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Chapter 30. Anti-Inflammatory Properties of Cinnamon Polyphenols and their Monomeric Precursors

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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 neurodegenerative 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), but they have serious side effects. This chapter introduces a variety of cinnamon species, and describe the anti-inflammatory properties of cinnamon extracts and their constituents. In addition, it will describe the chemical composition of the different cinnamon bioactives, and elucidate in detail their individual anti-inflammatory properties and try to explain the molecular mechanisms behind the anti-inflammatory action.
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CHAPTER
30
Anti-Inflammatory Properties of Cinnamon
Polyphenols and their Monomeric Precursors
Dhanushka Gunawardena*, Suresh Govindaraghavan*
,†
and Gerald
Mu
¨nch*
,‡,k
*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
k
CompleMed, University of Western Sydney, Campbelltown,
NSW, Australia
1. INTRODUCTION
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.
1
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.
2
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.
3,4
At the
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
observed.
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.
5,6
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.
409
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.
7
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
8,9
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.
10
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
coughs.
Cinnamon has also been used to alleviate indiges-
tion,
10
stomach cramps,
7
intestinal spasms, nausea,
and flatulence, to improve the appetite, and to treat
diarrhea.
11
It is reported to be beneficial for the control
of blood glucose levels in diabetes,
12,13
reduction in the
levels of low-density lipoprotein (bad cholesterol),
14,15
lessening of arthritic pain,
16
and for healing open
wounds and small cuts.
17
The positive health effects
associated with the consumption of cinnamon could,
in part, be attributed to its phenolic composition.
1820
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.”
21
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
wine.
22
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
23
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).
24
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.
25
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.
26
The potential
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.
27
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.
28
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.
29
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
macrophages
30
and the stilbene trans-resveratrol pos-
sessed anti-inflammatory activity because it sup-
pressed carragenen-induced pedal edema via the
inhibition of COX activity.
31
Furthermore, Landolfi
et al.
32
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.
33
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.
34
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.
35
Flavonols, including kaempferol, quercetin, morin
and myricetin, were found to be 5-LOX inhibitors.
36
Hamamelitannin and the galloylated proanthocyani-
dins were found to be the most potent inhibitors of
5-LOX with the IC
50
values ranging from 1.0 to
18.7 μM.
37
Some prenylated flavonoids, such as artonin
E, are the most effective inhibitors of porcine eukocyte
5-LOX.
38
There are few reports regarding 12-LOX inhi-
bition; kuwanson C and quercetin potently inhibit
12-LOX activity with IC
50
values of 19 and 12 μM,
respectively, using bovine PMNs (polymorphonuclear
neutrophil leukocytes) and 12-LOX from bovine plate-
lets.
39
In comparison, the IC
50
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-
cess.
40
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.
4
Quercetin was found to be an effective inhibitor of
PLA2 in rabbit
41
and human
42
leukocytes. It was also
demonstrated that quercetin selectively inhibited
sPLA2-II, compared to its lower inhibition of sPLA2-
IB.
43
Quercetagetin, kaempferol-3-O-galactoside, and
scutellarein inhibited human recombinant synovial
PLA2 with IC
50
values ranging from 12.2 to 17.6 μM.
44
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.
45
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
diseases.
46
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.
47
In
fact, polyphenols, such as quercetin and catechins, cou-
pled their inhibitory action on TNF-αand IL-1βto the
enhancement of IL-10 release.
47,48
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.
49
Three
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.
27
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-
inflammatory cytokines.
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.
26
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.
50,51
An interesting
in vivo study carried out on rats showed that EGCG
markedly attenuated the myocardial injury after ische-
mia and reperfusion.
37,5257
4. ANTI-INFLAMMATORY ACTIVITY OF
CINNAMON EXTRACTS
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
macrophages.
58
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,
59
and con-
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.
60
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.
61
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.
62
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.
63
Furthermore, a
more recent study suggested that the components of
CR inhibit inflammatory responses in the CNS in vitro
and in vivo.
64
A study conducted on mice with 70% ethanolic
extract of C. cassia bark gave promising results on
acute inflammation.
65
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
activation.
66
4.3 Cinnamomum osmophloeum
The constituents of C. osmophloeum twigs sup-
pressed NO production by LPS-stimulated macro-
phages.
