Eun Yong Chung1

Byung Hak Kim1

Anti-Inflammatory Effect of the Oligomeric Stilbene Myung Koo Lee1
a-Viniferin and its Mode of the Action through Yeo-Pyo Yun1
Seung Ho Lee2
Inhibition of Cyclooxygenase-2 and Inducible Nitric Kyung Rak Min1
Oxide Synthase Youngsoo Kim1
Original Paper

Abstract 3 mM to 10 mM inhibited the synthesis of COX-2 transcript in lipo-

The anti-inflammatory activity of a-viniferin, a trimer of resver-
atrol, has been demonstrated in an animal model of carrageenin-
induced paw edema, and inhibitory effects of the compound on
cyclooxygenase (COX) and inducible nitric oxide synthase
(iNOS) have been investigated in order to understand the mode
of the observed action. a-Viniferin at doses > 30 mg/kg (p. o.) or
> 3 mg/kg (i. v.) showed significant anti-inflammatory activity
on carrageenin-induced paw edema in mice. a-Viniferin showed
an inhibitory effect with an IC50 value of 4.9 mM on COX-2 activ-
ity but a very weak inhibitory effect with 55.2  2.1 % of the con-
trol (100 %) at 100 mM on COX-1 activity. a-Viniferin at doses of
polysaccharide (LPS)-activated murine macrophages Raw264.7.
a-Viniferin showed an IC50 value of 2.7 mM on nitric oxide (NO)
production in LPS-activated Raw264.7 cells when a-viniferin
and LPS were treated simultaneously, but did not inhibit the NO
production when a-viniferin was treated at 12 h after LPS stimu-
lation. a-Viniferin inhibited synthesis of iNOS transcript with an
IC50 value of 4.7 mM. Consequently, the inhibitory effect of a-vini-
ferin on the release of prostanoids and NO could play an impor-
tant role to show anti-inflammatory action.
Key words
a-Viniferin ´ stilbenoids ´ paw edema ´ COX-2 ´ iNOS

710
Introduction
a-Viniferin (Fig. 1) from Caragana chamlagu Lam., an oriental
folk medicine with anti-arthritic and anti-neuralgic effects, was
reported to show anti-inflammatory effect on croton oil-induced
paw edema [1]. The compound was also identified from
Caragana sinica (Buchoz) Rehd., Carex humilis Leysser, Iris
clarkei Linne, and Sophora hemsleyana Sieb. et Zucc. [2], [3], [4].
a-Viniferin has been reported to inhibit protein kinase C, acetyl-
cholinesterase and keratinocyte proliferation, and to antagonize
20-hydroxyecdysone action [2], [3], [4].
In this study, we have demonstrated the anti-inflammatory ac-
tivity of a-viniferin on the carrageenin-induced edema model in
mice. Furthermore, the effects of a-viniferin on cyclooxygenase
(COX) isozymes and inducible nitric oxide synthase (iNOS) have
been investigated in order to gain a better insight on mechanism
of the observed anti-inflammatory action.
Materials and Methods
Materials and animals
Dulbecco's modified Eagle's medium, arachidonic acid, lucigenin,
ibuprofen and NS-398 were purchased from Sigma-Aldrich, fetal
bovine serum (FBS) from HyClone, and lipopolysaccharide (LPS, E.
coli 0127:B8) from Difco. A Fast RNA kit and an RNA PCR kit were
obtained from Bioneer. a-Viniferin ([a]25
D : 51.4; EtOH, c 1.0) was

Affiliation
1
College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University,
Cheongju, Korea
2
College of Pharmacy, Yeungnam University, Kyeongsan, Korea

Correspondence
Prof. Youngsoo Kim, Ph. D. ´ College of Pharmacy ´ Chungbuk National University ´ Cheongju 361-763 ´ Korea ´
Fax: +82-43-268-2732 ´ E-mail: youngsoo@cbucc.chungbuk.ac.kr

Funding
This work was financially supported by a grant (KRF-99-042-F00167) from Korea Research Foundation

