Anti-Inflammatory Properties of Cinnamon
Polyphenols and their Monomeric Precursors
Dhanushka Gunawardena*, Suresh Govindaraghavan*
*Department of Pharmacology, School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia
Network Nutrition Pty Limited, North Ryde, NSW, Australia
Molecular Medicine Research Group, University
of Western Sydney, Campbelltown, NSW, Australia
CompleMed, University of Western Sydney, Campbelltown,
An increase in both the absolute number as well as
relative proportion of the elderly is one of the most
important developments facing human society in the
next decades. Chronic inflammation is a contributing
factor for many age-related diseases including neuro-
degenerative diseases, degenerative musculoskeletal
diseases, cardiovascular diseases, diabetes, cancer,
asthma, rheumatoid arthritis, and inflammatory bowel
disease. To date, pharmacotherapy of inflammatory
conditions is based on the use of non-steroidal anti-
inflammatory drugs (NSAIDs). Considering the preva-
lence of degenerative and inflammatory conditions, it
is not surprising that NSAIDs are among the most
commonly used drugs. However, the prolonged use of
NSAIDs comes at a price. NSAIDs can cause serious
gastrointestinal toxicity. Even more ominously, some
NSAIDs have been linked to increased blood pressure,
greatly increased risk of congestive heart failure, stroke
and myocardial infarction.
Plants have long been an important source for the dis-
covery of new drugs. Herbal medicines derive secondary
metabolites such as salicylic acid from the bark of the
willow tree (Salix alba) and have been used for the treat-
ment of inflammatory diseases in the past. In fact, the
development of acetylsalicylic acid, commonly known as
aspirin, as an anti-inflammatory drug at the German
drug and dye firm Bayer at the end of the nineteenth cen-
tury was motivated by the desire to find a less irritating
replacement for the traditional salicylate-based medi-
cines. Many other medicinal plants are known to have
anti-inflammatory activity but neither the underlying
mechanisms nor their potential for the development of
new drugs have been fully explored.
Inflammation is recognized as a biological process
in response to tissue injury. The defining clinical fea-
tures of inflammation are known in Latin as rubor
(redness), calor (warmth), tumor (swelling) and dolor
(pain). Hallmarks of inflammation were first described
by Aurelius Cornelius, a Roman physician and medical
writer who lived from about 30 BC to AD 45.
site of injury, an increase in blood vessel wall perme-
ability followed by the movement of serum proteins
and leukocytes (neutrophils, eosinophils and macro-
phages) from the blood to the extra-vascular tissue is
The inflammatory response is a complex self-
limiting process precisely regulated to prevent exten-
sive damage to the host. When the self-limiting nature
of this protective mechanism is inappropriately regu-
lated, it results in chronic inflammation, which is asso-
ciated with a number of chronic inflammatory diseases,
including asthma, rheumatoid arthritis, inflammatory
bowel disease, atherosclerosis, Alzheimer’s disease
(AD), and cancer.
Intracellular antioxidant mechan-
isms against inflammation-induced oxidative stress
involve antioxidant enzymes, including superoxide dis-
mutase (SOD), catalase (CAT), and glutathione peroxi-
dase (GPx) in tissues.
Polyphenols in Human Health and Disease.
DOI: http://dx.doi.org/10.1016/B978-0-12-398456-2.00030-X ©2014 Elsevier Inc. All rights reserved.
2. CINNAMON, A MEDICINAL SPICE
The genus Cinnamomum belongs to the family
Lauraceae, comprising over 250 species, and is found
distributed in tropical and subtropical regions of
America, Central America, Asia, Oceania and
Australasia. During the middle ages, the Arabs carried
cinnamon and other spices along the old caravan trade
routes to Alexandria, Egypt and then shipped to
Europe. They constructed many exotic stories about
the great difficulty of harvesting cinnamon to account
for its scarcity and justify the high price of this spice.
There are two main species of cinnamon:
Cinnamomum verum (true or Ceylon cinnamon) grown
in Sri Lanka, and Cinnamomum aromaticum (also called
cassia), which is grown in China. True cinnamon has
a yellowish-brown color
and tends to produce a
finer powder than cassia, which has a greyish-brown
color. There are two other common species of cinna-
mon: C. loureiroi (Saigon cinnamon, Vietnamese cassia,
or Vietnamese cinnamon) grown in Vietnam, and C.
burmannii (Korintje, Padang cassia, or Indonesian cin-
namon) grown in Indonesia.
Cinnamon has been used since ancient times both
as a culinary spice and for medicinal purposes. The
medicinal values of cinnamon were utilized by ancient
health practitioners such as Dioscorides and Galen in
their various treatments. In medieval times, cinnamon
was an ingredient of medicines for sore throats and
Cinnamon has also been used to alleviate indiges-
intestinal spasms, nausea,
and flatulence, to improve the appetite, and to treat
It is reported to be beneficial for the control
of blood glucose levels in diabetes,
reduction in the
levels of low-density lipoprotein (bad cholesterol),
lessening of arthritic pain,
and for healing open
wounds and small cuts.
The positive health effects
associated with the consumption of cinnamon could,
in part, be attributed to its phenolic composition.
3. POLYPHENOLS, THEIR MONOMERIC
PRECURSORS AND INFLAMMATION
Polyphenols are one of the major non-nutrient consti-
tuents of most common culinary herbs. The most recent
definition of polyphenols includes “secondary metabo-
lites derived exclusively from the shikimate derived phe-
nylpropanoids and/or the polyketide pathways
featuring more than one phenolic ring and being devoid
of any nitrogen-based functional group in their most
basic structural expression.”
For the sake of brevity,
we have included cinnamon polyphenols and their
monomeric biogenetic precursors in this discussion.
Polyphenols with varying phenolic structures are found
enriched in vegetables, fruits, grains, bark, roots, tea, and
Several hundred polyphenolic structures are
known, with edible plants containing far fewer polyphe-
nolic structures. The monomeric precursors of polyphe-
nols include flavan-3-ols (forming pro-anthocyanidin
polyphenols), gallic acid derivatives (forming gallo- and
ellagitannin polyphenols) and phloroglucinol derivatives
(forming phlorotannin polyphenols), which may contain
several hydroxyl groups
and with one or more sugar
residue (glycoside). Flavonoids are the most important
among monomeric phenolic compounds. Categories of
flavonoids include flavonols (e.g., quercetin), flavones
(e.g., apigenin, luteolin), flavonones (e.g., hesperetin),
flavan-3-ols (e.g., epicatechin, epigallocatechin-3-gallate
(EGCG)) and anthocyanins (e.g., cyanidin).
Multiple studies, both epidemiological and experi-
mental, suggest that polyphenols and their monomeric
precursors possess anti-inflammatory and antioxidant
activities that may contribute, via the diet, to the pre-
vention of chronic inflammatory diseases such as can-
cer, cardiovascular disease, inflammatory bowel
disease, and AD.
Recent data suggest that polyphe-
nols can work as modifiers of signal transduction path-
ways to elicit their beneficial effects. These natural
compounds express anti-inflammatory activity by
modulation of pro-inflammatory gene expression such
as cyclooxygenase, lipoxygenase, nitric oxide synthases
(NOS) and several pivotal cytokines, mainly by acting
through nuclear factor-kappa B (NF-κB) and mitogen-
activated protein kinase signaling.
molecular mechanisms of their anti-inflammatory
activities have also been suggested to include the inhi-
bition of enzymes related to inflammation, such as
cyclooxygenase and lipoxygenase, and many others
including PPAR, NOS, NF-κB, and NAG-1.
There are two molecular aspects: the arachidonic acid
(AA)-dependent pathway and the AA-independent
pathway. Cyclooxygenase, lipoxygenase, and PLA2 are
discussed as AA-dependent pathway proteins, whereas
NOS, NF-κB, PPAR, and NAG-1 are discussed as
AA-independent pathway proteins.
3.1 Arachidonic Acid-Dependent Pathway
3.1.1 COX Inhibition
Non-steroidal anti-inflammatory drugs act by inhi-
biting the formation of prostaglandins by prostaglan-
din H synthase (COX, also called cyclooxygenase),
which converts AA released by membrane phospholi-
pids into prostaglandins. Two isoforms of prostaglan-
din H synthase, COX-1 and COX-2, have been
identified, and one variant form (COX-3) has recently
410 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
also been reported.
COX-1 is constitutively expressed
in many tissues, while the expression of COX-2 is reg-
ulated by cytokines, mitogens, tumor promoters, and
growth factors. Non-steroidal anti-inflammatory drugs,
at low therapeutic doses, inhibit the activity of COX-1
and COX-2 and the subsequent formation of prosta-
glandins, mainly prostaglandin 2 (PGE2). However,
many NSAIDs cause serious gastrointestinal and car-
diovascular side effects; consequently, there has been a
need for new and safer anti-inflammatory agents.
Several compounds that are consumed daily in various
foods may provide alternative tools for treating inflam-
matory diseases by acting as COX inhibitors.
In 1980, Baumann et al.
were the first to report,
in a study that assessed rat medullar COX activity,
that some dietary polyphenols, such as galangin and
luteolin, inhibit AA peroxidation. Since then, research-
ers have reported that dietary polyphenols inhibit
COX activity at the transcriptional level as well as at
the enzyme level. The green tea catechin EGCG
displayed COX inhibition activity in LPS-induced
and the stilbene trans-resveratrol pos-
sessed anti-inflammatory activity because it sup-
pressed carragenen-induced pedal edema via the
inhibition of COX activity.
found that the flavones, chrysin, apigenein, and
phloretin depressed COX activity and inhibited plate-
let aggregation. The flavonoids 6-hydroxykaempferol
and quercetagenin, isolated from T. parthenium (fever-
few), and 6-hydroxyluteolin and scutellarein, isolated
from T. vulgaris (tansy), were all shown to inhibit COX
activity in leukocytes.
Although many studies have reported that polyphe-
nols inhibit COX-1 or COX-2, it has not yet been
reported that polyphenols inhibit COX-3.