67
In the presence of 25 μg/mL essential oil, the
inhibition of NO production was 68.8%. The IC
50
value
was 11.2 μg/mL. Tung et al.
67
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
pulmonary inflammation.
68,69
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
(EC
50
) for essential oil was 18.68 μg/mL.
70
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)
conditions.
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%.
71
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.
72
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.
73
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).
52,74
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-
type).
75
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
procyanidins.
76
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).
77
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-
α-L-rhamnopyranoside
78
(Figure 30.4).
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.
7981
C. osmophloeum twigs and leaf essential oils contains
trans-cinnamaldehyde and eugenol, which are reported
to possess excellent anti-inflammatory activities.
67
6. ANTI-INFLAMMATORY ACTIVITY OF
CINNAMON POLYPHENOLS
6.1 Proanthocyanidins
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
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
OH
OH OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
OO
B-type Iinkage
A-type Iinkage
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.
82
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
cyclooxygenase-2 (COX-2).
82
GC showed a preferential
inhibition of COX-2 compared to COX-1 at 10
24
M.
This selectivity was enhanced by a reduction of the
concentration tested (10
25
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
HO
HO HO
HO
OH
OH
OH OH OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OO
O
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
O
O
O
O
O
O
O
O
O
O
OO
O
OH
OH
OH
OH
OH
OH
OH
OH OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
OO
O
O
O
OH
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
OH
HO
OH
OH
OH
OH
OH
O
OO
O
O
O
O
OO
O
O
O
O
O
O
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH OH
HO
HO
HO
HO
HO
OH
OH
OH
OH
O
O
O
OH
OH
O
O
O
HO O
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
OH
OH O
O
O
OH
OH
OH
OH
OH
O
OO
OH
O
O
O
OH
OH
OH
HO
OH
OH
HO
HO
OH
OH
O
O
O
O
O
O
O
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
OH
OH
O
O
O
O
O
O
O
O
O
A
B
D
E
F
C
1
2
H
1
2
3
G
I
K
L
J
N
M
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
proanthocyanidine.
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
effective.
83,84
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.
52
Out of
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
procyanidin.
84
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
interferon-γ.
85
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.
86
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
OH
OH OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
OH
O
O
O
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
HO
OH
OH
HO O
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
O
O
OH
HO
OH
OH
OH
O
Catechin
Catechingallate Epicatechingallate
Epicatechin Afzelechin
HO HO
OO
Epiafzelechin
Gallocatechin Epigallocatechin
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)
77
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.
76
Pro-inflammatory cytokines TNF-α, IL-1βand IL-6
are sequentially released in the pleural exudates
induced by carrageenin in rats.
87
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.
88
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
melanogenesis.
89
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.
90
The same compounds have been shown to inhibit
TNF-α-induced VCAM-1 expression in human umbili-
cal vein endothelial cells cultures.
91
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.
86
O
O
OOO
O
O
O
O
O
H3C
HO
HO OH
O
OH
OH OH
OH OH
OH
OH
OH
OH
OH
OH
OH
Protocatechuic acid
Kaempferol
Quercetin Isorhamnetin
Rutin Quercetin-3-O-α-L-rhamnopyranoside
HO
HO
HO
HO
HO CH3
OH
OH OH
OH
OH
OH
OH
OH
OCH3
OH
OH
HO
HO
HO
O
O
O
O
O
O
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
MONOMERIC PRECURSORS
7.1 (2)-Catechin,( 2)-Epicatechin and
Gallocatechins
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.
92
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
(IFN-δ).
93
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.
94,95
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.
96100
7.2 Epiafzelechin
(2)-Epiafzelechin is a COX inhibitor and it exhib-
ited a dose-dependent inhibition on the COX activity
with an IC
50
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
treatment.
101
8. ANTI-INFLAMMATORY ACTIVITY OF
OTHER CINNAMON PHENOLICS
8.1 Quercetin
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.
102107
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.
108110
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.
56
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.
111
Min et al.
112
found that black rice
Cy-3-G as well as its metabolites, including PCA,
exerted anti-inflammatory effects in vitro as well as
in vivo.
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
model.
113
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
kidney.
114
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
4
-
induced hepatic damage.
115,116
The hepatoprotective
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.
117
Tyrosinase-derived reactive quinone intermediate(s) of
PCA was shown to bind nucleophilic residues of pro-
teins and sulfhydryl group including oxygen radical-
generating leukocytes.
