatory cytokines TNF-ais

important for bone disruption and osteoclastogenic cytokine

production. Kaempferol was reported to antagonize TNF-a-

induced p65 translocation and production of IL-6 and MCP-1as

well as RANKL-triggered osteoclast precursor cell differentia-

tion. These data indicate that kaempferol exerted a profound

anti-osteoclastogenic effect.92 Advanced glycation end products

(AGE) are oxidative products formed from nonenzymatic reac-

tion 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

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 NF-

kB 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 PPARgthat may exert a beneficial effect

on hyperglycemia and insulin resistance.96

Flavanols

Tea is a popular beverage worldwide. It is produced from the

leaves ofCamellia 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 epigallocatechin-

3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate(ECG), and epicatechin (EC). Numerous studies demonstrate the

potential of green tea in iron-chelating, radical-scavenging, anti-

inflammatory 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 N-

terminal kinase (JNK) and GSK-3b.99 Pretreatment with epi-

catechin 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 activa-tion, NO and TNF-aproduction as well as subsequent neuronal

injury both in the human dopaminergic cell line SH-SY5Y and in

primary rat mesencephalic culture, suggesting the neuro-

protective 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 withdietary 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 non-

alcoholic steatohepatitis in mice by decreasing triglyceride and

cholesterol levels, lipid peroxidation, and expression ofa-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 regula-

tory T cells by the production of anti-inflammatory cytokine IL-

10.105 Moreover, EGCG is reported to inhibit TNF-astimulated

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 ofMAPK 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 proin-

flammatory 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 tran-

scription factor in RA synovial fibroblasts.108 Furthermore,

EGCG suppresses osteoclast differentiation through down-regulating expression of nuclear factor activated T cells c1 (NF-

ATc1) 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 protec-

tive effect against atherosclerosis and cardiovascular diseases. In

high cholesterol-fed New Zealand white rabbits, diet supple-

mented 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 nar-

ingenin 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 adipo-

cytes was found to suppress atherogenesis by inhibiting mono-cyte 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 acti-

vation 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 atheroscle-

rosis. Hesperetin is found to inhibit platelet-derived growth

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 More-

over, hesperetin also increased NO releases from human umbil-

ical 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 hesperetinattenuated 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 recog-

nized 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 antith-rombogenic 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 macro-phages 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 rheu-

matoid arthritis, diabetes, metabolic disorders, neurodegenera-

tive diseases and chronic colitis by modulation of inflammatory

response. For instance, genistein inhibits production of proin-

flammatory 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 produc-tion 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 hepa-

tocytes 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-1band MCP-1 in plasma and liver

tissue in obese Zucker rats, suggesting a preventive effect of

dietary genistein on steatohepatitis through its anti-inflamma-

tory 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 dopa-

mine uptake in rat mesencephalic neuron-glia cultures through

reducing microglia activation and production of NO and TNF-

a131 may protect dopaminergic neuron injury-caused pathogen-

esis of Parkinsons disease. In Alzheimers disease, accumulationof astrocytes at sites of Abdeposition is the earliest neuropatho-

logical 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/IFNg-

induced expression of COX-2 and iNOS as well as produce PGE2

and NO in human islets that may improve insulin resistance andprevent 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 experi-

ments indicate that anthocyanins may contribute to chemo-

preventive 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-inflamma-

tory and anticancer.137 In an animal study, cyanidin was reportedto reduce PGE2levels 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-atheroscle-

rotic factor. Both cyanidin and delphinidin, other major antho-

cyanidins 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 cardiovas-

cular disease. It is suggested that proliferation of vascular

endothelial cells is important in the pathogenesis of atheroscle-

rosis.141 Delphinidin treatment inhibits serum and VEGF-

induced 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

important in preventing both plaque development and athero-

sclerosis.

