| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Aventis Pharma Research & Development, Dagenham Research Centre, Dagenham, Essex, United Kingdom Aventis Pharma Research & Development, Dagenham Research Centre, Dagenham, Essex, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The GC receptor (GR) is a member of the nuclear receptor superfamily,
which, on binding to their cognate ligands, directly or indirectly
regulates the transcription of target genes (3, 4, 5, 6). There
are at least three distinct mechanisms by which GCs can regulate gene
transcription. First, GCs can bind to a cytosolic GR, which
translocates to the nucleus and, in the case of positive regulation,
transactivates through cis-activating palindromic GC
response elements (GREs) located in the promoter region of responsive
genes. Second, GCs are able to bind to negative GREs, resulting in the
repression of gene transcription. However, GCs decrease the
transcription of genes involved in the inflammatory process that have
no identifiable GREs in their promoter regions, suggesting that an
alternative mechanism must mediate this inhibitory effect. In fact,
there is now evidence to suggest that GCs may control inflammation
predominantly through the transrepression of transcription factors,
such as AP-1, NF-
B, and NF-AT, that regulate inflammatory gene
expression. Furthermore, there is increasing acceptance of the
hypothesis that the side effects of steroids are likely to be due to
transactivation of genes through binding of the GR dimers to DNA,
whereas the antiinflammatory effects result from the binding of a
single GR to transcription factors or coactivators resulting in gene
repression, i.e., transrepression.
The development of a novel GC, which discriminates between the two main activities of GCs, i.e., transactivation and transrepression, could be predicted to exhibit increased specificity for antiinflammatory activity and consequently an improved therapeutic ratio in vivo. Such a compound, RU 24858, which exhibits this separation of activities in vitro, has recently been described (7). However, the in vivo correlates of this in vitro profile remain unexplored. In this study, we have examined whether the improved in vitro profile results in the maintenance of antiinflammatory activity (evaluated in the rat Sephadex model of lung edema with steroids dosed orally (p.o.) 24 h and 2 h before Sephadex (intratracheally)) with reduced systemic toxicity (evaluated by a loss in body weight, thymus involution, and bone turnover following 7 days p.o. treatment) compared with the standard steroids, prednisolone and budesonide. A preliminary report has been presented in abstract form at the American Thoracic Society meeting (8).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To investigate whether the dissociated GC, RU 24858, could be active as an antiinflammatory drug in vivo, we studied its effect in the rat Sephadex model of lung edema (9). The effects observed were compared with the activity of the standard oral GCs, prednisolone and budesonide.
Male Sprague Dawley rats were weighed and randomly allocated into study groups to receive compound or vehicle (distilled water containing 0.5% carboxymethylcellulose containing 0.2% Tween 80). RU 24858 (0.3, 1, 3, 10, 30, 100, 300 mg/kg), budesonide (0.03, 0.1, 0.3, 1, 3, 10 mg/kg), prednisolone (1, 3, 10, 30, 100, 300, 1000 mg/kg), or vehicle was administered orally by gavage in a dose volume of 2 ml/kg 24 and 2 h before Sephadex/vehicle administration. Sephadex (5 mg/kg) or vehicle (saline) was administered intratracheally under halothane anesthesia (4% in oxygen for 3 min). Twenty-four hours later, the animals were killed by overdose with Euthatal (10 ml/kg i.p.). The heart and lungs were removed en bloc, and wet lung weights were determined and corrected for 100 g initial body weight.
Femur model of GC-induced osteopenia
To investigate whether the dissociated GC, RU 24858, induced systemic toxicity to the same degree as the standard GCs, prednisolone and budesonide, we studied the effect of these compounds in the rat femur model of steroid-induced osteopenia (10).
Male Sprague Dawley rats (190–220 g; Harlan, U.K.) were allowed free access to food and water. Animals were weighed and randomly allocated into study groups to receive either vehicle (distilled water containing 0.5% carboxymethylcellulose and 0.2% Tween 80), RU 24858 (0.3, 1, 3, 10, 30, or 100 mg/kg/day), budesonide (0.3, 1, 3, 10, or 30 mg/kg/day), or prednisolone (1, 3, 10, 30, or 100 mg/kg/day). Compounds were prepared as a suspension in vehicle and orally administered to rats once daily (2 ml/kg) for 7 days. Body weight was measured daily throughout the study. Twenty-four hours after administration of the last dose of compound, rats were killed by i.p. injection of Euthatal (10 ml/kg). Blood was collected into ice-cold tubes by cardiac puncture, and the serum was obtained after centrifugation (2500 x g for 20 min at 4°C) stored at -20°C until analyzed. The thymus was dissected free of connective tissue and weighed. The left femur was exposed and removed with head intact in the acetabulum by cutting through the pelvic girdle and through the femur shaft above the knee joint. The tissue was then fixed in 10% neutral buffered Formalin for histological assessment.