118,119
Several recent studies
have, however, revealed that PCA is a major metabo-
lite of anthocyanins in humans.
120
Extensive investiga-
tions have shown that anthocyanins reduce the
development of atherosclerosis in different atheroscle-
rotic animal models
121,122
and the risk of atherosclero-
sis in human studies.
14,123
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/
L).
120
This made us hypothesize that anthocyanins
may exert their protective effects at least partially
through this important and major metabolite.
8.3 Rutin
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
50
value of the rutin and other flavonols on NO produc-
tion inhibitory activity in LPS-activated mouse
peritoneal macrophages
124
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.
40,125
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
normal animals.
126
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
enzymes.
127
The results showed that rutin exhibited a
significant (p,0.05) inhibitory effect on rat paw
oedema formation effectively.
128
8.4 Kaempferol
Kaempferol, a phytoestrogen and a flavonoid, pro-
tects against various oxidative stresses and inflamma-
tory age-related chronic disorders.
129,130
The IC
50
value
of kaempferol and other flavonols on NO production
inhibitory activity in LPS-activated mouse peritoneal
macrophages
124
is provided in Table 30.2.
Oxidative stress plays an important role in the path-
ogenesis of many diseases, including inflammatory
diseases.
131
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.
132134
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.
34,135138
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
124
Compound IC
50
(µM)
Kaempferol 29
Quercetin 36
Rhamnetin 42
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.
138
8.5 Isorhamnetin
30-Methoxy-3,40,5,7-tetrahydroxyflavone (isorhamne-
tin) is an abundant flavonoid found in many dietary
plants.
139
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.
56
The IC
50
value of
isorhamnetin and other flavonols on NO production
inhibitory activity in LPS-activated mouse peritoneal
macrophages
124
is provided in Table 30.2.
8.6 Cinnamaldehyde
Cinnamaldehyde suppressed NF-B activation within
macrophage-like RAW264.7 cells.
140
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.
141
Cinnamaldehyde, iso-
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.
142
These find-
ings demonstrated the anti-inflammatory (Table 30.3)
potential of cinnamaldehyde.
8.7 20-Hydroxycinnamaldehyde (HCA) and 20-
Benzoyloxycinnamaldehyde (BCA)
20-Hydroxycinnamaldehyde (HCA) from the stem
bark of C. cassia and its derivative 20-benzoyloxycinna-
maldehyde (BCA) were reported to show anti-
inflammatory effects
143
in RAW264.7 macrophage
cells.
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.
144
8.8 Eugenol (4-Allyl-2-Methoxyphenol)
Eugenol is a major component of cinnamon leaves
and has been reported to show potent antioxidant and
anti-inflammatory actions,
145147
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.
148
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
(COX-2).
149
9. CONCLUSION
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
RAW264.7 Macrophages
5,149,150
Compound IC
50
µM
Cinnamaldehyde 45.56
2-Hydroxycinnamaldehyde 8
Eugenol 100
Isoeugenol 10
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.
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425REFERENCES
5. INFLAMMATION AND POLYPHENOLS
... As shown in Figure 1, the crude extract and four fractions showed COX-2 inhibition activities with varying degrees, among which, the DCM (0.5 ± 0.0 µg/mL) and EA (0.2 ± 0.0 µg/mL) fractions showed statistically equal COX-2 inhibitory activities to the positive control (INM, 0.4 ± 0.1 µg/mL). The EA fraction possessed the lowest IC 50 value compared with INM and tested samples, followed by the DCM, n-BuOH, CE and PE fractions. ...
... compound, known as protocatechuic acid (PCA), has been shown to demonstrat ti-inflammatory and hepatoprotective activity in rats or mice models [50], and our supplemented the COX-2 inhibition and hepatic cell protection evidence in vitro. Next, the ROS level was detected based on the fluorescence probe DCFH-DA, which was finally oxidized by intracellular ROS to fluorescent DCF [28]. ...
... Meanwhile, the groups treated with compounds 2, 9 or the positive control at 5 µM (final concentration) exhibited statistically significant decreases in ROS quantity, which indicated that these two compounds could protect L02 cells from H 2 O 2 -induced injury by reducing ROS production. compound, known as protocatechuic acid (PCA), has been shown to demonstrate anti-inflammatory and hepatoprotective activity in rats or mice models [50], and our work supplemented the COX-2 inhibition and hepatic cell protection evidence in vitro. ...
