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(Received for publication, August 13, 1996, and in revised form, November 15, 1996)
From the Departments of ABSTRACT Indomethacin is a non-steroidal anti-inflammatory
drug (NSAID) and cyclooxygenase inhibitor that is frequently used as a
research tool to study the process of adipocyte differentiation.
Treatment of various preadipocyte cell lines with micromolar
concentrations of indomethacin in the presence of insulin promotes
their terminal differentiation. However, the molecular basis for the
adipogenic actions of indomethacin had remained unclear. In this
report, we show that indomethacin binds and activates peroxisome
proliferator-activated receptor INTRODUCTION Indomethacin and other NSAIDs1 are
used clinically for their anti-inflammatory, anti-pyretic, and
analgesic properties (1). The molecular basis for the therapeutic
actions of NSAIDs is believed to be their ability to inhibit
cyclooxygenase (COX) activity and thereby block the production of
prostaglandins (PGs). Two COX enzymes have been identified. COX-1 is
constitutively expressed, and the PGs produced by this enzyme are
thought to function in the so-called housekeeping functions of the
cell; in contrast, the COX-2 isozyme is an inducible enzyme that is
normally absent from cells but is expressed in response to growth
factors, tumor promoters, and cytokines (2). Most of the NSAIDs inhibit
both COX-1 and COX-2, although they vary in their relative potencies against the two COX isozymes (3).
Indomethacin is also widely used as a research tool to study the
process of adipocyte differentiation. While there is at least one
report of indomethacin blocking adipocyte differentiation (4),
treatment of several preadipocyte cell lines with this drug results in
their terminal differentiation (5-7). Early reports suggested that
indomethacin might function as an adipogenic agent through its
inhibition of COX activity. However, two lines of evidence indicate
that the adipogenic activity of indomethacin cannot simply be ascribed
to the inhibition of COX. First, the concentration of drug required to
induce differentiation is 2-3 orders of magnitude higher than that
required to inhibit COX activity, and second, several NSAIDs that
inhibit COX activity fail to induce adipocyte differentiation (7).
Thus, the mechanism underlying the adipogenic activity of indomethacin
has remained obscure.
Insight into the molecular mechanisms responsible for adipocyte
differentiation was recently provided by the identification of a
ligand-activated transcription factor, termed PPAR Work from several laboratories had shown that PGs have marked effects,
both positive and negative, on adipocyte differentiation (4, 16-19).
Interestingly, PPAR If prostanoids can function as PPAR EXPERIMENTAL PROCEDURES Indomethacin, flufenamic acid, fenoprofen,
ibuprofen, piroxicam, acetaminophen, and salicylic acid were purchased
from Sigma. The peroxisome proliferator Wy14,643 was
purchased from Biomol (Plymouth Meeting, PA) and
15-deoxy- To generate the pSG5-GAL4-PPAR The LBD of human PPAR C3H10T1/2 clone 8 murine fibroblasts (American Type
Culture Collection) were maintained in Dulbecco's modified Eagle's
medium (Life Technologies, Inc.) supplemented with 10% fetal calf
serum and 10 µg/ml penicillin and streptomycin. One day after
reaching confluence, the cells were treated with BRL49653 or the
various NSAIDs in the presence of 200 nM insulin. Fresh
media and test compounds were added every 2 days. Lipogenesis was
measured in cells at 9 days post-confluence as described previously
(29). For Northern analysis, total RNA was prepared from vehicle- and compound-treated cells using the RNeasy Total RNA Kit (Qiagen, Chatsworth, CA). Fifteen µg of total RNA was electrophoresed on a
formaldehyde gel and transferred to nitrocellulose. The blot was probed
with mouse aP2 and GAPDH probes labeled via the random priming
technique with [ RESULTS The PPARs are activated by a
large number of structurally diverse compounds including prostanoids,
long-chain fatty acids, the fibrate class of hypolipidemic drugs,
leukotriene antagonists, and anti-diabetic thiazolidinediones (13).
While chemically diverse, these compounds share certain structural
characteristics including a lipophilic backbone and an acid moiety,
usually a carboxylate. Indomethacin and many of the other NSAIDs are
amphipathic carboxylates that share these broad structural features
(Fig. 1). This suggested to us that indomethacin might
exert its adipogenic effects through direct activation of PPAR
We tested the possibility that indomethacin activates PPAR
We next sought to determine
whether indomethacin activates PPAR
Several
chemically distinct classes of NSAIDs are used clinically including
thiazinecarboxamides (e.g. piroxicam) and derivatives of
arylacetic acid (e.g. indomethacin), aminoarylcarboxylic
acid (e.g. flufenamic acid), arylpropionic acid
(e.g. ibuprofen and fenoprofen), and salicylic acid
(e.g. aspirin) (Fig. 1) (1). We next tested whether
representative compounds from the different classes of NSAIDs could
also activate PPAR
The ability of these compounds to interact with PPAR For comparative purposes, we also tested the various NSAIDs on the
PPAR We and others (24,
25, 28, 30-33) have shown that treatment of various fibroblast and
mesenchymal stem cell lines with PPAR
Our finding that flufenamic acid, fenoprofen, and ibuprofen also
activated PPAR We note that ibuprofen, which was a less efficacious activator of
PPAR DISCUSSION The NSAID indomethacin is frequently included as one of a mixture
of compounds used to promote the terminal differentiation of various
preadipocyte cell lines in vitro. This differentiation mixture also routinely includes insulin, corticosteroids, and isobutylmethylxanthine. Recent work has indicated that
isobutylmethylxanthine and corticosteroids induce the expression of the
genes encoding CCAAT/enhancer binding proteins In searching for the basis of its adipogenic activity, we have found
that indomethacin functions as a micromolar ligand for the adipogenic
transcription factor PPAR While indomethacin is widely used to promote the differentiation of
preadipocyte cell lines, in at least one instance indomethacin was
found to block this process (4). Our results together with the recent
findings that a subset of the PGs activate PPAR We have shown that the same NSAIDs that activate PPAR In summary, we have demonstrated that indomethacin and other NSAIDs are
efficacious activators of PPAR FOOTNOTES Acknowledgments We thank Tim Willson for preparation of Fig.