Received November 19, 2002 ´ Accepted April 13, 2003

Bibliography
Planta Med 2003; 69: 710±714 ´  Georg Thieme Verlag Stuttgart ´ New York ´ ISSN 0032-0943
 Fig. 1 Chemical structure of
a-viniferin.
isolated from Carex humilis (Cyperaceae) as described in our pre-
vious paper [5], and its purity was > 95 %. Mice of the ICR strain
were purchased from Jeil Animal Care Center, Kyeongki, Korea.
Measurement of carrageenin-induced paw edema in mice
Male ICR mice were accustomed at an animal room in our Col-
lege of Pharmacy with free access to a standard diet and water
ad libitum. Seven mice with 25  3 g body weight were used per
group for the experiments. Paw edema in the mice was induced
by carrageenin as described previously [6]. Briefly, samples were
given to the mice by oral administration or intravenous injection.
After 1 h, 10 mL of 2 % carrageenin or saline were injected to a sub-
plantar site of right or left hind paw, respectively. Volumes of
right and left hind paws of mice were measured at 1 h, 2 h, 4 h
and 6 h after carrageenin challenge. Paw edema was represented
as 100 % ” [(Rt - Ro)-(Lt - Lo)]/Ro, where Ro or Rt is the volume of
right hind paw at zero time or at indicated time after carrageenin
injection and Lo or Lt is the volume of left hind paw at zero time
or at indicated time after saline injection.
Assay of COX activity
COX activity was measured by chemiluminescence in a total of
200 mL reaction mixture consisting of 0.1 M Tris-HCl (pH 8.0)
containing 100 mM arachidonic acid and 25 mM luminol. The
COX-1 source was prepared from resting murine macrophages
Raw264.7, and the COX-2 source from LPS-stimulated
Raw264.7 cells. Murine macrophages Raw264.7 were cultured
in DMEM (10 mg/mL Dulbecco's modified Eagle's medium, 24
mM NaHCO3, 10 mM HEPES, 143 units/mL benzylpenicillin po-
tassium, 100 mg/mL streptomycin sulfate, pH 7.1) containing
10 % FBS at 37 8C with 5 % CO2 for 48 h and then collected for pre-
paration of COX-1 source. The Raw264.7 cells were cultured in
DMEM containing 10 % FBS and 300 mM aspirin at 37 8C with 5 %
CO2 for 24 h. After washing twice with PBS, the cells were added
with DMEM containing LPS (10 mg/mL). After incubation at
37 8C with 5 % CO2 for 24 h, the Raw264.7 cells were collected
and sonicated in 0.1 M Tris-HCl (pH 8.0) to obtain the COX-2
source.
Measurement of NO production
Two hundred mL of murine macrophages Raw264.7 (1 ” 106 cells/
mL) in DMEM containing 10 % FBS were dispensed into a 96-well
culture plate and incubated at 37 8C with 5 % CO2 for 24 h. After
washing twice with PBS, the Raw264.7 cells were added with
100 mL each of LPS (20 mg/mL) and the sample dissolved in
DMEM, and then incubated at 37 8C with 5 % CO2 for 24 h. After
centrifugation at 700 ” g for 30 min at 4 8C, 100 mL of the superna-
tant were reacted with 100 mL of the Griess reagent (1 % sulfani-
lamide and 0.1 % naphthylethylenediamine dihydrochloride in
2.5 % phosphoric acid) and then the nitrite content was measured
by the absorbance at a wavelength of 540 nm with sodium nitrite
as a standard.
RT-PCR of COX-2 and iNOS transcripts
Two mL of murine macrophages Raw264.7 (5 ” 105 cells/mL)
were dispensed into a 6-well plate, and then incubated at 37 8C
with 5 % CO2 for 48 h. After washing twice with PBS, the
Raw264.7 cells were treated with sample at 2 h before stimula-
tion with LPS (10 mg/mL). After incubation at 37 8C with 5 % CO2
for 6 h, the Raw264.7 cells were collected to purify total RNA by
Original Paper
using a FastRNA kit according to the supplier's instruction (Bio-
neer). The total RNA was subjected to RT-PCR using an RNA PCR
kit according to the supplier's instruction (Bioneer). Briefly, total
cellular RNA (2 mg) was incubated with avian myeloblastosis
virus reverse transcriptase at 50 8C for 25 min. The resulting
cDNA samples were subjected to 25 cycles of PCR, one cycle
with 30-sec denaturation at 94 8C, 30-sec annealing at 65 8C, and
2-min extension at 72 8C. The PCR primers were designed as
follows; COX-2 (583 base pairs) with forward 5¢-ACTCACT-
CAGTTTGTTGAGTCATTC-3¢ and reverse 5¢-TTTGATTAGTA CTGT-
AGGGTTAATG-3¢, iNOS (457 base pairs) with forward 5¢-
GTCAACTGCAAGAGAACGGAGAAC-3¢ and reverse 5¢-GAGCTCCT-
CCAGAGGGTAGGCT-3¢, and b-actin (745 base pairs) as an inter-
nal control with forward 5¢-CACCACACCTTCTACAATGACCTGC-3¢
and reverse 5¢-GCTCAGGAGGAGCAATGATCTTGAT-3¢. The RT-PCR
products were resolved on 1.2 % agarose gel by electrophoresis,
and quantified by scanning densitometry (Kodak).
Statistical analysis 711
Paw edema % is expressed as mean  SEM of two independent ex-
periments with seven mice per group. Effects on COX isozymes
and NO production are expressed as control %, mean  SEM of
three independent tests. Data were analyzed by ANOVA followed
by Student's t-test. Probability of less than 0.05 (P < 0.05) was
considered significant.
Results
a-Viniferin showed dose-dependent anti-inflammatory activity
on carrageenin-induced paw edema in mice (Fig. 2). Paw edema
in the control group increased as a function of time, 25.0  1.1 % to
25.2  2.2 % at 1 h, 33.3  1.7 % to 34.4  1.1 % at 2 h, 48.3  1.5 % to
48.8  1.6 % at 4 h and 45.9  1.3 % to 46.3  1.6 % at 6 h after carra-
geenin challenge. When administered orally, a-viniferin (30 mg/
kg dose) showed a significant anti-inflammatory effect with paw
edema, 29.8  1.1 % at 2 h, 42.4  1.2 % at 4 h and 39.4 %  1.2 % at
6 h; and a-viniferin (100 mg/kg dose) with 19.5  1.3 % at 1 h, 26.4
 1.3 % at 2 h, 36.5  1.1 % at 4 h and 34.5  1.8 % at 6 h after carra-
geenin challenge (Fig. 2A). When injected intravenously, a-vini-
ferin (3 mg/kg dose) showed a significant anti-inflammatory ef-
fect with paw edema, 42.7  1.1 % at 4 h and 39.9  1.2 % at 6 h; a-
viniferin (10 mg/kg dose) with 38.4  0.9 % at 4 h and 36.9  0.6 %
at 6 h; and a-viniferin (30 mg/kg dose) with 27.1  1.5 % at 2 h,
32.5  1.6 % at 4 h and 31.9  1.1 % at 6 h after carrageenin chal-
lenge (Fig. 2B). However, a-viniferin showed a weaker anti-in-
Chung EY et al. Anti-Inflammatory Effect of ¼ Planta Med 2003; 69: 710 ± 714
 Fig. 2 Anti-inflam- the nitrite content in the culture medium (Fig. 4A). Nitrite con-
matory activity of a- tent was 8.0  0.4 mM in the resting Raw264.7 cells, and in-
viniferin on carra- creased to 45.3  1.5 mM after LPS stimulation. a-Viniferin
geenin-induced paw
edema. Seven mice showed dose-dependent inhibitory effects with 39.1  4.0 % of
per group were the control (100 %) at 3 mM, 8.7  0.6 % at 10 mM and 1.3  0.5 % at
treated with sample 30 mM with an IC50 value of 2.7 mM on NO production when a-vi-
by oral administra- niferin was treated with LPS simultaneously. However, a-vinifer-
tion (A) or intrave-
in did not show significant inhibitory effects on the NO produc-
nous injection (B).
Samples in panel A tion when a-viniferin (1 mM to 30 mM) was treated at 12 h after
are the control of LPS stimulation. a-Viniferin inhibited the synthesis of iNOS tran-
carrageenin only script in LPS-activated murine macrophages Raw264.7, which
(*), carrageenin was analyzed by RT-PCR (Fig. 4B). A density ratio of iNOS versus
plus a-viniferin with
b-actin signal as an internal standard was 1.3 % in the resting
30 mg/kg (~) or
100 mg/kg (~), and Raw264.7 cells, and was increased to 60.7 % in LPS-activated
Original Paper