Femoral head histology
Preparation of histological specimens. Femurs were fixed in 10% neutral buffered Formalin for 7 days, then decalcified in 35% (v/v) formic acid in sodium citrate solution 13% (w/v) for 10 days (four changes). Tissues were washed in water for 48 h, then processed to paraffin wax overnight using an automated tissue processor (Tissue Tek VIP 3000; Bayer Diagnostics, Berkshire, U.K.). Three-micrometer-thick sections were cut (Shandon AS325 retraction microtome) with the trochanter, and the femoral head was included in the section, to allow standardization of tissue orientation and the level of sectioning. The sections were mounted on poly(L-lysine)-coated slides and dried at 37°C overnight. Sections were stained Alcian blue, as described below, using an automated slide stainer (Sakura DRS 601 Diversified Stainer; Bayer Diagnostics), and coverslipped.
Staining technique. Sections were rehydrated and incubated for 20 min with 1% (w/v) Alcian blue 8GX in 1% (v/v) acetic acid containing 10% (w/v) sodium chloride, then counterstained with hematoxylin and 1% (w/v) acid fuchsin/eosin mixture.
Quantitative histology of the femoral head growth plate
The femoral head growth plate was examined under a light microscope using x100 magnification. Images of the growth plate were captured onto computer (Apple MacIntosh 700) using Image Grabber software (Neotech) and assessed using Optilab software (Graphtek). One image was captured from each tissue section with five measurements of the growth plate width obtained from each calibrated image. Measurements involved drawing a line perpendicular to the growth plate between the edge of the hypertrophic zone distal to the articular cartilage and the end of the proliferating zone, clearly demarcated by the dark blue staining. Regions excluded from measurement were: the edges of the growth plate and naturally occurring gaps devoid of proliferating cells (which do not exhibit the distinct dark blue coloration). Sections showing evidence of antemortem trauma were also excluded.
Serum bone markers
Serum samples were thawed for 1 h at room temperature and
then centrifuged at 2500 x g for 10 min at 20°C.
Osteocalcin, alkaline phosphatase (ALP), acid phosphatase (ACP), and
the bone-specific tartrate-resistant ACP (TRAP) were all measured from
the same sample. Osteocalcin was measured by RIA (Biogenesis,
Bournemouth, U.K.) using a modification of the manufacturer’s
instructions. Briefly, samples were diluted 1/50 in RIA buffer (0.1225
M sodium chloride, 0.01 M sodium dihydrogen phosphate, 0.025 M EDTA
tetrasodium salt, 0.1% (w/v) Tween 20, and 0.1% (w/v) BSA, pH 7.4).
Standards and samples were incubated overnight with primary Ab, goat
anti-rat osteocalcin at 4°C on an orbital shaker. A total of 0.01
µCi of 125I-labeled rat osteocalcin was then
added to each tube vortex, mixed, and again incubated overnight, as
previously described. The precipitating Ab, donkey anti-goat IgG,
was diluted 1/40 in precipitation buffer (0.1 M sodium phosphate
buffer, pH 7.4, 2.5% (w/v) polyethylene glycol, 0.05% (w/v) sodium
azide). One milliliter was added to each tube and incubated for 2
h at 4°C on an orbital shaker. Tubes were then centrifuged at
1500 x g for 20 min at 4°C, supernatants were
decanted off, and pellets were washed with 500 µl of ice-cold
deionized water and respun. Pellets were counted for 1 min on a gamma
counter (LKB-Wallac 1275 Mini
).
Enzymes were measured directly after thawing on the IL-Monarch
Chemistry System (Instrumentation Laboratory, Warrington, U.K.); ALP
using a para-nitrophenyl phosphate reaction and ACP and TRAP using a
-naphthylphosphate reaction; kit instructions were followed.