1 and critical reading of the manuscript and Larry Hammacher for
assistance with cell culture.
REFERENCES
Volume 272, Number 6,
Issue of February 7, 1997
pp. 3406-3410
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
and 
Are
Activated by Indomethacin and Other Non-steroidal Anti-inflammatory
Drugs*
,,
Molecular Endocrinology and
§ Cell Biology, Glaxo Wellcome Research and Development,
Research Triangle Park, North Carolina 27709 and ¶ Affymax,
Santa Clara, California 95051
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
Acknowledgments
REFERENCES
(PPAR), a ligand-activated
transcription factor known to play a pivotal role in
adipogenesis. The concentration of indomethacin required to activate
PPAR is in good agreement with that required to induce the
differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that
several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic
acid, are also PPAR ligands and induce adipocyte differentiation of
C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate
PPAR are also efficacious activators of PPAR
, a liver-enriched
PPAR subtype that plays a key role in peroxisome proliferation.
Interestingly, several NSAIDs have been reported to induce peroxisomal
activity in hepatocytes both in vitro and in
vivo. Our findings define a novel group of PPAR ligands and
provide a molecular basis for the biological effects of these drugs on
adipogenesis and peroxisome activity.
, as a key
regulator of adipogenesis (8). PPAR, a member of the nuclear receptor superfamily, is selectively expressed in adipocytes and induced early during the course of differentiation of several preadipocyte cell lines (9, 10). Forced expression of PPAR in
fibroblast and myoblast cell lines results in efficient adipocyte differentiation in a PPAR-activator-dependent fashion
(8, 11). Thus, PPAR functions as a master regulator of adipocyte differentiation. Two other PPAR subtypes, termed PPAR and PPAR
, have been identified in addition to PPAR (12, 13). PPAR is the
predominant PPAR subtype expressed in liver and is activated by a group
of chemicals that induce the proliferation of peroxisomes in rodents
(14). Gene disruption experiments have demonstrated that PPAR is
required for the pleiotropic hepatic response to peroxisome
proliferators in rodents (15).
is activated by PGs and PG-like molecules
(20-23). Recently, the arachidonic acid metabolite
15-deoxy-
12,14-PGJ2 was shown to bind
directly to PPAR and to promote the efficient conversion of
fibroblast and mesenchymal stem cell lines to adipocytes (24, 25). The
finding that a PG functions as a PPAR ligand and promotes adipocyte
differentiation provided additional evidence that products of the COX
pathway play an important role in modulating adipogenesis.
ligands and induce adipogenesis,
how then does a COX inhibitor such as indomethacin, which blocks PG
synthesis, promote adipocyte differentiation? In this report, we show
that indomethacin and several other NSAIDs function as PPAR ligands,
suggesting a mechanism for the adipogenic actions of these compounds.
Furthermore, we demonstrate that these same NSAIDs also activate
PPAR, providing a basis for the reported effects of NSAIDs on
peroxisome activity in liver.
12,14-PGJ2 from Cayman Chemical
Company (Ann Arbor, MI).
LBD
and pSG5-GAL4-PPARLBD chimeric receptor expression plasmids,
cDNAs encoding the ligand binding domains (LBDs) of the human
PPAR (amino acids 167-468) (26) and the human PPAR (amino acids
176-477) (27) were amplified by polymerase chain reaction and
subcloned into the pSG5-GAL4 expression plasmid (28). The pCMV-PPAR
expression plasmid has been described (27). The
(UAS)5-tk-CAT and aP2-tk-CAT reporter plasmids were
previously described (28). Transient cotransfection assays using these
plasmids were performed as described previously (28).
(amino acids
176-477) (27) was overexpressed in Escherichia coli as a
histidine-tagged fusion protein and bacterial lysates prepared as
described previously (25). For competition binding assays, bacterial
extracts (approximately 100 µg of protein) containing the PPAR
ligand binding domain were incubated at 4 °C for 2-3 h with 40 nM [3H]BRL49653 (specific activity, 40 Ci/mmol) in the absence or presence of unlabeled competitor in buffer
containing 10 mM Tris (pH 8.0), 50 mM KCl, 10 mM dithiothreitol. Bound was separated from free radioactivity by elution through 1- ml Sephadex G-25 desalting columns
(Boehringer Mannheim). Bound radioactivity eluted in the column void
volume and was quantitated by liquid scintillation counting. Data shown
are the result of binding assays performed in duplicate, and each
experiment was repeated at least twice with similar results.
-32P]dCTP. The results of Northern
assays were quantitated using a Molecular Dynamics Computing
Densitometer and Image Quant software.
.
Fig. 1.
Chemical structures of the NSAIDs used in
this study. For comparison, the chemical structures of the PPAR
ligands BRL49653 and 15-deoxy-12,14-PGJ2 are
included.