carrageenin plus Raw264.7 cells. The density ratio of iNOS versus b-actin signal
ibuprofen with in LPS-activated Raw264.7 cells was decreased to 56.2 %, 39.2 %
100 mg/kg (l) as a and 2.6 % by pretreatment with a-viniferin at 1 mM, 3 mM and 10
positive control. mM, respectively.
Samples in panel B
are the control of
carrageenin only
(*), carrageenin Discussion
plus a-viniferin with
3 mg/kg (n), 10 mg/
a-Viniferin given by oral administration (30 mg/kg and 100 mg/
kg (l) or 30 mg/kg
(~), and carragee- kg doses) or intravenous injection (3 mg/kg, 10 mg/kg and
nin plus ibuprofen 30 mg/kg doses) significantly reduced the carrageenin-induced
with 30 mg/kg (~). paw edema in a dose-dependent manner (Fig. 2). In order to ob-
Data were collected tain a better insight into the mechanism of the observed anti-in-
as paw edema %,
mean  SEM of two
independent experi-
ments, and signifi- Fig. 3 Effect of a-
cant differences viniferin on COX iso-
from the control are zymes. Inhibitory ef-
P < 0.01 (**) and P < fects of a-viniferin
712 0.05 (*). (AVF) on COX activ-
ity (A) and COX-2
synthesis (B) are re-
presented. In panel
A, effects on COX-1
flammatory potency than ibuprofen, a non-steroidal anti-inflam-
(*) and COX-2 ac-
matory drug (NSAID) as a positive control. tivities (l) are repre-
sented as control %,
a-Viniferin showed a dose-dependent inhibitory effect on COX-2 mean  SEM of three
activity with 55.1  6.4 % of the control (100 %) at 3 mM, 36.9  independent tests.
Significant differ-
2.2 % at 10 mM, and 7.6  2.6 % at 30 mM but showed a very weak
ence from the con-
inhibitory effect on COX-1 activity with 67.1  3.4 % of the control trol is P < 0.001 (*).
(100 %) at 50 mM and 55.2  2.1 % at 100 mM (Fig. 3A). As a positive NS-398 and ibupro-
control, NS-398 showed an IC50 value of 1.5 mM on COX-2 activity fen as positive con-
but did not inhibit COX-1 activity. Ibuprofen, an NSAID known as trols showed IC50
values of 1.5 mM
non-selective inhibitor of COX-1 and 2, showed IC50 values of
and 8.6 mM on COX-
13.4 mM and 8.6 mM on COX-1 and 2 activities, respectively. a-Vi- 2 activity, respec-
niferin at concentrations of 3 mM to 10 mM showed inhibitory ef- tively. In panel B,
fects on the synthesis of COX-2 transcript in LPS-activated mur- the RT-PCR product
ine macrophages Raw264.7, which was analyzed by RT-PCR corresponding to
COX-2 or b-actin
(Fig. 3B). A density ratio of COX-2 versus b-actin signal as an in-
transcript in LPS-
ternal standard was 1.5 % in the resting Raw264.7 cells, and was activated murine
increased to 49.0 % in LPS-activated Raw264.7 cells. The density macrophages
ratio of COX-2 versus b-actin signal in LPS-activated Raw264.7 Raw264.7 is indicat-
cells was decreased to 44.7 %, 34.9 % and 25.8 % by pretreatment ed by an arrow, and
the density ratio %
with a-viniferin at doses of 1 mM, 3 mM and 10 mM, respectively.
of COX-2 versus b-
actin signal as an in-
The effect of a-viniferin on NO production in LPS-activated mur- ternal standard is
ine macrophages Raw264.7 was analyzed by measurement of also represented.