3.1.2 Lipoxygenases Inhibition
Lipoxygenases (LOXs) are the enzymes responsible
for generating leukotrienes (LTs) from AA. There are
three distinct LOX isozymes in different cells and
tissues. 15-LOX synthesizes anti-inflammatory
15-hydroxyeicosa-tetraenoic acid (HETE), 5-LOX and
12-LOX are involved in provoking inflammatory/aller-
gic disorders; and 5-LOX produces 5-HETE and LTs,
which are potent chemoattractants and lead to the
development of asthma. 12-LOX synthesizes 12-HETE,
which aggregates platelets and induces the inflamma-
tory response. Therefore, the effect of polyphenols on
5- and 12-LOXs has been extensively studied in order
to elucidate the anti-inflammatory properties.
Flavonols, including kaempferol, quercetin, morin
and myricetin, were found to be 5-LOX inhibitors.
Hamamelitannin and the galloylated proanthocyani-
dins were found to be the most potent inhibitors of
5-LOX with the IC
values ranging from 1.0 to
Some prenylated flavonoids, such as artonin
E, are the most effective inhibitors of porcine eukocyte
There are few reports regarding 12-LOX inhi-
bition; kuwanson C and quercetin potently inhibit
12-LOX activity with IC
values of 19 and 12 μM,
respectively, using bovine PMNs (polymorphonuclear
neutrophil leukocytes) and 12-LOX from bovine plate-
In comparison, the IC
value of the known LOX
inhibitor nordihydroguaiaretic acid (NDGA) is 2.6 μM.
3.1.3 Phospholipase A2 Inhibition
Phospholipase A2 (PLA2), which cleaves phospholi-
pids producing lysophospholipids and free fatty acids,
was originally identified as an intracellular protein
involved in cell signaling and in the production of free
fatty acids, such as arachidonic acid. It is known that
PLA2 plays an important role in the inflammation pro-
The inhibition of PLA2 could be a potential tar-
get for lowering the production of AA and therefore
decreasing prostaglandin synthesis. Phospholipases
are mainly classified into three large groups: secretory
PLA2 (sPLA2), cytosolic PLA2 (cPLA2), and calcium-
independent PLA2 (iPLA2). It is now known that this
family is comprised of at least 10 members with dis-
tinct cellular distributions and growing therapeutic
potential. Specifically, sPLA2-V and sPLA2-X are selec-
tively expressed in the epithelium of the human air-
way. SPLA2-IIA (group II phospholipase A2) is low
but becomes highly expressed during inflammation
and sepsis as a result of LPS, cytokine, and NF-κB
induction. This enzyme is now associated with allergic
rhinitis, rheumatoid arthritis, and septic shock. Finally,
the selective expression of sPLA2-V and sPLA2-X sug-
gests that these enzymes should be evaluated as tar-
gets for airway dysfunction. Thus, the PLA2 family
represents a therapeutic target with ever-increasing
potential. It is likely that PLA2 is an important intra-
and extracellular mediator of inflammation. The mod-
ulation of sPLA2 and/or cPLA2 activity is important
in controlling the inflammatory process.
Quercetin was found to be an effective inhibitor of
PLA2 in rabbit
leukocytes. It was also
demonstrated that quercetin selectively inhibited
sPLA2-II, compared to its lower inhibition of sPLA2-
Quercetagetin, kaempferol-3-O-galactoside, and
scutellarein inhibited human recombinant synovial
PLA2 with IC
values ranging from 12.2 to 17.6 μM.
3.2 AA-Independent Pathway
3.2.1 Nitric Oxide Synthase
Nitric oxide (NO), a gaseous free radical, is released
by a family of enzymes, including endothelial NOS
(eNOS), neuronal NOS (nNOS) and inducible NOS
4113. POLYPHENOLS, THEIR MONOMERIC PRECURSORS AND INFLAMMATION
5. INFLAMMATION AND POLYPHENOLS
(iNOS), with the formation of stoichiometric amounts
of L-citrulline from L-arginine. Compounds able to
reduce NO production by iNOS may thus be attractive
as anti-inflammatory agents and, for this reason, the
effects of polyphenols on iNOS activity have been
intensively studied. Current results suggest that poly-
phenols inhibit NO release by suppressing NOS
enzymes expression and/or NOS activity.
3.2.2 Cytokine System
Cytokines are the major mediators of local, intercellu-
lar communications required for an integrated response
to a variety of stimuli in immune and inflammatory pro-
cesses. Numerous cytokines have been identified in tis-
sues across a range of immuno-mediated inflammatory
Also, a “balance” between the effects of pro-
inflammatory (e.g., IL-1β,IL-2,TNF-α, Il-6, IL-8 and IFN-
γ) and anti-inflammatory cytokines (e.g., IL-10, IL-4,
TGF-β) is thought to determine the outcome of disease,
whether in the short- or long-term. It has been observed
that several flavonoids are able to decrease the expression
of different pro-inflammatory cytokines/chemokines
such as TNF-α,IL-1β, IL-6, IL-8, MCP-1 in LPS-activated
mouse primary macrophages, PMA or phytohemaggluti-
nin (PHA) stimulated human peripheral blood mononu-
clear cells, activated human astrocytes, human synovial
cells, activated human mast cell line HMC-1, nasal muco-
sal fibroblasts and A549 bronchial epithelial cells.
fact, polyphenols, such as quercetin and catechins, cou-
pled their inhibitory action on TNF-αand IL-1βto the
enhancement of IL-10 release.
3.2.3 Peroxisome Proliferator Activated Receptors
The expression of many inflammatory cytokines is
regulated at the transcriptional level, which can either
enhance or inhibit the inflammation process.
Peroxisome proliferator-activated receptors (PPARs)
are nuclear hormone receptors that are activated by
specific endogenous and exogenous ligands.
isoforms (α,β/δ, and γ) have been identified, and are
encoded by separate genes. Among these, PPARαacti-
vation is responsible for the pleiotropic effects of per-
oxisome proliferators, such as enzyme induction,
peroxisome proliferation and amelioration of inflam-
mation. PPARαalso plays a critical role in the regula-
tion of cellular uptake and β-oxidation of fatty acids.
Furthermore, PPARδ(also known as PPARβ) is widely
expressed with relatively higher levels in the brain,
colon, and skin. Although there have been extensive
studies on PPARαand inflammation, very little is
known about the effect of PPARδon inflammation.
Few studies have regarded polyphenols as PPAR
ligands, but it is probable that polyphenols may also
affect PPAR protein expression, which results in the
activation of the PPAR pathway, as PPAR pathways
are closely connected to other inflammatory pathways
including NF-κB, COX-2 expression, and pro-
3.2.4 Nuclear Transcription Factor Kappa B
NF-κB is a ubiquitous factor that resides in the cyto-
plasm. When it becomes activated, it is translocated to
the nucleus, where it induces gene transcription. NF-
κB is activated by free radicals, inflammatory stimuli,
carcinogens, tumor promoters, endotoxins, γ-radiation,
ultraviolet (UV) light, and X-rays. Therefore, agents
that can suppress NF-κB activation have the potential
to suppress cytokine expression and, therefore,
decrease inflammatory response. Recent data suggest
that dietary polyphenols can work as modifiers of sig-
nal transduction pathways to elicit beneficial effects.
Polyphenols have been shown to exert their anti-
inflammatory activity by modulating NF-κB activation
and act on multiple steps of the activation process.
The influence of EGCG on NF-κB pathway has been
extensively studied demonstrating its inhibitory effects
on NF-κB obtained by counteracting the activation of
IKK and the degradation of IκBα.
in vivo study carried out on rats showed that EGCG
markedly attenuated the myocardial injury after ische-
mia and reperfusion.
4. ANTI-INFLAMMATORY ACTIVITY OF
4.1 Cinnamomum zeylanicum
C. zeylanicum polyphenol extract has been found to
affect immune responses by regulating anti- and pro-
inflammatory and GLUT gene expression in mouse
Another laboratory study found that
the water-soluble C. zeylanicum extract reverses TNF-
α-induced overproduction of intestinal apoB48 by
regulating gene expression involving inflammatory,
insulin, and lipoprotein signaling pathways,
cluded that the water-soluble extract improves inflam-
mation related intestinal dyslipidemia. Of interest is a
recent study that found that an aqueous extract of
C. zeylanicum inhibited tau aggregation and filament
formation, hallmarks of AD.
The anti-inflammatory effect of Cinnamomum zeyla-
nicum was also investigated using ethanol extract
obtained from bark. In vitro and in vivo experiments
were performed targeting TNF-αusing flow cytome-
try. Ethanol extract of C. zeylanicum showed suppres-
sion of intracellular release of TNF-αin murine
neutrophils as well as leukocytes in pleural fluid. The
extract was found to inhibit TNF-αgene expression in
412 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
LPS-stimulated human blood mononuclear cells
(PBMCs) at 20 μg/mL concentration.
4.2 Cinnamomum cassia
Cinnamomi Ramulus (CR), the young twig of C. cassia
and other Cinnamomum species, has been shown to
have anti-inflammatory properties.
CR reduced the
increased expression of iNOS and COX-2 caused by
lipopolysaccharide (LPS) stimulation in RAW264.7
cells, which are macrophages in the periphery. CR has
also exhibited anti-inflammatory activities that sup-
press the release of NO and PGE2.
more recent study suggested that the components of
CR inhibit inflammatory responses in the CNS in vitro
and in vivo.
A study conducted on mice with 70% ethanolic
extract of C. cassia bark gave promising results on
The extract inhibited the
increase in vascular permeability induced by acetic
acid. It inhibited the paw oedema induced by carra-
geen as well as seratonin, while it was ineffective
against bradykinin and histamine produced during
inflammation. Little effect was observed on secondary
lesions in the development of adjuvant-induced arthri-
tis. It is also useful in pulmonary inflammations.
Ninety-five percent ethanol extract of C. cassia
exerted strong anti-inflammatory activity by suppres-
sing Src and spleen tyrosine kinase-mediated NF-κB
4.3 Cinnamomum osmophloeum
The constituents of C. osmophloeum twigs sup-
pressed NO production by LPS-stimulated macro-
In the presence of 25 μg/mL essential oil, the
inhibition of NO production was 68.8%. The IC
was 11.2 μg/mL. Tung et al.
demonstrated that essen-
tial oil of C. osmophloeum twigs has excellent anti-
inflammatory activity in HepG2 (human hepatocellular
liver carcinoma) cells and Kirtikar and Basu and others
have also reported that cinnamon extract relieves
4.4 Cinnamomum insularimontanum
The NO inhibitory activity of fruit essential oil of C.
insularimontanum was evaluated by using a LPS-
stimulated RAW264.7 cell assay. The fruit’s essential
oil revealed the significant inhibitory effects on
NO production in LPS-stimulated RAW264.7 cells.