[View Larger Version of this Image (27K GIF file)]
via a
transient transfection assay. An established chimera system was used
(28) in which the LBD of PPAR was fused to the DNA binding domain of
the yeast transcription factor GAL4. The advantage of the GAL4 chimera
assay is that it minimizes background due to the cell's endogenous
receptors. Expression plasmid for the GAL4-PPAR LBD chimera was
transfected into CV-1 cells together with a reporter construct
containing five copies of the GAL4 response element driving expression
of the reporter chloramphenicol acetyltransferase (UAS5-tk-CAT). Dose-response analysis revealed that
indomethacin is an efficacious activator of PPAR, inducing PPAR
activity roughly 40-fold at 1 × 10
4 M
(Fig. 2). This activation is comparable with the maximal
induction obtained with the PPAR ligands
15-deoxy-12,14-PGJ2 and the anti-diabetic
thiazolidinedione BRL49653 (25, 28) (see below). Indomethacin activated
PPAR with an EC50 of approximately 4 × 105 M (Fig. 2). Similar EC50 and
fold activation values were obtained for indomethacin in transient
transfection assays performed with an expression vector for wild-type
PPAR and a reporter driven by the fatty acid binding protein/aP2
enhancer region which contains two PPAR response elements (10) (Fig.
2). Thus, indomethacin is an efficacious activator of PPAR.
Fig. 2.
Indomethacin activates PPAR. CV-1
cells were transfected with expression plasmid pSG5-GAL4-PPARLBD
encoding the chimeric GAL4-PPAR receptor and the
UAS5-tk-CAT reporter plasmid (dotted line) or,
alternatively, expression plasmid for pSG5-PPAR1 encoding the
wild-type PPAR1 receptor and reporter plasmid aP2-tk-CAT (solid line). Cells were treated with increasing
concentrations (M) of indomethacin, and cell extracts were
subsequently assayed for CAT activity.
[View Larger Version of this Image (17K GIF file)]
through direct interactions with
the receptor. We and others (24, 28) have previously shown that the
anti-diabetic thiazolidinedione BRL49653 can bind to PPAR with high
affinity. The ability of indomethacin to bind to PPAR was assessed
in a competition binding assay using [3H]BRL49653 and
bacterially expressed PPAR LBD. As shown in Fig. 3,
indomethacin competed efficiently with [3H]BRL49653 for
binding to the PPAR LBD, with an IC50 of approximately 1 × 104 M. In control experiments,
acetaminophen, an NSAID that does not activate PPAR (see below),
failed to compete with [3H]BRL49653 for binding to the
PPAR LBD (Fig. 3). These data demonstrate that indomethacin can
interact directly and specifically with the PPAR LBD and thus define
a novel PPAR ligand.
Fig. 3.
Indomethacin binds to PPAR.
Competition binding assays were performed with histidine-tagged
PPARLBD and 40 nM [3H]BRL49653 in the
presence of increasing concentrations (M) of unlabeled
indomethacin (circles) or acetaminophen (squares)
as competitor.
[View Larger Version of this Image (19K GIF file)]
and PPAR
. CV-1 cells were transfected with the
GAL4-PPARLBD expression plasmid and the UAS5-tk-CAT reporter and treated with 1 × 104 M of
piroxicam, flufenamic acid, ibuprofen, fenoprofen, and salicylic acid.
As shown in Fig. 4A, flufenamic acid,
fenoprofen, and ibuprofen were efficient activators of PPAR,
activating the receptor to a degree comparable to that obtained with
the PPAR ligands BRL49653 and
15-deoxy-12,14-PGJ2 and the peroxisome
proliferator Wy14,643. However, in contrast to indomethacin, no
activation of PPAR was observed in transfected cells treated with
1 × 105 M of these compounds (data not
shown). Thus, indomethacin is the most potent of the NSAIDs that we
tested for PPAR activation. Treatment of transfected cells with
piroxicam resulted in only a modest activation of PPAR
(approximately 5-fold), whereas treatment with salicylic acid or
acetaminophen resulted in little or no induction of reporter expression
(Fig. 4A). We note that the compounds that activated PPAR
efficiently (>6-fold) were all amphipathic acids (Fig. 1) and thus
conform in their general structural features to known PPAR
activators.
Fig. 4.
Selected NSAIDs activate PPAR and PPAR.
A, CV-1 cells were transfected with the
UAS5-tk-CAT reporter plasmid and expression plasmids
pSG5-GAL4-PPARLBD (PPAR) or pSG5-GAL4-PPARLBD (PPAR).
Transfected cells were treated with 1 × 104
M of the various NSAIDs, Wy14,643 or
15-deoxy-12,14-PGJ2, or 1 × 105 M of BRL49653 and cell extracts
subsequently assayed for CAT activity. Data are presented as the fold
induction relative to vehicle-treated (0.1% Me2SO) cells
and are shown as the mean ± S.D. B, competition
binding assays were performed with histidine-tagged PPARLBD and 40 nM [3H]BRL49653 in the presence of vehicle
alone (1% Me2SO) or 1 × 103
M of each of the indicated NSAIDs as unlabeled competitor.
Results are shown as the mean of assays performed in duplicate ± S.D.
[View Larger Version of this Image (33K GIF file)]
was assessed in
the competition binding assay using [3H]BRL49653. These
studies revealed a good correlation between the compounds that
activated PPAR in the transfection assay and those that interacted
directly with the receptor. Although flufenamic acid, fenoprofen, and
ibuprofen competed efficiently with [3H]BRL49653 for
binding to the PPAR LBD, little or no competition was seen with
piroxicam, salicylic acid, or acetaminophen (Fig. 4B). Taken
together, the transfection and binding analyses demonstrate that some
but not all NSAIDs bind and activate PPAR.
and PPAR subtypes using the transfection assay. Little or no
activation of PPAR was seen in the presence of 1 × 104 M of these compounds (data not shown).