Chung EY et al. Anti-Inflammatory Effect of ¼ Planta Med 2003; 69: 710 ± 714
 Fig. 4 Effect of a- the supernatant, an index of NO production, of LPS-activated
viniferin on NO pro- murine macrophages Raw264.7 was decreased when a-viniferin
duction and iNOS and LPS were treated simultaneously (Fig. 4A). However, no inhi-
synthesis. Inhibitory
effects of a-viniferin bitory effect on NO production was shown by treatment of a-vi-
(AVF) on NO produc- niferin, when iNOS synthesis could be completed already, at 12 h
tion (A) and iNOS after LPS stimulation. This result would indicate that a-viniferin
synthesis (B) are re- did not inhibit iNOS activity. RT-PCR analysis was performed to
presented. In panel
examine whether the inhibitory effect of a-viniferin on NO pro-
A, a-viniferin was
treated at the same duction was influenced by down-regulation of iNOS synthesis
time with LPS (l) (Fig. 4B). The iNOS transcript in murine macrophages Raw264.7
and at 12 h after LPS was induced by LPS stimulation, which was decreased by pre-
stimulation (*). Ni- treatment of a-viniferin with an IC50 value of 4.7 mM. Therefore,
trite content in the
a-viniferin seems to down-regulate iNOS synthesis in LPS-
supernatant, an in-
dex of NO produc- activated murine macrophages Raw264.7.