Materials
Budesonide, prednisolone, Tween 80 (polyoxyethylenesorbitan monooleate), poly(L-lysine) solution, EDTA tetrasodium salt, Tween 20 (polyoxyethylenesorbitan monolaurate), BSA, DMSO, and polyethylene glycol (m.w. 15,000–20,000) were supplied by Sigma (Poole, U.K.). Carboxymethylcellulose (sodium salt), paramat extra paraffin wax, xylene, acid fuchsin, and Alcian blue 8GX were supplied by BDH Merck (Lutterworth, U.K.). Euthatal and Halothane were supplied by Rhone-Merieux (Harlow, U.K.). Neutral buffered Formalin (10%) was supplied by Surgipath Europe (St. Neots, U.K.). Citric acid and formic acid were supplied by Aldrich Chemical (Gillingham, U.K.). Saline (0.9% w/v) was obtained from Fresenius (Basingstoke, U.K.). Hematoxylin and eosin Y were preprepared stains from Shandon (Runcorn, U.K.). Osteocalcin assay reagents were supplied by Biogenesis: goat anti-rat osteocalcin, 125I-labeled rat osteocalcin, and donkey anti-goat IgG (5160-4004). Enzyme reagent kits were supplied by Instrumentation Laboratory: ALP, ACP, and TRAP. RU 24858 was synthesized by the Medicinal Chemistry Department at Aventis Pharma (Dagenham, U.K.).
Statistical analysis
All values presented are mean ± SE of eight determinations. The percentage inhibition of Sephadex-induced lung edema (compared with the Sephadex-administered, vehicle-treated group) was determined for each GC-treated group. The dose-response curve for inhibition of lung edema by GCs was calculated by least squares, nonlinear iterative regression with the ‘PRISM’ curve-fitting program (Graphpad Instat software program, San Diego, CA). A sigmoidal fit was obtained for the data generated from the Sephadex model. The effective dose causing a 50% reduction of the maximum (ED50) lung edema was calculated.
In the chronic dosing regime, all values presented are mean ± SE of eight determinations. Dose-dependent decreases in body weight gain, thymus weight, serum osteocalcin, and femur growth plate widths were assessed compared with the vehicle-treated control group. The dose causing a 50% reduction in body weight gain on day 7 (ED50) was calculated. The dose causing a 30% decrease in serum osteocalcin levels and the maximal decrease in femur growth plate width were calculated.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Sephadex instillation induced a significant edema response in the
lung (between 17% and 36.6% increase in wet weight). This increase in
wet lung weight was inhibited in a dose-dependent manner by RU 24858
(0.3–300 mg/kg, p.o.), prednisolone (1–1000 mg/kg, p.o.), and
budesonide (0.03–10 mg/kg, p.o.) (Fig. 1
). The ED50 for
inhibition of lung edema with RU 24858, prednisolone, and budesonide
were 0.88, 20.99, and 2.31 mg/kg, respectively. Therefore, the rank
order of potency obtained for the antiinflammatory activity of these
compounds was RU 24858 > budesonide > prednisolone.
|
Dose-dependent decreases were observed in all the main systemic
parameters, with the exception of the femur growth plate width, with
all three GCs. A significant, dose-related decrease in body weight gain
was seen in animals during the 7-day treatment period with RU 24858
(0.3–100 mg/kg, p.o., ED50 = 0.6 mg/kg),
prednisolone (1–100 mg/kg, p.o., ED50 = 1–3
mg/kg), and budesonide (0.3–30 mg/kg, p.o., ED50
= 0.55 mg/kg) when compared with vehicle control-treated animals (Figs. 2A,
3A, and
4A; Table I). Thymus involution, observed as a
decrease in thymus weight, was produced by 7-day dosing by all three
compounds (ED50 were obtained for RU 24858,
prednisolone, and budesonide of 1, 5, and 0.75 mg/kg, respectively;
Figs. 2B, 3B, and 4B; Table I).
|
|
). In addition, higher doses of steroid
elicited apoptosis of cells within the proliferative and hypertrophic
zones. These effects were also associated within marginalization of
chondrocytes on the proximal aspect of the growth plate. No other
pathologies were apparent in any of the sections examined. RU 24858 had
a biphasic effect on femur growth width that decreased to a maximal
26% at 3 mg/kg/day (Fig. 6, Table I
).
prednisolone and budesonide evoked similar decreases in the femur
growth plate width (maximal decrease >100 mg/kg/day and maximal
decrease at 10 mg/kg/day, respectively; Fig. 6).