However, indomethacin, fenoprofen, ibuprofen, and flufenamic acid were
efficacious activators of PPAR at this concentration, with
fenoprofen activating the receptor to a degree comparable to that
obtained with the strong peroxisome proliferator Wy14,643 (Fig.
4A). Thus, the same NSAIDs that activate PPAR are also
efficacious activators of the PPAR subtype.
ligands, including
15-deoxy-12,14-PGJ2 and the anti-diabetic
thiazolidinediones, promotes their efficient conversion to adipocytes.
As discussed, indomethacin is used to promote the terminal
differentiation of preadipocyte cell lines. We next examined whether
the concentration of indomethacin required to activate PPAR in CV-1
cells was consistent with that required to induce adipocyte
differentiation. C3H10T1/2 mouse mesenchymal stem cells were treated
with various concentrations of indomethacin and subsequently assayed
for lipogenesis, an established measure of adipocyte differentiation
(29). Dose-response analysis revealed the EC50 for
indomethacin in the lipogenesis assay to be approximately 8 × 105 M (Fig. 5A).
This value is in good agreement with that reported in a previous study
(3 × 105 M) using TA1 cells, a stable
adipogenic cell line derived from C3H10T1/2 cells (7), and is also
consistent with the EC50 value of indomethacin for PPAR
activation in the transfection assay (Fig. 2). Taken together, these
data suggest that PPAR is the target for the adipogenic actions of
indomethacin.
Fig. 5.
Selected NSAIDs induce differentiation of
C3H10T1/2 cells to adipocytes. A, C3H10T1/2 cells were
treated with increasing concentrations (M) of indomethacin
for 9 days, and lipogenesis was subsequently measured. Data points
represent the mean of assays performed in triplicate ± S.D.
B, C3H10T1/2 cells were treated for 9 days with 1 × 104 M of the indicated NSAIDs (ibuprofen was
also tested at 5 × 104 M as indicated),
1 × 106 M BRL49653, 1 × 104 M Wy14,643, or 3 × 106 M
15-deoxy-12,14-PGJ2. Lipogenesis is shown as
fold induction for each of the compounds relative to cells treated with
vehicle (0.1% Me2SO) alone. Results are shown as the mean
of assays performed in triplicate ± S.D. C, Northern
analysis was performed using total RNA prepared from C3H10T1/2 cells
treated for 9 days with vehicle alone (0.1% Me2SO), 1 × 106 M BRL49653, or 1 × 104 M of the indicated NSAIDs. The blot was
hybridized sequentially with aP2 and GAPDH probes. Specific aP2 and
GAPDH mRNA signals were quantitated via scanning densitometry.
Values shown represent aP2 signal normalized to GAPDH signal.
[View Larger Version of this Image (17K GIF file)]
at micromolar concentrations suggested that these
NSAIDs might also promote adipocyte differentiation. We tested this
possibility using C3H10T1/2 cells and the lipogenesis assay. In
agreement with previous studies, treatment of the C3H10T1/2 cells with
either 1 × 106 M of the
thiazolidinedione BRL49653 or 3 × 106 M
15-deoxy-12,14-PGJ2 resulted in marked
increases in adipocyte differentiation (Fig. 5B) (25, 28).
As expected, concentrations of the hypolipidemic agent Wy14,643
sufficient to activate PPAR also induced lipogenesis (Fig.
5B) (9, 28). Treatment of C3H10T1/2 cells with 1 × 104 M of either flufenamic acid or fenoprofen
promoted lipogenesis, albeit less efficiently than indomethacin (Fig.
5B). The results of the lipogenesis assay were confirmed by
oil red O staining for lipid accumulation in treated cells (data not
shown). The NSAIDs that did not activate PPAR efficiently in the
transfection assay, including piroxicam, salicylic acid, and
acetaminophen, failed to induce lipogenesis in the C3H10T1/2 cells
(Fig. 5B). We conclude that NSAIDs other than indomethacin
can also promote adipocyte differentiation at concentrations at which
they activate PPAR.
in CV-1 cells than either flufenamic acid or fenoprofen (Fig.
4A), failed to promote lipogenesis in C3H10T1/2 cells when tested at 1 × 104 M (Fig.
5B). However, increasing the concentration of indomethacin to 5 × 104 M resulted in significant
lipogenesis (Fig. 5B). In Northern analysis, 1 × 104 M ibuprofen induced weak expression of
the gene encoding aP2, an adipocyte-specific fatty acid binding protein
whose expression is directly regulated by PPAR (Fig. 5C)
(10). Consistent with the results of the transfection studies, 1 × 104 M indomethacin stimulated aP2 gene
expression approximately 3-fold more efficiently than ibuprofen (Fig.
5C). Taken together, these data indicate that ibuprofen is
less potent than indomethacin, flufenamic acid, or fenoprofen in the
activation of PPAR in both CV-1 and C3H10T1/2 cells.
and ,
respectively, members of the basic region-leucine zipper family of
transcription factors (34). These two transcription factors are induced
early during the course of 3T3-L1 cell conversion to adipocytes and
appear to play key roles in the differentiation cascade (34-37). The
mechanism underlying the adipogenic activity of indomethacin, however,
has remained unclear. Early speculation focused on the ability of indomethacin to inhibit COX activity. However, Knight et al.
(7) showed that the concentration of indomethacin required to promote the differentiation of TA1 cells to adipocytes was 1-2 orders of
magnitude greater than the concentrations needed to block prostaglandin synthesis. Furthermore, not all COX inhibitors promoted adipocyte differentiation. Likewise, we have found that several COX inhibitors, including the potent NSAID piroxicam (38), fail to promote adipocyte differentiation. These data provide compelling evidence that the effects of indomethacin are not mediated through the inhibition of
prostaglandin production.