RAW264.7 cells treated with fruit essential oil at
dosages of 150 μg/mL caused a dose-dependent NO
inhibitory activity. The 50% effective concentration
) for essential oil was 18.68 μg/mL.
4.5 Cinnamomum camphora
C. camphora Sieb has long been prescribed in tradi-
tional medicine for the treatment of inflammation-
related diseases such as rheumatism, sprains,
bronchitis, and muscle pains. The inhibitory effects of
C. camphora were investigated on various inflammatory
phenomena to explore its potential anti-inflammatory
mechanisms under non-cytotoxic (less than 100 μg/mL)
The total crude extract (100 μg/mL) prepared with
80% methanol (MeOH extract) and its fractions
(100 μg/mL) obtained by solvent partition with hexane
and ethyl acetate (EtOAc) significantly blocked the
production of interleukin (IL)-1β, IL-6 and the tumor
necrosis factor (TNF)-αfrom RAW264.7 cells stimu-
lated by lipopolysaccharide (LPS) up to 2070%.
The hexane and EtOAc extracts (100 μg/mL) also
inhibited NO production in LPS/interferon (IFN)-
γ-activated macrophages by 65%.
The MeOH extract (100 μg/mL) as well as two frac-
tions (100 μg/mL) prepared by solvent partition with
n-butanol (BuOH) and EtOAc strongly suppressed
prostaglandin E2 (PGE2) production in LPS/IFN-
γ-activated macrophages up to 70%.
4.6 Cinnamomum massoiae
Twelve alcoholic extracts and twelve hexane extracts
of plant materials selected on the basis of medicinal
folklore for asthma treatment in Indonesia were stud-
ied for their activity in inhibiting histamine release
from RBL-2H3 cells (rat basophilic leukemia cell line),
a tumor analog of mast cells. The results of screening
indicated that alcoholic extract of C. massoiae cortex
inhibited IgE-dependent histamine release from RBL-
2H3 cells. The inhibitory effects were found to be more
than 80% for extract concentrations of 0.5 mg/mL.
That result indicates that the extracts contain active
compounds that inhibit mast-cell degranulation, and
provides insight into the development of new drugs
for treating asthma and/or allergic disease.
5. CINNAMON POLYPHENOLS AND
THEIR MONOMERIC PRECURSORS
5.1 Cinnamon Polyphenols
Proanthocyanidins (PA) are the major polyphenolic
component in commercial cinnamon, and are known
to occur widely in common foods such as apple skin,
4135. CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
broccoli, olives, onions, green and black tea, cinnamon,
parsley, grapefruit, oranges and their juices, dark choc-
olate, cocoa, and red wine.
Proanthocyanidins are mixtures of oligomers and
polymers composed of flavan-3-ol units, linked mainly
through C4C8 bonds; however, C4C6 bonds also
exist. The flavan-3-ol units can also be doubly linked
by an additional ether bond between C2 and O7 (e.g.,
cinnamtannin B1). Proanthocyanidins containing the
single interflavan linkage are known as B-type,
whereas those containing double interflavan linkages
are known as A-type (Figure 30.1). The size of the
proanthocyanidin molecule is determined by the
degree of polymerization (DP).
They are divided
into three major classes (procyanidins, propelargoni-
dins, and prodelphinidins) according to the type of
their monomeric precursors.
Cinnamomum zeylanicum bark contains dimeric, tri-
meric, and oligomeric proanthocyandins with doubly
linked bis-flavan-3-ol units (A-type procyanidins)
(Figure 30.2). Among the several cinnamon species,
only the bark of C. zeylanicum contained, as major phe-
nolic metabolites, a series of proanthocyanidins with
the doubly linked (A-type) unit, while the barks of C.
burmanni and C. cassia, and the root bark of C. camphora
consisted of linearly linked proanthocyanidins (B-
5.2 Monomeric Precursors
The cinnamon monomeric precursors are the pheno-
lic subunits that produce the condensed polyphenols.
The common monomeric precursors (flavan-3-ols) of
the cinnamon proanthocyanidins are afzelechin,
epiafzelechin, catechin, epicatechin, and their gallic
acid derivatives. The common flavan-3-ols in
proanthocyanidins are shown in Figure 30.3. The
proanthocyanidins that consist exclusively of (epi)cate-
chin are procyanidins. Proanthocyanidins containing
(epi)afzelechin or (epi)gallocatechin as subunits are
called propelargonidin or prodelphinidin, respectively.
Propelargonidin or prodelphinidin are mostly hetero-
geneous in their constituent units and co-exist with the
5.3 Other Cinnamon Phenolics
Anti-inflammatory cinnamon monophenolic com-
pounds include protocatechuic acid, urolignoside,
quercetin, rutin, kaempferol, isorhamnetin, cinnamald-
hyde, 2-hydroxycinnamaldehyde, and eugenol.
One laboratory study investigated the proximate
composition, minerals, amino acids, polyphenolic com-
pounds, and presence of some anti-nutritional factors
in Sri Lankan cinnamon (C. zeylanicum) and Chinese
cinnamon (C. cassia) barks. The results showed that the
tannins levels (0.652.18 %) were high in these two
bark samples, compared to other plant sources and
there were no significant differences observed in the
amounts of catechin and isorhamentin between the
two barks; whereas rutin, quercetin and kaempferol
were significantly higher in Sri Lankan cinnamon than
that in Chinese cinnamon (Table 30.1).
Water extracts of cinnamon fruits have been
reported to contain high levels of phenolics, i.e., proto-
catechuic acid, urolignoside, rutin, and quercetin-3-O-
C. verum is interesting in that it yields three types of
oils from the leaf, stem bark and root bark. The major
constituent in the leaf oil is eugenol, in the stem bark
oil it is cinnamaldehyde, while camphor is the major
constituent in the root bark oil. C. cassia produces only
one type of oil, usually called bark oil, obtained by dis-
tilling leaves and bark together. Almost 95% of the oil
consists of cinnamaldehyde.
C. osmophloeum twigs and leaf essential oils contains
trans-cinnamaldehyde and eugenol, which are reported
to possess excellent anti-inflammatory activities.
6. ANTI-INFLAMMATORY ACTIVITY OF
6.1.1 Proanthocyanidins and COX Inhibition
In vitro studies of prodelphinidins (the proanthocya-
nidins that consists of (epi)gallocatechin as subunits)
showed a decrease in the secretion of prostaglandin E2
(PGE2) from human chondrocytes as well as their
FIGURE 30.1 Structure of cinnamon polymeric polyphenols.
414 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
inhibition potential on COX-1 and COX-2 in vitro.
The synthesis of PGE2 was significantly reduced
by gallocatechin dimer (GCGC), gallocatechin-
epigallocatechin (GCEGC) and GCGCGC at
10 and 100 μg/mL. Moreover, these compounds inhib-
ited purified cyclooxygenase-1 (COX-1) and
GC showed a preferential
inhibition of COX-2 compared to COX-1 at 10
This selectivity was enhanced by a reduction of the
concentration tested (10
M). The same pattern was
observed with the dimer.
6.1.2 Proanthocyanidins and LOX-1 [Lectin-like
Oxidized LDL Receptor-1] Inhibition
Procyanidin is one of the components that inhibits
oxidized LDL (oxLDL) uptake since nearly half of the
OH OH OH
FIGURE 30.2 Cinnamon polyphenols.
A, procyanidin B; B, procyanidin A; C, cin-
namtannin B; D, procyanidin C; E, parameri-
tannin A; F, G, and H, A type
proanthocyanidin trimers; I, J, and K, procya-
nidine tetramers; L, M, and N, polymeric
4156. ANTI-INFLAMMATORY ACTIVITY OF CINNAMON POLYPHENOLS
5. INFLAMMATION AND POLYPHENOLS
potent hit extracts. Purified procyanidins inhibited
oxLDL binding in LOX-1-CHO (Chinese hamster
ovary) cells. Furthermore, oligomeric procyanidins
(OPC) suppressed lipid accumulation in the vascular
wall of stroke-prone spontaneously hypertensive rats
(SHR-SP) in which an anti-LOX-1 antibody was also
LOX-1-inhibiting properties were almost identical
among procyanidins $trimer and the dimer also potently
inhibited LOX-1. Moreover, four different isomers of tri-
mer procyanidins almost equally inhibited oxLDL bind-
ing to LOX-1. These results implicate that intake of
procyanidin-rich foods potentially inhibits LOX-1; regard-
less of food source since the polymerization levels of
procyanidins significantly differ among foods.
more than 400 foodstuff extracts derived from various
sources, more than half of those displaying potent LOX-1
inhibition are known to contain a large amount of
6.1.3 Proanthocyanidins, NOS and Cytokines
The anti-inflammatory effects of a grape seed extract
containing a rich amount of dimeric and oligomeric
procyanidins were demonstrated by the decreasing
NO and prostaglandin E2 levels, avoidance of translo-
cation of NF-κB p65 to the nucleus, and by the
downregulation of the expression of iNos and IκBαin
RAW264.7 macrophages (mouse leukemic monocyte
macrophage cell line) stimulated with LPS and
Proanthocyanidins isolated from Ribes nigrum leaves
interfered with the accumulation of circulating leuko-
cytes, associated with a reduction of pro-inflammatory
factors such as TNF-α, IL-1βand CINC-1, a decrease of
NOx level, and a decrease in plasma exudation.
In a recent study, it was shown that proanthocyani-
dines (PA) significantly suppressed the content of lipo-
peroxidation product malondialdehyde (MDA) in
carrageenan-induced inflamed paws of rats and
FIGURE 30.3 Structures of the flavan-3-ol monomers in proanthocyanidins.