|
|
Treatment with all three compounds evoked a dose-related
inhibition of serum osteocalcin levels (approximately
ED30 were obtained for RU 24858, prednisolone,
and budesonide of 10, 100, and 12.7 mg/kg, respectively; Fig. 5, Table I). Serum biochemistry
demonstrated a dose-dependent decrease in the bone enzyme markers, ALP,
ACP, and the bone-specific tartrate-resistant bone isoform (TRAP), with
all compounds reflecting a reduction in bone cell turnover (Table II). The systemic effects described above
have been observed with all three compounds. RU 24858 appears to have a
similar potency to budesonide, both of which were more potent than
prednisolone (Table II). From the results reported above, the compounds
elicit systemic side effects with the following order of potency:
budesonide 
RU 24858 > prednisolone.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Many of the proinflammatory genes whose products mediate the
inflammatory process in asthma are regulated by the transcription
factors AP-1 and NF-B. In the early 1990s, a number of groups
recognized that the GR can regulate gene transcription by forming
protein-protein interactions with these transcription factors without
the necessity for DNA binding. AP-1, which is a dimer of
c-jun and c-fos, contributes to the regulation of
cytokines and adhesion molecules. Direct protein-protein interaction
between AP-1 and the liganded GR was shown to result in repression of
transcriptional activity by blocking the interaction of both
transcription factors with their respective response elements
(11). Mutation studies of the GR have revealed that this
repressive action is most likely mediated by GR monomers rather than
dimers. Heck et al. (12) illustrated, through the
introduction of mutations in the DNA-binding domain of the GR, that
transactivation and transrepression can be dissociated. Mutations
resulting in failure of the GR to dimersize and bind DNA were
associated with a failure to transactivate GRE-dependent promoters in
cell transfection studies. However, repression of the AP-1-dependent
promoter by the mutant GR was as effective as the wild-type
receptor.
Various mechanisms have been invoked to explain the transrepressing
actions of steroids. Although evidence exists for the direct protein
interaction through the leucine zipper (B-zip) region of AP-1 and the
DNA-binding domain of the GR resulting in failure of DNA binding, this
is unlikely to be the sole mechanism (13). Furthermore, it
is now known that GCs can change chromatin structure and that this
property may be essential for their gene-regulatory activity. DNA is
wound around histone proteins to form nucleosomes and the chromatin
fiber in chromosomes. Increased transcription is associated with
uncoiling of DNA wound around histone. This is secondary to the
acetylation of the histone residues by the enzymatic action of
coactivator molecules such as the CREB-binding protein, which is
activated by the binding of transcription factors such as AP-1 and
NF-B (14). Because binding sites on these coactivator
molecules may be limited, this may result in competition between
transcription factors and the activated GR for the limited binding
sites available, resulting in an inhibition of inflammatory gene
transcription. GC-mediated repression of proinflammatory gene
transcription may also occur by deacetylation of histone, resulting in
tighter coiling of DNA and reduced access of transcription factors to
their binding sites.
The physiological significance of the DNA-binding and
dimerization-independent transrepressive actions of the GR is revealed
in studies in homozygous mice carrying a dimerization- and DNA-binding
defective mutant of GR (GRdim). DNA binding and
transcriptional regulation of genes containing GREs and nGREs were
confirmed to be unresponsive to GCs, whereas repression of
AP-1-mediated gene expression was shown to be intact. The
GRdim homozygotes appeared normal and survived to
adulthood in sharp contrast to mice, which were deficient in their GR.
This suggests that GRE-mediated gene regulation is not essential for
survival or development, whereas the ability of GR to transrepress
transcription factors is essential (15, 16, 17). However,
these studies do not address whether in these mutants GCs are capable
of regulating the activity of other transcription factors such as
NF-B, and thereby repress the expression of proinflammatory genes,
e.g., cytokines. Furthermore, although GRdim/dim
mice are resistant to GC-induced thymus involution, it is not clear
whether these mice would demonstrate an antiinflammatory effect in the
lung following GC treatment. These studies suggest that different
domains of the GR are responsible for different actions, but can this
be exploited pharmacologically, leading to agents with more selective
greater antiinflammatory activity compared with current drugs? The
evidence is that different steroids can preferentially elicit different
responses from the GR. Of considerable importance to the development of
more selective steroids is the consideration as to whether different
mechanisms can be invoked by different ligands following activation of
the GR (18).