. PPAR is abundantly expressed in
adipose tissue where it functions as a key modulator of the adipocyte
differentiation program (8-10). PPAR ligands, including the
anti-diabetic thiazolidinediones and the arachidonic acid metabolite
15-deoxy-12,14-PGJ2, are potent inducers of
the differentiation of several different fibroblastic cell lines to
adipocytes (30-33). Our finding that the concentration of indomethacin
required to induce C3H10T1/2 cell differentiation correlates with that
required to activate PPAR in the transfection assay provides strong
evidence that the adipogenic actions of this NSAID are mediated through
its binding and activation of PPAR.
(23-25) may provide
an explanation for this paradox. At lower concentrations, indomethacin
may block COX activity, thus inhibiting the formation of adipogenic PGs
and activators of PPAR such as
15-deoxy-12,14-PGJ2 and prostacyclin without
directly affecting the PPARs. At higher concentrations, however,
indomethacin not only inhibits COX activity but also acts as a PPAR
agonist, promoting adipocyte differentiation. Thus, indomethacin may
function to either inhibit or induce adipogenesis depending upon the
particular concentration of drug used in the experiment.
also activate
PPAR. PPAR is the predominant PPAR subtype expressed in the
rodent liver (14, 21). Targeted gene disruption experiments have shown
that PPAR is essential for the induction of peroxisomal enzymes and
peroxisome proliferation in the rodent liver (15). Interestingly,
several NSAIDs have been reported to have marked effects on peroxisome
activity in hepatocytes when used either in vitro or
in vivo. Indomethacin and ibuprofen induced -oxidation in
peroxisomes of cultured hepatocytes (39). Furthermore, treatment of
rats with ibuprofen induced peroxisomal -oxidation, reduced serum
triglycerides and cholesterol, and increased liver weight (39).
Finally, treatment of rats with benoxaprofen, an NSAID closely related
to ibuprofen, at doses comparable to those used clinically induced
peroxisomal -oxidation and increased cytochrome P4504A1 apoprotein
and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional
protein levels in liver (40). Expression of both of these genes is
known to be induced by PPAR in response to peroxisome proliferators
(15, 41, 42). As a whole, the effects of these NSAIDs on liver function
are similar to those seen in experiments performed with the fibrate
class of hypolipidemic drugs (43), agents that are established
activators of PPAR (14). Our data strongly suggest that the actions
of NSAIDs on peroxisomal and liver functions are mediated through the
activation of PPAR. We note, however, that we do not have a binding
assay for mammalian PPAR and, as a consequence, have not been able to demonstrate direct interactions between the NSAIDs and PPAR. Thus, it remains possible that the NSAIDs modulate PPAR activity through an indirect mechanism. It is interesting that NSAIDs are associated with a variety of detrimental side effects, including hepatotoxicity (1). While there is currently no evidence of a link
between these negative effects and PPARs, evaluation of the activities
of NSAIDs on PPARs may be useful in minimizing the potential for
unwanted side effects as new drugs of this class are developed.
and PPAR at micromolar concentrations. These data provide evidence for a common mechanism underlying the seemingly disparate biological effects of these compounds on the induction of adipocyte differentiation in
vitro and peroxisome proliferation in vivo.
To whom correspondence should be addressed: Dept. of Molecular
Endocrinology, Rm. 3.3124, Glaxo Wellcome Research and Development, Five Moore Dr., Research Triangle Park, NC 27709. Tel.: 919-483-5601; Fax: 919-483-6147; E-mail: sak15922{at}glaxo.com.
1
The abbreviations used are: NSAID, non-steroidal
anti-inflammatory drug; COX, cyclooxygenase; PPAR, peroxisome
proliferator-activated receptor ; PGs, prostaglandins; LBDs, ligand
binding domains; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CAT,
chloramphenicol acetyltransferase; UAS, upstream activation sequence;
Me2SO, dimethyl sulfoxide.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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L. Klotz, I. Dani, F. Edenhofer, L. Nolden, B. Evert, B. Paul, W. Kolanus, T. Klockgether, P. Knolle, and L. Diehl Peroxisome Proliferator-Activated Receptor {gamma} Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy J. Immunol., February 15, 2007; 178(4): 2122 - 2131. [Abstract] [Full Text] [PDF]
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M. Sastre, I. Dewachter, S. Rossner, N. Bogdanovic, E. Rosen, P. Borghgraef, B. O. Evert, L. Dumitrescu-Ozimek, D. R. Thal, G. Landreth, et al. Nonsteroidal anti-inflammatory drugs repress {beta}-secretase gene promoter activity by the activation of PPAR{gamma} PNAS, January 10, 2006; 103(2): 443 - 448. [Abstract] [Full Text] [PDF]
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D. Lu, H. B. Cottam, M. Corr, and D. A. Carson Repression of {beta}-catenin function in malignant cells by nonsteroidal antiinflammatory drugs PNAS, December 20, 2005; 102(51): 18567 - 18571. [Abstract] [Full Text] [PDF]
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L. Klotz, M. Schmidt, T. Giese, M. Sastre, P. Knolle, T. Klockgether, and M. T. Heneka Proinflammatory Stimulation and Pioglitazone Treatment Regulate Peroxisome Proliferator-Activated Receptor {gamma} Levels in Peripheral Blood Mononuclear Cells from Healthy Controls and Multiple Sclerosis Patients J. Immunol., October 15, 2005; 175(8): 4948 - 4955. [Abstract] [Full Text] [PDF]