TABLE 30.1 Polyphenol Content of Sri Lankan and Chinese
Cinnamon Barks (mg/100 g)
Sri Lankan Cinnamon Chinese Cinnamon
Rutin 0.896 60.028 0.672 60.057
Quercetin 0.550 60.095 0.172 60.019
Kaempferol 0.492 60.134 0.016 60.000
Isorhamentin 0.113 60.015 0.103 60.000
Catechin 2.30 60.049a 1.90 60.141
416 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
markedly lessened the activity of NOS and the content
of NO in exudates of carrageenan-induced paw edema
in rats. These results demonstrated that inhibition of
lipoperoxidation and NO formation was one of the
anti-inflammatory mechanisms of PA.
Pro-inflammatory cytokines TNF-α, IL-1βand IL-6
are sequentially released in the pleural exudates
induced by carrageenin in rats.
These cytokines cause
chemotaxis to attract granulocytes and monocytes and
then, migrating leukocytes produce, in turn, further
cytokines, such as TNF-αand IL-1β, and other pro-
inflammatory mediators. IL-6 has been proposed as a
crucial mediator for the development of carrageenin-
induced pleurisy and for the accumulation of leuko-
cytes in the inflammatory site. Indeed, in carrageenin-
induced pleurisy in IL-6 knock-out mice, the degree of
plasma exudation, leukocyte migration and the release
of TNF-αand IL-1βwere greatly reduced. Moreover, a
positive feedback plays an important part in the devel-
opment of the oedema as levels of TNF-αand IL-1β
are attenuated in IL-6 knock-out mice.
Inhibitory activity of proanthocyanidins isolated
from peanut skin tested on inflammatory cytokine pro-
duction and melanin synthesis in cultured cell lines
and administration of peanut skin extract (PSE,
200 μg/mL) decreased melanogenesis in cultured
human melanoma HMV-II co-stimulated with phorbol-
12-myristate-13-acetate. It also decreased production of
inflammatory cytokines (PSE at 100 μg/mL), tumor
necrosis factor-αand interleukin-6, in cultured human
monocytic THP-1 cells in response to lipopolysaccha-
ride. The isolated compounds from PSE also showed
anti-inflammatory activities. They showed suppressive
activities against melanogenesis and cytokine produc-
tion at concentrations ranging from 0.110 μg/mL.
Among the tested compounds, suppressive activities
of proanthocyanidin dimers or trimers in two assay
systems were stronger than those obtained with mono-
mer or tetramers. These data indicate that proantho-
cyanidin oligomers have the potential to reduce
dermatological conditions such as inflammation and
Recent studies have demonstrated that proanthocya-
nidins reduce the expression of soluble adhesion mole-
cules, intercellular adhesion molecule-1 (ICAM-1),
vascular cell adhesion molecule-1 (VCAM-1), and E-
selectin in the plasma of systemic sclerosis patients.
The same compounds have been shown to inhibit
TNF-α-induced VCAM-1 expression in human umbili-
cal vein endothelial cells cultures.
A possible mecha-
nism of the anti-inflammatory effect of PACs would be
an interference with the expression or the effect of
adhesion molecules. This interference would result in
a reduction of polymorphonuclear cell migration and
subsequently in a reduction of the release of pro-
inflammatory factors such as TNF-αand IL-1β.
FIGURE 30.4 Some phenolic compounds present in cinnamon.
4176. ANTI-INFLAMMATORY ACTIVITY OF CINNAMON POLYPHENOLS
5. INFLAMMATION AND POLYPHENOLS
7. ANTI-INFLAMMATORY ACTIVITY OF
7.1 (2)-Catechin,( 2)-Epicatechin and
Several foods of plant origin such as grapes, cocoa,
cinnamon and apples are rich in oligomeric procyani-
dins (OPCs) and the monomeric flavan-3-ols epicate-
chin and catechin.
There is substantial evidence that the anti-
inflammatory effects of catechins may be due, in part,
to their NO and peroxynitrite scavenging ability and
inhibition of NOS activity. However, catechins have
varying effects on the three different isoforms of NOS.
The neuronal NOS (nNOS) isoform produces toxic
effects through NO, and catechin inhibition of nNOS
may be a mechanism of anti-inflammatory activity.
Stevens et al.
showed that EGCG and oligomeric
proanthocyanidins (which are made up of esterified
catechins) inhibited nNOS activity in BL21 (DE3)
Escherichia coli cells. In addition, in mouse peritoneal
cells, nNOS activity was inhibited by EGCG after stim-
ulation with lipopolysaccharide (LPS) and interferon g
EGCG, an extensively studied, potent antioxidant,
has been shown to inhibit LPS-induced TNF-αproduc-
tion and to induce inducible NOS in mouse macro-
phages. Several studies have focused on the potential
anti-inflammatory and anticarcinogenic mechanisms of
EGCGs through the inhibition of activation of NF-κB
and thus impairment of the induction of inflammatory
cytokines and immune responses.
Catechins, especially epicatechin gallate (ECG),
almost completely blocked TNF-αinduced NF-κB
activity and consequently strongly diminished the
secretion of IL-8 and uPA following TNF-αtreatment.
Both IL-8 and uPA are proteins overexpressed in pan-
creatic cancer cells and linked to invasion, angiogene-
sis and metastasis.
(2)-Epiafzelechin is a COX inhibitor and it exhib-
ited a dose-dependent inhibition on the COX activity
with an IC
value of 15 μM. (2)-Epiafzelechin exhib-
ited about a 3-fold weaker inhibitory potency on the
enzyme activity than indomethacin as a positive con-
trol. (2)-Epiafzelechin exhibited significant anti-
inflammatory activity on carrageenin-induced mouse
paw edema when the compound (100 mg/kg) was
orally administrated 1 hour before carrageenin
8. ANTI-INFLAMMATORY ACTIVITY OF
OTHER CINNAMON PHENOLICS
Quercetin is an excellent scavenger of ROS and reac-
tive nitrogen species, and an excellent candidate for
reducing oxidative stress, i.e., an important contributor
to inflammation. Quercetin inhibits NF-κB activation,
thereby directly reducing the cytokine production via
this transcription factor.
Quercetin is able to downregulate the inflammatory
response of bone marrow-derived macrophages
in vitro. Quercetin also inhibits cytokine and inducible
NOS expression through the inhibition of the NF-κB
pathway both in vitro and in vivo.
Quercetin suppressed LPS-induced activation of
STAT-1 in macrophages suggesting that its effects on
STAT-1 are stimulus and cell-type independent.
Quercetin inhibited LPS-induced STAT-1 activation
and inhibited iNOS expression and NF-κB activation.
Quercetin also inhibited IFN-γ-induced signal trans-
ducer and activator of transcription 1 (STAT-1) activa-
tion in mouse BV-2 microglia.
8.2 Protocatechuic Acid
Protocatechuic acid (PCA) (3,4-dihydroxybenzoic
acid) was shown to inhibit low-density lipoprotein
(LDL) oxidation mediated by macrophage in an
in vitro cell model.
Min et al.
found that black rice
Cy-3-G as well as its metabolites, including PCA,
exerted anti-inflammatory effects in vitro as well as
PCA reduced monocyte adhesion and NF-κB activa-
tion in vitro, decreased VCAM-1 and ICAM-1 in vitro
and in vivo, and inhibited the formation of early ath-
erosclerotic lesions in the ApoE-deficient mouse
PCA treatment significantly lowered serum marker
enzymes and liver antioxidants of diabetic rats in
inflammatory conditions. Furthermore, it also reduced
plasma C-reactive proteins and von Willebrand factor
levels, interleukin-6, tumor necrosis factor-α, and
monocyte chemoattractant protein-1 levels in heart and
It was suggested that PCA was able to ame-
liorate complications in metabolic disorders through
its beneficial effects like triglyceride-lowering, anticoa-
gulatory, antioxidative and anti-inflammatory activi-
ties. PCA was shown to inhibit cyclooxygenase-2, NOS
(in vitro) in the expression of cyclo-oxygenase, myelo-
peroxidase, as well as nitrite and nitrate levels in CCl
induced hepatic damage.
activity of PCA against tert-butyl hydroperoxide
418 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
(t-BHP)-induced liver injury has been attributed to its
antioxidant and anti-inflammatory properties.
Tyrosinase-derived reactive quinone intermediate(s) of
PCA was shown to bind nucleophilic residues of pro-
teins and sulfhydryl group including oxygen radical-
Several recent studies
have, however, revealed that PCA is a major metabo-
lite of anthocyanins in humans.
tions have shown that anthocyanins reduce the
development of atherosclerosis in different atheroscle-
rotic animal models
and the risk of atherosclero-
sis in human studies.
In a recent human study, it
has been shown that after the consumption of antho-
cyanins, the maximal level of PCA in the blood
(approximately 492 nmol/L) is far higher than that of
anthocyanins themselves (approximately 1.9 nmol/
This made us hypothesize that anthocyanins
may exert their protective effects at least partially
through this important and major metabolite.
Rutin, quercetin-3-O-rhamnosylglucoside, is a natu-
ral flavone derivative. The anti-inflammatory activity
of rutin was investigated in vivo and in vitro. The IC
value of the rutin and other flavonols on NO produc-
tion inhibitory activity in LPS-activated mouse
is shown in Table 30.2. The
anti-inflammatory effect of rutin may be explained, at
least in part, by the inhibition of production of inflam-
matory mediators, which play an important role in
neutrophil recruitment and activation. Indeed, it has
been reported that rutin inhibited PLA2 activity, an
important enzyme in arachidonic acid cascade, from
human synovial fluid.
The anti-inflammatory activity of equimolar rutin
and quercetin was compared using the TNBS rat colitis
model. Rutin treatment resulted in amelioration of coli-
tic status, based on reductions in colonic damage score,
weight:length ratio, myeloperoxidase and alkaline
phosphatase activities. Quercetin gavages had no sub-
stantial effect on inflammation. Mechanistically, rutin
had a strong inhibitory effect on IL-2 secretion by con-
canavalin A-treated mesenteric node cells ex vivo.
Similarly, the colonic mRNA levels of IL-1β, TNF-α,
MCP-1 and especially IL-17 were generally lower in
rutin-treated animals. Preliminary results from the
genomic analysis applied to the rutin anti-
inflammatory effect indicate that B cell markers are
upregulated compared to the TNBS colitic group.