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 infruits, cereals, berries, beans, nuts, cocoa and wine. The abun-

dance 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 ultra-

violet (UV) radiation-induced skin tumor in mice. Dietary GSPs

inhibited UVB-induced infiltration of proinflammatory leuko-

cytes 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 processof 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-3-

gallate (TF-2a), theaflavin-30-gallate (TF-2b), and theaflavin-

3,30-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 compo-

nents, TF-3 is generally considered to be the more effectivecomponent for a protective effect against inflammatory

processes.150

Conclusion

Chronic inflammation is linked to numerous human diseases.

Increasingly epidemiological and experimental studies demon-

strate that modulation of inflammatory response by natural

phytochemicals plays an important role in the prevention, miti-

gation, 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 preventand lower the risk of chronic diseases. In this review, we dis-

cussed 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 skel-

etal 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 anti-

inflammatory 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 inflam-

matory response needs to be studied in the future.

Abbreviations

Ab amyloid b peptide

AGE advanced glycation end products

AP-1 activator protein-1

ApoE apolipoprotein E

APP amyloid precursor protein

a-SMA a-smooth muscle actin

ATF activator transcription factor

CBP/p300 cAMP response element binding protein/p300

CD Crohns disease

C/EBP CCAAT enhancer binding protein

c-FLIP cellular FLICE-like inhibitory protein

CIA collagen-induced arthriticCOPD chronic obstructive pulmonary disease

COX-2 cyclooxygenase-2

CRP c-active protein

CVD cardiovascular disease

DSS dextran sulfate sodium

EC epicatechin

ECG epicatechin-3-gallate

EGC epigallocatechin

EGCG epigallocatechin-3-gallate

ERK1/2 external signal regulated kinase 1/2

eNOS endothelial NO synthase

GLUT4 glucose transporter type 4

GSK-3b glycogen synthase kinase 3bHC gp-39 human cartilage glycoprotein-39

HDL high-density lipoprotein

HIF-1a hypoxia inducible factor-1a

H2O2 hydrogen peroxide

HUVEC human umbilical vein endothelial cell

ICAM-1 intercellular adhesion molecule-1

IL Interleukin

IL-1ra IL-1 receptor antagonist protein

IBD inflammatory bowel disease

IFN-g interferon-g

IKK IkB kinase

iNOS inducible nitric oxide synthase

IRS-1 insulin receptor substrate-1JNK c-Jun N-terminal kinase

5-LOX 5-lipoxygenase

LPS lipopolysaccharides

MAPK mitogen-activated protein kinase

MCP-1 monocyte chemoattractant protein-1

MMP matrix metalloproteinase

MPO myeloperoxidase

MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

mTOR mammalian target of rapamycin

NADPH

oxidase

nicotinamide adenine dinucleotide phosphate-

oxidase

NAFLD non-alcoholic fatty liver disease

NF-ATc1 nuclear factor of activated T cells c1

NF-kB nuclear factor-kappa B

NFAT nuclear factor of activated T-cells

NIK NF-kB-inducing kinase

NO nitric oxide

NSAID nonsteroidal anti-inflammatory drugs

1O2 singlet oxygen

O2 superoxide anion

OH hydroxyl radical

ox-LDL oxidized low-density-lipoprotein

p70S6K p70 ribosomal S6 kinase

PDGF platelet-derived growth factor

PGE2 prostaglandin E2PI3K phosphoinositide-3 kinase

pIRS-1 phosphorylated IRS-1

PKC protein kinase C

PPARg peroxisome proliferator-activated receptorg

RA rheumatoid arthritis

RANKL receptor activator for nuclear factorkB ligand

ROS reactive oxygen species

SOCS suppressor of cytokine signaling

STAT signal transducers and activators of

transcription

TGF-b transforming growth factor-b

Th cell T helper cell

TNBS 2,4,6-trinitrobenzene sulfonic acid

TNF-a tumor necrosis factor-a

TPA 12-O-tetradecanoyl-phorbol-13-acetate

UC ulcerative colitis

VCAM-1 vascular cell adhension molecule-1

VEGF vascular endothelial growth factor

VLDL very-low-density lipoprotein

VSMC vascular smooth muscle cells

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