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L A A Brosens, J J Keller, G J A Offerhaus, M Goggins, and F M Giardiello Prevention and management of duodenal polyps in familial adenomatous polyposis Gut, July 1, 2005; 54(7): 1034 - 1043. [Full Text] [PDF]
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S. Fukuen, M. Iwaki, A. Yasui, M. Makishima, M. Matsuda, and I. Shimomura Sulfonylurea Agents Exhibit Peroxisome Proliferator-activated Receptor {gamma} Agonistic Activity J. Biol. Chem., June 24, 2005; 280(25): 23653 - 23659. [Abstract] [Full Text] [PDF]
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M. T. Heneka, M. Sastre, L. Dumitrescu-Ozimek, A. Hanke, I. Dewachter, C. Kuiperi, K. O'Banion, T. Klockgether, F. Van Leuven, and G. E. Landreth Acute treatment with the PPAR{gamma} agonist pioglitazone and ibuprofen reduces glial inflammation and A{beta}1-42 levels in APPV717I transgenic mice Brain, June 1, 2005; 128(6): 1442 - 1453. [Abstract] [Full Text] [PDF]
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M. E. Winters, A. I. Mehta, E. F. Petricoin III, E. C. Kohn, and L. A. Liotta Supra-additive Growth Inhibition by a Celecoxib Analogue and Carboxyamido-triazole Is Primarily Mediated through Apoptosis Cancer Res., May 1, 2005; 65(9): 3853 - 3860. [Abstract] [Full Text] [PDF]
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R. K. Vikramadithyan, K. Hirata, H. Yagyu, Y. Hu, A. Augustus, S. Homma, and I. J. Goldberg Peroxisome Proliferator-Activated Receptor Agonists Modulate Heart Function in Transgenic Mice with Lipotoxic Cardiomyopathy J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 586 - 593. [Abstract] [Full Text] [PDF]
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A. Sivarajah, M. C. McDonald, and C. Thiemermann The Cardioprotective Effects of Preconditioning with Endotoxin, but Not Ischemia, Are Abolished by a Peroxisome Proliferator-Activated Receptor-{gamma} Antagonist J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 896 - 901. [Abstract] [Full Text] [PDF]
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G. Eibl, Y. Takata, L. G. Boros, J. Liu, Y. Okada, H. A. Reber, and O. J. Hines Growth Stimulation of COX-2-Negative Pancreatic Cancer by a Selective COX-2 Inhibitor Cancer Res., February 1, 2005; 65(3): 982 - 990. [Abstract] [Full Text] [PDF]
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Y. Rival, A. Stennevin, L. Puech, A. Rouquette, C. Cathala, F. Lestienne, E. Dupont-Passelaigue, J.-F. Patoiseau, T. Wurch, and D. Junquero Human Adipocyte Fatty Acid-Binding Protein (aP2) Gene Promoter-Driven Reporter Assay Discriminates Nonlipogenic Peroxisome Proliferator-Activated Receptor {gamma} Ligands J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 467 - 475. [Abstract] [Full Text] [PDF]
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H. Yajima, E. Ikeshima, M. Shiraki, T. Kanaya, D. Fujiwara, H. Odai, N. Tsuboyama-Kasaoka, O. Ezaki, S. Oikawa, and K. Kondo Isohumulones, Bitter Acids Derived from Hops, Activate Both Peroxisome Proliferator-activated Receptor {alpha} and {gamma} and Reduce Insulin Resistance J. Biol. Chem., August 6, 2004; 279(32): 33456 - 33462. [Abstract] [Full Text] [PDF]
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N. Morioka, K. Kumagai, K. Morita, S. Kitayama, and T. Dohi Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP+)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP+ in PC12 Cells J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 800 - 807. [Abstract] [Full Text] [PDF]
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A. E. Lovett-Racke, R. Z. Hussain, S. Northrop, J. Choy, A. Rocchini, L. Matthes, J. A. Chavis, A. Diab, P. D. Drew, and M. K. Racke Peroxisome Proliferator-Activated Receptor {alpha} Agonists as Therapy for Autoimmune Disease J. Immunol., May 1, 2004; 172(9): 5790 - 5798. [Abstract] [Full Text] [PDF]
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M. S. Shaik, A. Chatterjee, and M. Singh Effect of a Selective Cyclooxygenase-2 Inhibitor, Nimesulide, on the Growth of Lung Tumors and Their Expression of Cyclooxygenase-2 and Peroxisome Proliferator- Activated Receptor-{gamma} Clin. Cancer Res., February 15, 2004; 10(4): 1521 - 1529. [Abstract] [Full Text] [PDF]
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A. F. Badawi, M. B. Eldeen, Y. Liu, E. A. Ross, and M. Z. Badr Inhibition of Rat Mammary Gland Carcinogenesis by Simultaneous Targeting of Cyclooxygenase-2 and Peroxisome Proliferator-activated Receptor {gamma} Cancer Res., February 1, 2004; 64(3): 1181 - 1189. [Abstract] [Full Text] [PDF]
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N. Babbar, N. A. Ignatenko, R. A. Casero Jr., and E. W. Gerner Cyclooxygenase-independent Induction of Apoptosis by Sulindac Sulfone Is Mediated by Polyamines in Colon Cancer J. Biol. Chem., November 28, 2003; 278(48): 47762 - 47775. [Abstract] [Full Text] [PDF]
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M. Sastre, I. Dewachter, G. E. Landreth, T. M. Willson, T. Klockgether, F. van Leuven, and M. T. Heneka Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of {beta}-Secretase J. Neurosci., October 29, 2003; 23(30): 9796 - 9804. [Abstract] [Full Text] [PDF]