Neither oral rutin nor intraperitoneal quercetin had
any effect on splenocytes or mesenteric node cells in
It is well known that the early phase of
carrageenan-induced oedema is related to the produc-
tion of inflammatory mediators such as arachidonic
acid metabolites, while the delayed phase of inflamma-
tory response has been linked to neutrophil migration
and accumulation within the inflammatory site where
they release reactive oxygen species and proteolytic
The results showed that rutin exhibited a
significant (p,0.05) inhibitory effect on rat paw
oedema formation effectively.
Kaempferol, a phytoestrogen and a flavonoid, pro-
tects against various oxidative stresses and inflamma-
tory age-related chronic disorders.
of kaempferol and other flavonols on NO production
inhibitory activity in LPS-activated mouse peritoneal
is provided in Table 30.2.
Oxidative stress plays an important role in the path-
ogenesis of many diseases, including inflammatory
Kidney is especially vulnerable to oxida-
tive stress during aging, as shown by oxidant-induced
nephritis, vasculitis, toxic nephropathies, pyelonephri-
tis, and acute renal failure.
These diseases are
likely to be mediated in part by age-related oxidative
insults due to redox imbalance.
The anti-inflammatory effects of kaempferol on NF-
κB activity and its related gene expressions in the
presence of oxidative stress in aged kidney were eluci-
dated. The data show that treatment with kaempferol
inhibited accumulated oxidative stress and restored
the GSH/GSSG ratio. In aged rats, kaempferol modu-
lated redox status and exerted potent antioxidative
capacity. The results from western blot, EMSA, and
the reporter assay demonstrated that kaempferol inhib-
ited proteolytic degradation of IκB, binding of the
p50/p65 heterodimer, and NF-κB-dependent gene
expressions in aged rat kidney.
Kaempferol significantly suppressed the NIK/IKK
and MAPK pathways that lead to NF-κB activation in
aged kidney tissues. This study documented that
kaempferol restored redox imbalance through its
TABLE 30.2 Effects of Flavonols on Nitric Oxide Production in
LPS-activated Mouse Peritoneal Macrophages
Rutin .100 (1)*
Isoquercitrin .100 (3)*
*Value in parentheses represents the inhibition (%) at 100 µM.
4198. ANTI-INFLAMMATORY ACTIVITY OF OTHER CINNAMON PHENOLICS
5. INFLAMMATION AND POLYPHENOLS
efficient RS scavenging capacity and modulated pro-
inflammatory NF-κB activation via the NIK/IKK and
MAPK pathways in aging. These studies demonstrated
that kaempferol as an efficient anti-inflammatory com-
pound with the ability to attenuate oxidative stress-
induced inflammation in aged rat kidney.
tin) is an abundant flavonoid found in many dietary
Isorhamnetin inhibits NO production and
iNOS protein and mRNA expression; it also reduces
iNOS expression, and that effect may well be mediated
by inhibition of NF-κB activation.
isorhamnetin and other flavonols on NO production
inhibitory activity in LPS-activated mouse peritoneal
is provided in Table 30.2.
Cinnamaldehyde suppressed NF-B activation within
macrophage-like RAW264.7 cells.
It has been dem-
onstrated that CA is capable of blocking inducible
nitric oxide synthase (iNOS) and NO production by
mediation of NF-B activation blockade in LPS-
stimulated RAW264.7 cells.
lated from the leaves of C. osmophloeum, was reported
to inhibit the secretion of IL-1βand TNF-αwithin LPS
or lipoteichoic acid (LTA) stimulated murine J774A.1
macrophages. Cinnamaldehyde also suppressed the
production of these cytokines from LPS-stimulated
human blood monocytes derived primary macro-
phages and human THP-1 monocytes.
ings demonstrated the anti-inflammatory (Table 30.3)
potential of cinnamaldehyde.
8.7 20-Hydroxycinnamaldehyde (HCA) and 20-
20-Hydroxycinnamaldehyde (HCA) from the stem
bark of C. cassia and its derivative 20-benzoyloxycinna-
maldehyde (BCA) were reported to show anti-
in RAW264.7 macrophage
A potential anti-inflammatory effect of HCA/BCA
was assessed in LPS-stimulated microglial cultures
and microglia/neuroblastoma co-cultures. HCA/BCA
significantly decreased the production of NO and
TNF-αin microglial cells. HCA/BCA also attenuated
the expression of iNOS and pro-inflammatory cyto-
kines such as interleukin-1β(IL-1β) and TNF-αat
mRNA level via blockade of ERK, JNK, p38 MAPK,
and NF-κB activation. Moreover, HCA/BCA was
neuroprotective by reducing microglia-mediated neu-
roblastoma cell death in a microglia-neuroblastoma co-
culture. Affinity chromatography and LC-MS/MS
analysis identified low-density lipoprotein receptor-
related protein 1 (LRP1) as a potential molecular target
of HCA in microglial cells. Studies using the receptor-
associated protein (RAP) that blocks a ligand binding
to LRP1 and the siRNA-mediated LRP1 gene silencing,
showed that HCA inhibited LPS-induced microglial
activation via LRP1 suggesting that HCA/BCA is anti-
inflammatory and neuroprotective in the CNS by
targeting LRP1, and may have a therapeutic potential
against neuroinflammatory diseases.
8.8 Eugenol (4-Allyl-2-Methoxyphenol)
Eugenol is a major component of cinnamon leaves
and has been reported to show potent antioxidant and
and it effectively
improved functional and structural pulmonary
changes induced by LPS, modulating lung inflamma-
tion and remodeling in an in vivo model of acute lung
injury (ALI), through a mechanism involving inhibi-
tion of TNF-αrelease and NF-κB activation. This may
lead to potential new therapies for ALI as well as other
chronic lung inflammatory diseases.
Effect of eugenol on the production of NO by
RAW264.7 macrophages showed anti-inflammatory
effect; both eugenol and isoeugenol inhibited LPS-
dependent production of NO, through the inhibition of
protein synthesis of iNOS. Isoeugenol was shown to be
the more effective than eugenol (Table 39.3) by inhibit-
ing LPS-dependent expression of cyclooxygenase-2
Dietary polyphenols comprise a vast array of biolog-
ically active compounds that are ubiquitous in plants,
many of which have been used in traditional Oriental
medicine for thousands of years. In this review, we
summarized the current findings of the molecular
TABLE 30.3 Effects of Cinnamaldehyde and 2-hydroxycinnamalde-
hyde on NO Production Inhibitory Activity in LPS-activated
420 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
targets of cinnamon polyphenols, their monomeric pre-
cursors and other phenolics as anti-inflammatory com-
pounds. Better knowledge of the consumption and
bioavailability of dietary polyphenols will be essential
in the future to properly evaluate their role in the pre-
vention of diseases. After the consumption of a given
source of polyphenols or of a given diet, we should be
able to evaluate the contribution to the prevention of
oxidative stress with regard to other dietary antioxi-
dants. We should also be able to predict the tissue
levels of specific metabolites that may bind to specific
receptors and trigger the responses beneficial for our
health, and this should lead to some dietary recom-
mendations that are optimized for particular popula-
tion groups and to the design of new food products
that will satisfy future needs.
Moreover, there is great potential for dietary poly-
phenols to become the next generation of dietary fac-
tors to confer health effects for inflammation beyond
synthetic drugs. Further, dietary polyphenols may pro-
vide an excellent model system for the development of
more effective drugs in the future.
1. Rainsford KD. Profile and mechanisms of gastrointestinal and
other side effects of nonsteroidal anti-inflammatory drugs
(NSAIDs). Am J Med 1999;107(6A):27S35S.
2. Ji H-F, Li X-J, Zhang H-Y. Natural products and drug discovery.
Can thousands of years of ancient medical knowledge lead us to
new and powerful drug combinations in the fight against cancer
and dementia? EMBO Rep 2009;10(3):194200.
3. Huang S-S, Chiu C-S, Chen H-J, Hou W-C, Sheu M-J, Lin Y-C, et
al. Antinociceptive activities and the mechanisms of anti-
inflammation of asiatic acid in mice. Evid Based Compl Alternat
4. Yoon J-H, Baek SJ. Molecular targets of dietary polyphenols
with anti-inflammatory properties. Yonsei Med J 2005;46
5. Liao J-C, Deng J-S, Chiu C-S, Hou W-C, Huang S-S, Shie P-H, et al.
Anti-inflammatory activities of Cinnamomum cassia constituents
in vitro and in vivo.Evid Based Compl Alternat Med
6. Chang C-T, Huang G-J, Huang S-S, Lin S-S, Amagaya S, Ho H-y,
et al. Anti-inflammatory activities of tormentic acid from suspen-
sion cells of Eriobotrya japonica ex vivo and in vivo.Food Chem
7. Braun L. Cinnamon. J Compl Med 2006;5(5):678.
8. Schneider M. Cinnamon. Quadrant 2003;47:78.
9. Ravindran PN, Nirmal Babu K, Shylaja M. Cinnamon and Cassia:
the Genus Cinnamomum. Boca Raton: CRC Press; 2004. p. 384
10. Waxman S. The healing power of herbs. Good Housekeeping
11. Winston JC. New status for an ancient spice: Cinnamon. Vibrant
12. Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoestro-
gens in obesity and diabetes. Am J Clin Nutr 2002;76(6):1191201.
13. Vera T. Cinnamon protects against diabetes. Better Nutrition
14. Qin Y, Xia M, Ma J, Hao Y, Liu J, Mou H, et al. Anthocyanin
supplementation improves serum LDL- and HDL-cholesterol
concentrations associated with the inhibition of cholesteryl ester
transfer protein in dyslipidemic subjects. Am J Clin Nutr 2009;90
15. Dr. Peter G. Cinnamon lowers reader’s cholesterol. The Times
Transcript 2006;Sect. E.2.
16. Tsuji-Naito K. Aldehydic components of cinnamon bark extract
suppresses RANKL-induced osteoclastogenesis through NFATc1
downregulation. Bioorg Med Chem 2008;16(20):917683.
17. Farahpour MR, Habibi M. Evaluation of the wound healing
activity of an ethanolic extract of ceylon cinnamon in mice.
Veterinarni Medicina 2012;57(1):537.
18. Pieroni A, Torry B. Does the taste matter? Taste and medicinal
perceptions associated with five selected herbal drugs among
three ethnic groups in West Yorkshire, Northern England. J
Ethnobiol Ethnomed 2007;3(1):21.