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... Moreover, some studies have reported cinnamon to possess hypoglycemic properties that are beneficial in lowering cholesterol levels (Bandara et al. 2012). It also has wound healing properties and acts as an anti-inflammatory compound (Gunawardena et al. 2014;Haddi et al. 2017;Tung et al. 2008). The major component of cinnamon EO that is responsible for its antimicrobial activity is cinnamaldehyde. ...
... Moreover, some studies have reported cinnamon to possess hypoglycemic properties that are beneficial in lowering cholesterol levels (Bandara et al. 2012). It also has wound healing properties and acts as an anti-inflammatory compound (Gunawardena et al. 2014;Haddi et al. 2017;Tung et al. 2008). The major component of cinnamon EO that is responsible for its antimicrobial activity is cinnamaldehyde. ...
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... [76] Multiple health benefits of BW, such as anti-cancer, antiatherogenic, antioxidant, and hypoglycemic effects have been attributed to rutin. [13,[77][78][79][80][81] Possible mechanisms behind the hypoglycemic effect of polyphenols Some possible proposed mechanisms for the hypoglycemic impact of rutin include the decrease in carbohydrates absorption by the small intestine, inhibition of tissue gluconeogenesis, increase in tissue glucose uptake, stimulation of insulin secretion from beta cells, and protection of Langerhans islet against degeneration. [82] Similar to dietary fiber, studies have shown that rutin promotes the phosphorylation of serinethreonine protein kinase and prevents the degradation of peroxisome proliferator-activated receptorγ. ...
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... Cinnamon (Cinnamomum zeyeanicum) is one of the spices that have the highest antibacterial activity. Cinnamon extracts exhibited strong anti-inflammatory properties, related with their polyphenols [44,45]. Cinnamon extract (300 mg/day) decreased insulin resistance in fructose-fed diabetic rats [46]. ...
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... For example, cinnamon-derived polyphenols have been proven to have superior anti-inflammatory characteristics-a factor that is instrumental in the treatment of inflammation-related conditions, including inflammatory bowel disease, rheumatoid arthritis, asthma, cancer, diabetes, cardiovascular diseases, degenerative musculoskeletal diseases, and neurodegenerative conditions. The need for plant-based alternatives is supported by the limitations of traditional non-steroidal anti-inflammatory drugs (NSAIDs) [20], the manifestation of appropriate antioxidant properties [21,22], and a variety of naturally occurring precursors, including agro-wastes. ...
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This Sumba expedition is one of LIPI's efforts in demonstrating its role in the field of science and technology, especially in strengthening the management of living natural resources (SDAH) and sustainable ecosystems. The information presented in this book is the result of research expeditions in the Sumba area, especially the Laiwangi-Wanggameti National Park (TNLW) conducted by a research team from the Deputy for Life Sciences (IPH-LIPI). This book also provides a different perspective on the potential of the East Sumba region, both through the richness of flora, fauna, and microbes in it. As a result, it can be seen that the East Sumba area is very diverse, not only has beauty, but also has high value for science and has the potential to be developed.
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Chapter
MC3T3-E1 cell is an osteogenic line established from newborn mouse calvaria by Kodama and others.1 Our laboratory has demonstrated that the cells release prostaglandin (PG) E2 into the culture medium as an essentially sole arachionate metabolite, and the PGE2 production is stimulated markedly by the addition of EGF, TGFβ, epinephrine or various PGs.2–5 Several lines of evidence suggested that the increased PGE2 synthesis was attributed to the induction of cyclooxygenase enzyme by these compounds. Furthermore, we reported that the increased cyclooxygenase activity by PGs (PGF2α, PGE2, PGE1 and iloprost) was mostly attributed to the induction of cyclooxygenase-2 rather than cyclooxygenase-1.6 The quantification of c AMP and IP3 and the examination of the effects of various protein kinase inhibitors indicated that iloprost and PGE1 induced cyclooxygenase-2 through a pathway mediated by cAMP and A kinase. On the other hand, PGF2α induced cyclooxygenase-2 via PI turnover and protein kinase C. PGE2 was probably coupled with two or more pathways.