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M. Mendez and M. C. LaPointe PPAR{gamma} Inhibition of Cyclooxygenase-2, PGE2 Synthase, and Inducible Nitric Oxide Synthase in Cardiac Myocytes Hypertension, October 1, 2003; 42(4): 844 - 850. [Abstract] [Full Text] [PDF]
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N. Niho, M. Takahashi, T. Kitamura, Y. Shoji, M. Itoh, T. Noda, T. Sugimura, and K. Wakabayashi Concomitant Suppression of Hyperlipidemia and Intestinal Polyp Formation in Apc-deficient Mice by Peroxisome Proliferator-activated Receptor Ligands Cancer Res., September 15, 2003; 63(18): 6090 - 6095. [Abstract] [Full Text] [PDF]
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L Jackson, W Wahli, L Michalik, S A Watson, T Morris, K Anderton, D R Bell, J A Smith, C J Hawkey, and A J Bennett Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer Gut, September 1, 2003; 52(9): 1317 - 1322. [Abstract] [Full Text]
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S. A. Sagi, S. Weggen, J. Eriksen, T. E. Golde, and E. H. Koo The Non-cyclooxygenase Targets of Non-steroidal Anti-inflammatory Drugs, Lipoxygenases, Peroxisome Proliferator-activated Receptor, Inhibitor of {kappa}B Kinase, and NF{kappa}B, Do Not Reduce Amyloid {beta}42 Production J. Biol. Chem., August 22, 2003; 278(34): 31825 - 31830. [Abstract] [Full Text] [PDF]
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S. Weggen, J. L. Eriksen, S. A. Sagi, C. U. Pietrzik, V. Ozols, A. Fauq, Todd. E. Golde, and E. H. Koo Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid {beta}42 Production by Direct Modulation of {gamma}-Secretase Activity J. Biol. Chem., August 22, 2003; 278(34): 31831 - 31837. [Abstract] [Full Text] [PDF]
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Q. Yan, J. Zhang, H. Liu, S. Babu-Khan, R. Vassar, A. L. Biere, M. Citron, and G. Landreth Anti-Inflammatory Drug Therapy Alters {beta}-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease J. Neurosci., August 20, 2003; 23(20): 7504 - 7509. [Abstract] [Full Text] [PDF]
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A. N. Hata, R. Zent, M. D. Breyer, and R. M. Breyer Expression and Molecular Pharmacology of the Mouse CRTH2 Receptor J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 463 - 470. [Abstract] [Full Text] [PDF]
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Y. Yajima, M. Sato, M. Sumida, and S. Kawashima Mechanism of Adult Primitive Mesenchymal ST-13 Preadipocyte Differentiation Endocrinology, June 1, 2003; 144(6): 2559 - 2565. [Abstract] [Full Text] [PDF]
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J. Liu, H. Li, S. H. Burstein, R. B. Zurier, and J. D. Chen Activation and Binding of Peroxisome Proliferator-Activated Receptor gamma by Synthetic Cannabinoid Ajulemic Acid Mol. Pharmacol., May 1, 2003; 63(5): 983 - 992. [Abstract] [Full Text] [PDF]
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G. Hawcroft, S. H. Gardner, and M. A. Hull Activation of Peroxisome Proliferator-Activated Receptor gamma Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 632 - 637. [Abstract] [Full Text] [PDF]
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C. Dello Russo, V. Gavrilyuk, G. Weinberg, A. Almeida, J. P. Bolanos, J. Palmer, D. Pelligrino, E. Galea, and D. L. Feinstein Peroxisome Proliferator-activated Receptor gamma Thiazolidinedione Agonists Increase Glucose Metabolism in Astrocytes J. Biol. Chem., February 14, 2003; 278(8): 5828 - 5836. [Abstract] [Full Text] [PDF]
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A. Goel, D. K. Chang, L. Ricciardiello, C. Gasche, and C. R. Boland A Novel Mechanism for Aspirin-mediated Growth Inhibition of Human Colon Cancer Cells Clin. Cancer Res., January 1, 2003; 9(1): 383 - 390. [Abstract] [Full Text] [PDF]
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V. Blais, J. Zhang, and S. Rivest In Altering the Release of Glucocorticoids, Ketorolac Exacerbates the Effects of Systemic Immune Stimuli on Expression of Proinflammatory Genes in the Brain Endocrinology, December 1, 2002; 143(12): 4820 - 4827. [Abstract] [Full Text] [PDF]
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M. Wick, G. Hurteau, C. Dessev, D. Chan, M. W. Geraci, R. A. Winn, L. E. Heasley, and R. A. Nemenoff Peroxisome Proliferator-Activated Receptor-gamma Is a Target of Nonsteroidal Anti-Inflammatory Drugs Mediating Cyclooxygenase-Independent Inhibition of Lung Cancer Cell Growth Mol. Pharmacol., November 1, 2002; 62(5): 1207 - 1214. [Abstract] [Full Text] [PDF]
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P. S. Carlton, R. Gopalakrishnan, A. Gupta, B. W. Liston, S. Habib, M. A. Morse, and G. D. Stoner Piroxicam Is an Ineffective Inhibitor of N-Nitrosomethylbenzylamine-induced Tumorigenesis in the Rat Esophagus Cancer Res., August 1, 2002; 62(15): 4376 - 4382. [Abstract] [Full Text] [PDF]
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R. Yamazaki, N. Kusunoki, T. Matsuzaki, S. Hashimoto, and S. Kawai Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis in Association with Activation of Peroxisome Proliferator-Activated Receptor gamma in Rheumatoid Synovial Cells J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 18 - 25. [Abstract] [Full Text] [PDF]
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 N. S. WAYMAN, Y. HATTORI, M. C. MCDONALD, H. MOTA-FILIPE, S. CUZZOCREA, B. PISANO, P. K. CHATTERJEE, and C. THIEMERMANN Ligands of the peroxisome proliferator-activated receptors (PPAR-{gamma} and PPAR-{alpha}) reduce myocardial infarct size FASEB J, July 1, 2002; 16(9): 1027 - 1040. [Abstract] [Full Text] [PDF]