19. Lv J, Huang H, Yu L, Yu LL, Whent M, Niu Y, et al. Phenolic
composition and nutraceutical properties of organic and conven-
tional cinnamon and peppermint. Food Chem 2012;132
20. Lee R, Balick MJ. Sweet wood—cinnamon and its importance as
a spice and medicine. Explore NY 2005;1(1):614.
21. Quideau S, Deffieux D, Douat-Casassus C, Pouyse
´gu L. Plant
polyphenols: chemical properties, biological activities, and syn-
thesis. Angew Chem Int Ed Engl 2011;50(3):586621.
22. Bravo L. Polyphenols: chemistry, dietary sources, metabolism,
and nutritional significance. Nutr Rev 1998;56(11):31733.
23. Panickar KS, Anderson RA. Effect of polyphenols on oxidative
stress and mitochondrial dysfunction in neuronal death and
brain edema in cerebral ischemia. Int J Mol Sci 2011;12
24. Pan MH, Lai CS, Ho CT. Anti-inflammatory activity of natural
dietary flavonoids. Food Funct 2010;1(1):1531.
25. Singh M, Arseneault M, Sanderson T, Murthy V, Ramassamy C.
Challenges for research on polyphenols from foods in
Alzheimer’s disease: bioavailability, metabolism, and cellular
and molecular mechanisms. J Agric Food Chem 2008;56
26. Santangelo C, Varı
`R, Scazzocchio B, Di Benedetto R, Filesi C,
Masella R. Polyphenols, intracellular signalling and inflamma-
tion. Ann Ist Sup Sanita
27. Kim J-H, Yamaguchi K, Lee S-H, Tithof PK, Sayler GS, Yoon J-H,
et al. Evaluation of polycyclic aromatic hydrocarbons in the acti-
vation of early growth response-1 and peroxisome proliferator
activated receptors. Toxicol Sci 2005;85(1):58593.
28. Joan C. Cyclooxygenase-2 biology. Curr Pharm Des 2003;9
29. Baumann J, von Bruchhausen F, Wurm G. Flavonoids and
related compounds as inhibition of arachidonic acid peroxida-
tion. Prostaglandins 1980;20(4):62739.
30. Gerhauser C, Klimo K, Heiss E, Neumann I, Gamal-Eldeen A,
Knauft J, et al. Mechanism-based in vitro screening of potential
cancer chemopreventive agents. Mutat Res 2003;523:16372.
31. Jang M, Pezzuto JM. Cancer chemopreventive activity of resver-
atrol. Drugs Exp Clin Res 1999;25(23):6577.
32. Landolfi R, Mower RL, Steiner M. Modification of platelet func-
tion and arachidonic acid metabolism by bioflavonoids.
Structure-activity relations. Biochem Pharmacol 1984;33
33. Williams CA, Harborne JB, Geiger H, Hoult JR. The flavonoids
of Tanacetum parthenium and T. vulgare and their anti-
inflammatory properties. Phytochemistry 1999;51(3):41723.
34. Yamamoto K, Arakawa T, Taketani Y, Takahashi Y, Hayashi Y,
Ueda N, et al. TNF alpha-dependent induction of
5. INFLAMMATION AND POLYPHENOLS
cyclooxygenase-2 mediated by NF-κB and NF-IL6. Adv Exp Med
´a-Lafuente A, Guillamo
´n E, Villares A, Rostagno MA,
´nez JA. Flavonoids as anti-inflammatory agents: implications
in cancer and cardiovascular disease. Inflamm Res 2009;58(9):53752.
36. Laughton MJ, Evans PJ, Moroney MA, Hoult JRS, Halliwell B.
Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by
flavonoids and phenolic dietary additives. Biochem Pharmacol
37. Hartisch C, Kolodziej H, vonBruchhausen F. Dual inhibitory
activities of tannins from Hamamelis virginiana and related poly-
phenols on 5-lipoxygenase and Lyso-PAF:acetyl-CoA acetyl-
transferase. Planta Med 1997;63(2):10610.
38. Reddy GR, Ueda N, Hada T, Sackeyfio AC, Yamamoto S, Hano
Y, et al. A prenylflavone, artonin E, as arachidonate 5-
lipoxygenase inhibitor. Biochem Pharmacol 1991;41(1):1158.
39. Chi YS, Jong HG, Son KH, Chang HW, Kang SS, Kim HP.
Effects of naturally occurring prenylated flavonoids on enzymes
metabolizing arachidonic acid: cyclooxygenases and lipoxy-
genases. Biochem Pharmacol 2001;62(9):118591.
40. Lindahl M, Tagesson C. Flavonoids as phospholipase A
tors: importance of their structure for selective inhibition of
group II phospholipase A
41. Lanni C, Becker EL. Inhibition of neutrophil phospholipase A
by p-bromophenylacyl bromide, nordihydroguaiaretic acid,
5,8,11,14-eicosatetraynoic acid and quercetin. Int Arch Allergy
Appl Immunol 1985;76(3):2147.
42. Lee TP, Matteliano ML, Middleton JE. Effect of quercetin on
human polymorphonuclear leukocyte lysosomal enzyme release
and phospholipid metabolism. Life Sci 1982;31(24):276574.
43. Lindahl M, Tagesson C. Selective inhibition of group II phospho-
by quercetin. Inflammation 1993;17(5):57382.
44. Gil B, Sanz MJ, Terencio MC, Ferra
´ndiz ML, Bustos G, Paya
et al. Effects of flavonoids on Naja naja and human recombinant
synovial phospholipases A
and inflammatory responses in
mice. Life Sci 1994;54(20):PL333338.
´I. Biochemical aspects of
nitric oxide synthase feedback regulation by nitric oxide.
Interdiscip Toxicol 2011;4(2):638.
46. Hiscott J, Ware C. Cytokines. Curr Opin Immunol 2011;23(5):5613.
47. Comalada M, Ballester I, Bailo
´n E, Sierra S, Xaus J, Ga
´lvez J, et
al. Inhibition of pro-inflammatory markers in primary bone
marrow-derived mouse macrophages by naturally occurring fla-
vonoids: analysis of the structure-activity relationship. Biochem
48. Crouvezier S, Powell B, Keir D, Yaqoob P. The effects of pheno-
lic components of tea on the production of pro- and anti-
inflammatory cytokines by human leukocytes in vitro.Cytokine
49. Bishop-Bailey D, Bystrom J. Emerging roles of peroxisome
proliferator-activated receptor-beta/delta in inflammation.
Pharmacol Ther 2009;124(2):14150.
50. Wheeler DS, Catravas JD, Odoms K, Denenberg A, Malhotra V,
Wong HR. Epigallocatechin-3-gallate, a green tea-derived polyphe-
nol, inhibits IL-1β-dependent proinflammatory signal transduction
in cultured respiratory epithelial cells. J Nutr 2004;134(5):103944.
51. Aneja R, Hake PW, Burroughs TJ, Denenberg AG, Wong HR,
Zingarelli B. Epigallocatechin, a green tea polyphenol, attenuates
myocardial ischemia reperfusion injury in rats. Mol Med 2004;10
52. Gu L, Kelm MA, Hammerstone JF, Beecher G, Holden J,
Haytowitz D, et al. Concentrations of proanthocyanidins in com-
mon foods and estimations of normal consumption. JNutr
53. Gu L, Kelm MA, Hammerstone JF, Zhang Z, Beecher G, Holden
J, et al. Liquid chromatographic/electrospray ionization mass
spectrometric studies of proanthocyanidins in foods. J Mass
54. Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of sur-
vival, proliferation, invasion, angiogenesis, and metastasis of
tumor cells through modulation of inflammatory pathways by
nutraceuticals. Cancer Metastasis Rev 2010;29(3):40534.
55. Hall MA, Maurer AJ. Spice extracts, lauricidin and propylene-
glycol as inhibitors of Clostridium botulinum in turkey frankfurter
slurries. Poultry Sci 1986;65(6):116771.
¨inen M, Nieminen R, Vuorela P, Heinonen M, Moilanen
E. Anti-inflammatory effects of flavonoids: genistein, kaempfer-
ol, quercetin, and daidzein inhibit STAT-1 and NF-κB activa-
tions, whereas flavone, isorhamnetin, naringenin, and
pelargonidin inhibit only NF-κB activation along with their
inhibitory effect on iNOS expression and NO production in acti-
vated macrophages. Mediators Inflamm 2007;2007:45673.
57. Han X, Shen T, Lou H. Dietary polyphenols and their biological
significance. Int J Mol Sci 2007;8(9):95088.
58. Cao H, Urban JJF, Anderson RA. Cinnamon polyphenol extract
affects immune responses by regulating anti- and proinflamma-
tory and glucose transporter gene expression in mouse macro-
phages. J Nutr 2008;138(5):83340.
59. Qin B, Dawson H, Polansky MM, Anderson RA. Cinnamon
extract attenuates TNF-α-induced intestinal lipoprotein ApoB48
overproduction by regulating inflammatory, insulin, and lipo-
protein pathways in enterocytes. Horm Metab Res 2009;41
60. Peterson DW, George RC, Scaramozzino F, LaPointe NE,
Anderson RA, Graves DJ, et al. Cinnamon extract inhibits tau
aggregation associated with Alzheimer’s disease in vitro.J
Alzheimers Dis 2009;17(3):58597.
61. Joshi K, Awte S, Bhatnaga P, Walunj S, Gupta R, Joshi S, et al.
Cinnamomum zeylanicum extract inhibits proinflammatory cyto-
kine TNFμ:in vitro and in vivo studies. Res Pharmac Biotechnol
62. Hwang S-H, Choi YG, Jeong M-Y, Hong Y-M, Lee J-H, Lim S.
Microarray analysis of gene expression profile by treatment of
Cinnamomi Ramulus in lipopolysaccharide-stimulated BV-2 cells.
63. Park HJ, Lee JS, Lee JD, Kim NJ, Pyo JH, Kang JM, et al. The
anti-inflammatory effect of Cinnamomi Ramulus.J Korean Oriental
64. Pyo JH. Effects of Cinnamomi Ramulus major component trans-
cinnamaldehyde on 6-hydroxydopamine-induced dopaminergic
dysfunction in mice. 2008.