tion, was deter-
mined using the
Griess reagent. Ef-
fect of a-viniferin is
represented as con-
trol %, mean  SEM
of three indepen-
dent tests. Signifi-
cant difference from
the control is P <
0.001 (*). In panel
B, RT-PCR product
corresponding to
iNOS or b-actin tran-
script in LPS-activat-
ed murine macro-
phages Raw264.7 is indicated by an arrow, and density ratio % of
iNOS versus b-actin signal as an internal standard is also represented.
flammatory action, we have investigated the inhibitory effects of
a-viniferin on COX isozymes and iNOS.
COX catalyzes a rate-limiting step of prostanoid biosynthesis,
which is a pharmacological target of NSAIDs. There are two iso-
zymes of COX; COX-1 is constitutively expressed in various tis-
sues including the stomach, whereas COX-2 does not appear to
be expressed in most tissues and is rapidly up-regulated in re-
sponse to cytokines and growth factors [7], [8]. Gastric intestinal
damage due to NSAIDs is caused by inhibition of COX-1 but not
COX-2 [9]. a-Viniferin showed a potent inhibitory effect on COX-
2 activity with an IC50 value of 4.9 mM but a very weak inhibitory
effect on COX-1 activity (Fig. 3A). Therefore, a-viniferin was
identified as a selective inhibitor of COX-2 activity, which could
show a similar mode of anti-inflammatory action as NSAIDs
without causing unwanted side effects. In addition, a-viniferin
inhibited the synthesis of COX-2 transcript in LPS-activated mur-
ine macrophages Raw264.7 (Fig. 3B).
Physiological and normal production of NO from phagocytes is
beneficial for the host's defense against microorganisms, para-
sites and tumor cells [10]. However, overproduction of NO can
be harmful and result in several diseases. Macrophages can in-
crease production of NO and superoxide anion simultaneously
in pathological conditions including inflammation [11]. NO is
produced by iNOS in activated macrophages with L-arginine as
a substrate, and reacts with superoxide anion to form peroxyni-
trite, a cytotoxic oxidant species [12]. Nitrite concentration in
Original Paper
a-Viniferin inhibited the synthesis of both COX-2 and iNOS tran-
scripts, where the compound showed a stronger down-regula-
tion of iNOS transcript than COX-2 transcript (Figs. 3B and 4B).
The promoter region of murine iNOS gene contains several con-
sensus sequences for binding of transcription factors such as
NF-kB, STAT, C/EBP, CREB and OCT [13]. a-Viniferin did not inhib-
it NF-kB transactivation in LPS-stimulated murine macrophages
Raw264.7, which was identified by a reporter gene assay with
triplicated NF-kB consensus sequence connected to alkaline
phosphatase gene as a reporter plasmid (data not shown). The
signaling pathways affected by a-viniferin in the LPS-induced
iNOS synthesis will be elucidated in a future study.
a-Viniferin is an oligomeric stilbene with resveratrol as the build-
ing block. Resveratrol was first detected in Polygonum cuspidatum
Sieb. et Zucc., and is presumed to be beneficial for human health
[14]. Anti-inflammatory activity of resveratrol was demonstrated
by reduction of carrageenin-induced paw edema [15]. Resveratrol 713
was reported to inhibit COX-1 activity preferentially and is known
to suppress COX-2 synthesis [16]. Resveratrol was reported to in-
hibit NO production through interference of NF-kB signaling [17].
Thereby, a-viniferin seems to display modes of anti-inflammatory
action different from resveratrol.
In this study, we have demonstrated the anti-inflammatory action
of a-viniferin, an oligomeric stilbene compound from Carex
humilis Leysser as a source. a-Viniferin reduced carrageenin-in-
duced paw edema in mice by intravenous injection with 3 mg/kg,
a tested minimal dose, which could correspond to a whole-body
concentration of about 10 mM. The compound showed IC50 values
of 4.9 mM on COX-2 activity and of 2.7 mM on NO production in
LPS-stimulated murine macrophages Raw264.7. Therefore, the in-
hibitory effects of a-viniferin on the release of prostanoids and NO
may play an important role to show anti-inflammatory action in
vivo even though the compound will not be distributed evenly
throughout the body. These findings expand the importance of a-
viniferin as a beneficial agent, and will help to clarify protective
mechanisms of the compound against inflammatory conditions.
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Chung EY et al. Anti-Inflammatory Effect of ¼ Planta Med 2003; 69: 710 ± 714