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S. J. Baek, L. C. Wilson, C.-H. Lee, and T. E. Eling Dual Function of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Inhibition of Cyclooxygenase and Induction of NSAID-Activated Gene J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1126 - 1131. [Abstract] [Full Text] [PDF]
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S. Kim, J. Whelan, K. Claycombe, D. B. Reath, and N. Moustaid-Moussa Angiotensin II Increases Leptin Secretion by 3T3-L1 and Human Adipocytes via a Prostaglandin-Independent Mechanism J. Nutr., June 1, 2002; 132(6): 1135 - 1140. [Abstract] [Full Text] [PDF]
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M. M. Hayes, B. R. Lane, S. R. King, D. M. Markovitz, and M. J. Coffey Peroxisome Proliferator-activated Receptor gamma Agonists Inhibit HIV-1 Replication in Macrophages by Transcriptional and Post-transcriptional Effects J. Biol. Chem., May 3, 2002; 277(19): 16913 - 16919. [Abstract] [Full Text] [PDF]
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N. Janabi Selective Inhibition of Cyclooxygenase-2 Expression by 15-Deoxy-{Delta}12,1412,14-prostaglandin J2 in Activated Human Astrocytes, But Not in Human Brain Macrophages J. Immunol., May 1, 2002; 168(9): 4747 - 4755. [Abstract] [Full Text] [PDF]
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 M. Peters-Golden Open Mind, Open Airways . Broadening the Paradigm of Prostaglandins and Allergic Airway Inflammation Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1035 - 1036. [Full Text] [PDF]
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A. V. Pontsler, A. St. Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor gamma and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein J. Biol. Chem., April 5, 2002; 277(15): 13029 - 13036. [Abstract] [Full Text] [PDF]
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C. Waskewich, R. D. Blumenthal, H. Li, R. Stein, D. M. Goldenberg, and J. Burton Celecoxib Exhibits the Greatest Potency amongst Cyclooxygenase (COX) Inhibitors for Growth Inhibition of COX-2-negative Hematopoietic and Epithelial Cell Lines Cancer Res., April 1, 2002; 62(7): 2029 - 2033. [Abstract] [Full Text] [PDF]
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 R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
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Y. Oyama, N. Akuzawa, R. Nagai, and M. Kurabayashi PPAR{gamma} Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells Circ. Res., February 22, 2002; 90(3): 348 - 355. [Abstract] [Full Text] [PDF]
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H. Hirai, K. Tanaka, S. Takano, M. Ichimasa, M. Nakamura, and K. Nagata Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2 J. Immunol., February 1, 2002; 168(3): 981 - 985. [Abstract] [Full Text] [PDF]
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M. B. Hansen-Petrik, M. F. McEntee, B. Jull, H. Shi, M. B. Zemel, and J. Whelan Prostaglandin E2 Protects Intestinal Tumors from Nonsteroidal Anti-inflammatory Drug-induced Regression in ApcMin/+ Mice Cancer Res., January 1, 2002; 62(2): 403 - 408. [Abstract] [Full Text] [PDF]
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G. Hawcroft, M. D'Amico, C. Albanese, A. F. Markham, R. G. Pestell, and M. A. Hull Indomethacin induces differential expression of {beta}-catenin, {gamma}-catenin and T-cell factor target genes in human colorectal cancer cells Carcinogenesis, January 1, 2002; 23(1): 107 - 114. [Abstract] [Full Text] [PDF]
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D. J. A. Adamson, D. Frew, R. Tatoud, C. R. Wolf, and C. N. A. Palmer Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor-gamma Signaling Mol. Pharmacol., January 1, 2002; 61(1): 7 - 12. [Abstract] [Full Text] [PDF]
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 B. A. in 't Veld, A. Ruitenberg, A. Hofman, L. J. Launer, C. M. van Duijn, T. Stijnen, M. M.B. Breteler, and B. H.C. Stricker Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease N. Engl. J. Med., November 22, 2001; 345(21): 1515 - 1521. [Abstract] [Full Text] [PDF]
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R. J. Pettersen, Z. A. Muna, K. K.J. Kuiper, E. Svendsen, F. Muller, P. Aukrust, R. K. Berge, and J. Erik Nordrehaug Sustained retention of tetradecylthioacetic acid after local delivery reduces angioplasty-induced coronary stenosis in the minipig Cardiovasc Res, November 1, 2001; 52(2): 306 - 313. [Abstract] [Full Text] [PDF]
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 T. Cyrus, L. X. Tang, J. Rokach, G. A. FitzGerald, and D. Pratico Lipid Peroxidation and Platelet Activation in Murine Atherosclerosis Circulation, October 16, 2001; 104(16): 1940 - 1945. [Abstract] [Full Text] [PDF]
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I. TEGEDER, J. PFEILSCHIFTER, and G. GEISSLINGER Cyclooxygenase-independent actions of cyclooxygenase inhibitors FASEB J, October 1, 2001; 15(12): 2057 - 2072. [Abstract] [Full Text] [PDF]
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I. Shureiqi and S. M. Lippman Lipoxygenase Modulation to Reverse Carcinogenesis Cancer Res., September 1, 2001; 61(17): 6307 - 6312. [Abstract] [Full Text] [PDF]
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