65. Kubo M, Ma S, Wu J, Matsuda H. Antiinflammatory activities of
70% methanolic extract from Cinnamomi cortex. Biol Pharm Bull
66. Yu T, Lee S, Yang WS, Jang H-J, Lee YJ, Kim TW, et al. The abil-
ity of an ethanol extract of Cinnamomum cassia to inhibit Src and
spleen tyrosine kinase activity contributes to its anti-
inflammatory action. J Ethnopharmacol 2012;139(2):56673.
67. Tung Y-T, Chua M-T, Wang S-Y, Chang S-T. Anti-inflammation
activities of essential oil and its constituents from indigenous
cinnamon (Cinnamomum osmophloeum) twigs. Bio Res Technol
68. Kirtikar KR, Basu BD. editors. Indian Medicinal Plants, III. 3rd ed.
Ms Bishen Singh, Mahendra Pal Singh; 18491917.
69. Chopra RN, Nayar SL, Chopra IC, Asolkar LV, Kakkar KK,
Chakre OJ, et al. Glossary of Indian medicinal plants; with supple-
ment. New Delhi: Council of Scientific & Industrial Research;
422 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
70. Lin T-Y, Lin C-T, Chen C-J, Tung JC, Wang S-Y. Anti-
inflammation activity of fruit essential oil from Cinnamomum
insularimontanum Hayata. Bioresour Technol 2008;99(18):87837.
71. Lee HJ, Hyun E-A, Yoon WJ, Kim BH, Rhee MH, Kang HK, et
al. In vitro anti-inflammatory and anti-oxidative effects of
Cinnamomum camphora extracts. J Ethnopharmacol 2006;103
72. Ikawati Z, Wahyuono S, Maeyama K. Screening of several
Indonesian medicinal plants for their inhibitory effect on hista-
mine release from RBL-2H3 cells. J Ethnopharmacol 2001;75
73. Baumann LS. Polyphenols. Skin Allergy News 2010;41(1):14.
74. Jayaprakasha GK, Ohnishi-Kameyama M, Ono H, Yoshida M,
Jaganmohan Rao L. Phenolic constituents in the fruits of
Cinnamomum zeylanicum and their antioxidant activity. J Agric
Food Chem 2006;54(5):16729.
75. Gen-ichiro Nonaka, Satoshi Morimoto, Itsuo Nishioka. Tannins
and related compounds. Part 13. Isolation and structures of tri-
meric, tetrameric, and pentameric proanthocyanidins from cin-
namon. J Chem Soc Perkin Trans 1983;B:213945.
76. Li wen-Guang Z-Y, Wu Yong-Jie, Tian Xuan. Anti-
inflammatory effect and mechanism of proanthocyanidins from
grape seeds. Acta Phamacol Sin 2001;22(12):111720.
77. Khalid S, Al-Numair, Dilshad A, SaifEldein B, Ahmed, Al-
Assaf AH. Nutritive value, levels of polyphenols and anti-
nutritional factors in Sri Lankan cinnamon (Cinnamomum
zeyalnicum) and Chinese cinnamon (Cinnamomum cassia).
Research Bulletin, Food Sci Agric Res Center, King Saud
78. Jayaprakasha GK, Rao LJ, Sakariah KK. Chemical composition
of the volatile oil from the fruits of Cinnamomum zeylanicum
Blume. Flav Frag J 1997;12(5):3313.
79. Taylor KJ, Anderson R, Graves D. A hydroxychalcone derived
from cinnamon functions as a mimetic for insulin in 3T3L1
Adipocytes. J Am Coll Nutr 2001;20:32736.
80. Senanayake UM. The nature, description and biosynthesis of vola-
tiles of Cinnamomum Spp. PhD Thesis, University of New
South Wales, Australia; 1977.
81. Ravindran PN, Nirmal-Babu K, Shylaja M. Cinnamon and Cassia:
The Genus Cinnamomum. London: CRC Press; 2003.
82. Garbacki N, Angenot L, Bassleer C, Damas J, Tits M. Effects of
prodelphinidins isolated from Ribes nigrum on chondrocyte
metabolism and COX activity. Naunyn-Schmiedebergs Arch
83. Nakano A, Matsuda H, Sawamura T, Inoue N, Sato Y, Nishimichi
N, et al. LOX-1 mediates vascular lipid retention under hyperten-
sive state. J Hypertens 2010;28(6):1273.
84. Nishizuka T, Fujita Y, Sato Y, Nakano A, Kakino A, Ohshima S,
et al. Procyanidins are potent inhibitors of LOX-1: a new player
in the French paradox. Proc Japan Acad Series B, Physical and
Biological Sciences 2011;87(3):10413.
`s V, Calay D, Cedo
´A, Raes M, Pinent M,
et al. Additive, antagonistic, and synergistic effects of procyani-
dins and polyunsaturated fatty acids over inflammation in
RAW 264.7 macrophages activated by lipopolysaccharide.
86. Garbacki N, Tits M, Angenot L, Damas J. Inhibitory effects of
proanthocyanidins from Ribes nigrum leaves on carrageenin acute
inflammatory reactions induced in rats. BMC Pharm 2004;4(1):25.
87. Utsunomiya I, Nagai S, Oh-ishi S. Sequential appearance of IL-
1 and IL-6 activities in rat carrageenin-induced pleurisy. J
88. Cuzzocrea SSL, De Sarro G, Costantino G, Rombo
Mazzon E, Ialenti A, et al. Role of IL-6 in the pleurisy and
lung injury caused by carrageenin. Immunol
89. Tatsuno T, Jinno M, Arima Y, Kawabata T, Hasegawa T,
Yahagi N, et al. Anti-inflammatory and anti-melanogenic
proanthocyanidin oligomers from peanut skin. Biol Pharma Bull
90. Garbacki N, Kinet M, Nusgens B, Desmecht D, Damas J.
Proanthocyanidins, from Ribes nigrum leaves, reduce endothe-
lial adhesion molecules ICAM-1 and VCAM-1. J Inflam (London,
91. Sen CK, Bagchi D. Regulation of inducible adhesion molecule
expression in human endothelial cells by grape seed proantho-
cyanidin extract. Mol Cell Biochem 2001;216(1):17.
92. Stevens JF, Miranda CL, Wolthers KR, Schimerlik M, Deinzer
ML, Buhler DR. Identification and in vitro biological activities
of hop proanthocyanidins: inhibition of nNOS activity and
scavenging of reactive nitrogen species. J Agric Food Chem
93. Sutherland BA, Rahman RMA, Appleton I. Mechanisms of
action of green tea catechins, with a focus on ischemia-induced
neurodegeneration. J Nutr Biochem 2006;17(5):291306.
94. Hong Byun E, Fujimura Y, Yamada K, Tachibana H. TLR4 sig-
naling inhibitory pathway induced by green tea polyphenol
epigallocatechin-3-gallate through 67-kDa laminin receptor. J
95. Li J, Ye L, Wang X, Liu J, Wang Y, Zhou Y, et al.
(2)-Epigallocatechin gallate inhibits endotoxin-induced
expression of inflammatory cytokines in human cerebral
microvascular endothelial cells. Neuroinflammation 2012;
¨rbitz C, Heise D, Redmer T, Goumas F, Arlt A, Lemke J, et
al. Epicatechin gallate and catechin gallate are superior to epi-
gallocatechin gallate in growth suppression and anti-
inflammatory activities in pancreatic tumor cells. Cancer Sci
97. Trauzold A, Pagerols-Raluy L, Siebert R, Wajant H, Kalthoff H,
¨der C, et al. CD95 and TRAF2 promote invasiveness of pan-
creatic cancer cells. FASEB J 2005;19(6):620.
98. Salvi A, Arici B, De Petro G, Barlati S. Small interfering RNA
urokinase silencing inhibits invasion and migration of human
hepatocellular carcinoma cells. Mol Cancer Ther 2004;3:6718.
99. Li A, Varney ML, Singh RK. Expression of interleukin 8 and its
receptors inhuman colon carcinoma cells with different meta-
static potentials. Clin Cancer Res 2001;7:3298304.
100. Wang W, Abbruzzese JL, Evans DB, Chiao PJ. Overexpression
of urokinasetype plasminogen activator in pancreatic adenocar-
cinoma is regulated by constitutively activated RelA. Oncogene
101. Min KR, Kim Y, Hwang BY, Lim HS, Kang BS, Oh GJ, et al.
(2)-Epiafzelechin: Cyclooxygenase-1 inhibitor and anti-
inflammatory agent from aerial parts of Celastrus orbiculatus.
Planta Medica 1999;65(5):4602.
102. Boots AW, Wilms LC, Swennen EL, Kleinjans JC, Bast A,
Haenen GR. In vitro and ex vivo anti-inflammatory activity of
quercetin in healthy volunteers. Nutrition 2008;24
103. Fischer K-D, Tedford K, Wirth T. New roles for Bcl10 in B-cell
development and LPS response. Trends Immunol 2004;25
104. De Groote D, Dehart I, Zangerle PF, Gevaert Y, Fassotte MF,
Beguin Y, et al. Direct stimulation of cytokines (IL-1β, TNF-α,
IL-6, IL-2, IFN- γand GM-CSF) in whole blood. I.
Comparison with isolated PBMC stimulation. Cytokine 1992;4
5. INFLAMMATION AND POLYPHENOLS
105. Swennen ELR, Bast A, Dagnelie PC. Immunoregulatory effects
of adenosine 50-triphosphate on cytokine release from stimu-
lated whole blood. Eur J Immunol 2005;35(3):8528.
106. Thorn J. The inflammatory response in humans after inhalation
of bacterial endotoxin: a review. Inflam Res 2001;50(5):25461.
107. Wilms LC, Hollman PC, Boots AW, Kleinjans JC. Protection by
quercetin and quercetin-rich fruit juice against induction of oxi-
dative DNA damage and formation of BPDE-DNA adducts in
human lymphocytes. Mutat Res 2005;582:15562.
108. Galvez J, De La Cruz JP, Zarzuelo A, De Medina FS, Jimenez J,
De La Cuesta FS. Oral administration of quercitrin modifies
intestinal oxidative status in rats. Gen Pharmacol 1994;25
109. Grisham MB, Pavlick KP, Laroux FS, Hofeman J, Bharwani S,
Wolf RE. Nitric oxide and chronic gut inflammation: controver-
sies in inflammatory bowel disease. J Investig Med
110. Middleton E, Kandaswami C, Theoharides TC. The effects of
plant flavonoids on mammalian cells: implications for inflam-
mation, heart disease, and cancer. Pharmacol Rev.
111. Masella R, Varı
`R, D’Archivio M, Di Benedetto R, Matarrese P,
Malorni W, et al. Extra virgin olive oil biophenols inhibit cell-
mediated oxidation of LDL by increasing the mRNA transcrip-
tion of glutathione-related enzymes. J Nutr 2004;134(4):785.
112. Min SW, Ryu SN, Kim DH. Anti-inflammatory effects of black
rice, cyanidin-3-O-β-D-glycoside, and its metabolites, cyanidin
and protocatechuic acid. Int Immunopharmacol 2010;10
113. Wang D, Wei X, Yan X, Jin T, Ling W. Protocatechuic acid, a
metabolite of anthocyanins, inhibits monocyte adhesion and
reduces atherosclerosis in apolipoprotein E-deficient mice. J
Agric Food Chem 2010;58(24):12722.
114. Lin CY, Huang CS, Huang CY, Yin MC. Anticoagulatory, anti-
inflammatory and antioxidative effects of protocatechuic acid
in diabetic mice. J Agric Food Chem 2009;57(15):66617.
115. Lende AB, Kshirsagar AD, Deshpande AD, Muley MM, Patil
RR, Bafna PA, et al. Anti-inflammatory and analgesic activity
of protocatechuic acid in rats and mice. Inflammopharmacology
116. Hsu CC, Hsu CL, Tsai SE, Fu TY, Yen GC. Protective effect
of Millettia reticulata Benth against CCl
damage and inflammatory action in rats. J Med Food 2009;12
117. Liu CL, Wang JM, Chu CY, Cheng MT, Tseng TH. In vivo pro-
tective effect of protocatechuic acid on tert-butyl hydroperoxide
induced rat hepatotoxicity. J Food Chem Toxicol 2002;40:63541.
118. Nakamura Y, Torikai K, Ohigashi H. A catechol antioxidant
protocatechuic acid potentiates inflammatory leukocyte-
derived oxidative stress in mouse skin via a tyrosinase bioacti-
vation pathway. Free Radical Biol Med 2001;30(9):96778.
119. Lee K-H, Kim A-J, Choi E-M. Antioxidant and antiinflamma-
tory activity of pine pollen extract in vitro.Phytother Res 2009;23
120. Vitaglione P, Donnarumma G, Napolitano A, Galvano F, Gallo
A, Scalfi L, et al. Protocatechuic acid is the major human
metabolite of cyanidin-glucosides. J Nutr 2007;137(9):2043.
121. Ling WH, Wang LL, Ma J. Supplementation of the black rice
outer layer fraction to rabbits decreases atherosclerotic plaque
formation and increases antioxidant status. J Nutr 2002;132
122. Xia M, Ling WH, Ma J, Kitts DD, Zawistowski J.
Supplementation of diets with the black rice pigment fraction
attenuates atherosclerotic plaque formation in apolipoprotein E
deficient mice. J Nutr 2003;133(3):744.
123. Anette K, Lars R, Petter L, Ingvild P, et al. Anthocyanins inhibit
nuclear factor-κB activation in monocytes and reduce plasma
concentrations of pro-inflammatory mediators in healthy
adults. J Nutr 2007;137(8):1951.
124. Matsuda H, Morikawa T, Ando S, Toguchida I, Yoshikawa M.
Structural requirements of flavonoids for nitric oxide produc-
tion inhibitory activity and mechanism of action. Bioorg Med
125. You KM, Jong HG, Kim HP. Inhibition of cyclooxygenase/
lipoxygenase from human platelets by polyhydroxylated/meth-
oxylated flavonoids isolated from medicinal plants. Arch
Pharmacol Res 1999;22(1):1824.
˜lez R, Mascaraque C, Lo
˜pez-Posadas R, Monte MJ,
Romero-Calvo I, Daddaoua A, et al. The intestinal anti-
inflammatory activity of the flavonoid rutin requires oral
administration and may involve effects on mucosal lympho-
cytes. Available from: ,http://www.biochemistry.org/
127. Cuzzocrea S, Zingarelli B, Hake P. Anti-inflammatory effects of
mercaptoethylguanidine, a combined inhibitor of nitric oxide
synthase and peroxynitrite scavenger, in carrageenan-induced
models of inflammation. Biol Med 1998;24:4509.
128. Borissova P, Valcheva ST, Belcheva A. Antiinflammatory effect
of flavonoids in the natural juice from Aronia melanocarpa, rutin
and rutin-magnesium complex on an experimental model of
inflammation induced by histamine and serotonin. Acta Physiol
Pharmacol Bulg 1994;20:2530.
129. Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoes-
trogens in obesity and diabetes. Am J Clin Nutr 2002;76(6):1191.
130. Usui T. Pharmaceutical prospects of phytoestrogens. Endocr J
131. Purushothaman KR, Meerarani P, Moreno PR. Inflammation
and neovascularization in diabetic atherosclerosis. Indian J Exp
132. Csiszar A, Toth J, Peti-Peterdi J, Ungvari Z. The aging kidney:
role of endothelial oxidative stress and inflammation. Acta
Physiol Hung 2007;94:10715.
133. Ruiz-Torres P, Gonzalez-Rubio M, Lucio-Cazan
˜a F, Ruiz-
Villaespesa A, Rodriguez-Puyol M, Rodriguez-Puyol D.
Reactive oxygen species and platelet-activating factor synthesis
in age-related glomerulosclerosis. J Lab Clin Med
134. Baud L, Ardaillou R. Involvement of reactive oxygen species in
kidney damage. British Med Bull 1993;49(3):6219.
135. Murphy WJ, Muroi M, Zhang X, Suzuki T, Russell SW. Both a
basal and an enhancer IB element is required for full induction
of the mouse inducible nitric oxide synthase gene. J Endotoxin
136. Moriuchi H, Moriuchi M, Fauci AS. Nuclear factor-kappa B
potently up-regulates the promoter activity of RANTES, a che-
mokine that blocks HIV infection. J Immunol 1997;158(7):3483.
137. Ping D, Jones PL, Boss JM. TNF regulates the in vivo occupancy
of both distal and proximal regulatory regions of the MCP-1/JE
gene. Immunity 1996;4(5):45569.
138. Park MJ, Choi JS, Yu BP, Chung HY, Lee EK, Heo H-S, et al.
The anti-inflammatory effect of kaempferol in aged kidney tis-
sues: the involvement of nuclear factor-κB via nuclear factor-
inducing kinase/IκB kinase and mitogen-activated protein
kinase pathways. J Med Food 2009;12(2):3518.
139. Morand C, Crespy V, Manach C, Besson C, Demigne C,
Remesy C. Plasma metabolites of quercetin and their antioxi-
dant properties. Am J Physiol 1998;275(1):212.
140. Reddy aM, Seo JH, Ryu SY. Cinnamaldehyde and 2-
methoxycinnamaldehyde as NF-κB inhibitors from
Cinnamomum cassia.Planta Medica 2004;70(9):8237.
424 30. ANTI-INFLAMMATORY PROPERTIES OF CINNAMON POLYPHENOLS AND THEIR MONOMERIC PRECURSORS
5. INFLAMMATION AND POLYPHENOLS
141. Youn HS, Lee JK, Choi YJ, Saitoh SI, Miyake K, Hwang DH, et
al. Cinnamaldehyde suppresses toll-like receptor 4 activation
mediated through the inhibition of receptor oligomerization.
Biochem Pharmacol 2008;75(2):494502.
142. Chao LK, Hua K-F, Hsu H-Y, Cheng S-S, Lin IF, Chen C-J, et al.
Cinnamaldehyde inhibits pro-inflammatory cytokines secretion
from monocytes/macrophages through suppression of intracel-
lular signaling. Food Chem Toxicol 2008;46(1):22031.
143. Lee SH, Hong JT, Lee SY, Son DJ, Lee H, Yoo HS, et al. Inhibitory
effect of 20-hydroxycinnamaldehyde on nitric oxide production
through inhibition of NF-κB activation in RAW264.7 cells.
Biochem Pharmacol 2005;69(5):791.
144. Hwang H, Jeon H, Ock J, Hong SH, Han Y-M, Kwon B-M, et al.
20-Hydroxycinnamaldehyde targets low-density lipoprotein
receptor-related protein-1 to inhibit lipopolysaccharide-induced
microglial activation. J Neuroimmunol 2011;230(1):5264.
145. Ma Q, Kinneer K. Chemoprotection by phenolic antioxidants.
Inhibition of tumor necrosis factor alpha induction in macro-
phages. J Biol Chem 2002;277(4):2477.
146. Murakami Y, Shoji M, Hanazawa S, Tanaka S, Fujisawa S.
Preventive effect of bis-eugenol, a eugenol ortho dimer, on
lipopolysaccharidestimulated nuclear factor kappa B activation
and inflammatory cytokine expression in macrophages. Biochem
147. Murakami Y, Shoji M, Hirata A, Tanaka S, Yokoe I, Fujisawa S.
Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopoly-
saccharidestimulated nuclear factor kappa B activation and
cyclooxygenase-2 expression in macrophages. Arch Biochem
˜es CB, Riva DR, DePaula LJ, Brando-Lima A, Koatz
VLG, Leal-Cardoso JH, et al. In vivo anti-inflammatory action of
eugenol on lipopolysaccharide-induced lung injury. J Appl
149. Li W, Tsubouchi R, Qiao S, Haneda M, Murakami K, Yoshino
M. Inhibitory action of eugenol compounds on the production
of nitric oxide in RAW264.7 macrophages. Biomedical Res
150. Lee SH, Lee SY, Lee H, Hong JT, Son DJ, Yoo HS, et al.
Inhibitory effect of 20-hydroxycinnamaldehyde on nitric
oxide production through inhibition of NF-κB activation in
RAW 264.7 cells. Biochem Pharmacol 2005;69(5):7919.
5. INFLAMMATION AND POLYPHENOLS