Recently, a novel class of synthetic GCs has recently been identified
that exert strong AP-1 inhibition, whereas they only weakly activate
the GRE-based reporter genes. In addition, these dissociated GCs were
shown to inhibit IL-1
secretion and to display antiinflammatory
activity in vivo (7). A subsequent study has demonstrated
that these compounds are able to inhibit TNF--induced IL-6 secretion
in murine fibroblasts and HeLa cells. In addition, these compounds are
able to directly interfere with NF-B-dependent gene activation
without changing the expression level of inhibitor B
(18). In parallel to NF-B-dependent transrepression,
transactivation experiments were performed in the same study with
GRE-dependent promoter reporter gene variants in murine fibroblasts. In
agreement with Vayssière et al. (7), in human HeLa
cells and a rat hepatoma cell line, the dissociated steroids RU 24858
and RU 40066 did not substantially stimulate GRE-dependent
transactivation in murine fibroblast cells. Surprisingly, however, and
in contrast to previous observations reported by this group in human
and rat cells, RU 24782 displayed similar transactivating ability as
dexamethasone on the GRE-dependent reporter gene variants in mouse
fibroblast cells. These data illustrate the divergent potencies of
dissociated steroids in GRE-dependent reporter gene activation in human
and murine cells.
In this study, we investigated the activity of one of these dissociated
compounds, RU 24858, which claimed to differentiate between the two
main actions of GCs (i.e., transactivation and transrepression), while
possessing potent in vivo antiinflammatory activity (7).
In vitro studies have shown that that this compound exhibits
significant AP-1 transrepression while only weakly activating the
GRE-based reporter genes. Furthermore, the in vitro antiinflammatory
activity of RU 24858 was confirmed by inhibition of IL-1 secretion
from activated monocytes, while the compound was unable to induce
tyrosine amino transferase activity, confirming the lack of
transactivating activity. However, this study did not address whether
RU 24858 could exhibit the same dissociation by demonstrating
antiinflammatory properties without steroid adverse side effects in
vivo. We have demonstrated that RU 24858 exhibits comparable
antiinflammatory activity to the standard steroid, budesonide, in the
Sephadex model of lung edema in the rat. We have chosen to study the
consequences of GC excess on decrease in body weight, thymus
involution, and quantitative osteopenia of the femur growth plate, as
these effects can be easily modeled and reproducible measurements
obtained in animal models of this kind. Thymus involution is an
appropriate parameter to investigate the ability of GCs to
transactivate given that GC-induced thymocyte apoptosis requires
GR-mediated gene activation (19).
Interestingly, RU 24858 showed no differentiation, compared with
standard steroids, in the ability to induce systemic changes (e.g.,
loss in body weight, thymus involution) and in the quantitative
osteopenia of the femur observed after 7 days treatment. For all
steroids tested, depression in systemic osteocalcin levels indicates
inhibition of bone turnover via the osteoblast axis. In addition, bone
remodeling via the osteoclast was also attenuated, as evidenced by the
depression in ACP. Taken together, these results are consistent with
the known effects of GCs on the bone-remodeling axis, i.e., depression
of both the key cell types involved (20). In addition, the
osteocalcin data would support depression of calcium uptake into the
skeleton, which would further enhance these inhibitory effects.
Inhibition of bone growth is one of the major limitations of steroid
usage. Any steroid, which has an improved therapeutic ratio in terms of
this parameter, will exhibit an advantage in the market place. Bone
changes in this study have the following rank order of potency: RU
24858 budesonide > prednisolone. In addition, these
compounds show the same rank order of potency on decrease in body
weight and thymus involution. Down-regulation of NF-B DNA binding,
accompanied by increased expression of I-B (inhibitory protein
that dissociates from NF-B) and I-B, precedes thymocyte cell
death, suggesting that NF-B may be important for the survival of
immature thymocytes (21). Dissociated steroids, such as RU
24858, have been shown to directly interfere with NF-B-dependent
gene activation without changing the expression level of I-B
(18). These data suggest that the ability of RU 24858 to
evoke thymus involution is due to the transrepression of NF-B or the
ability to induce other genes that mediate cell death. Preliminary
evidence describing the GC-induced expression of known and novel genes
(e.g., a cDNA clone, encoding a human -galactoside-binding protein)
has been reported that has been shown to be inhibitory to cell growth
(19, 22).
In summary, RU 24858 was equipotent compared with budesonide in eliciting side effects, suggesting that in vitro separation of transrepression from transactivation activity does not translate to an increased therapeutic ratio for GCs in vivo. However, although the parameters we have chosen in this study (e.g., weight loss, thymus involution, osteopenia of the femur growth plate) to represent the undesirable side effects of steroids are appropriate, we have not studied whether RU 24858 exhibits an improved safety profile on other known side effects of GCs. In fact, diminution of any of the other side effects of GCs (e.g., diabetes mellitus, glaucoma, opportunistic infection, behavioral changes) with a GC that retained significant antiinflammatory activity would be an important development.
In conclusion, although the development of selective steroids, which differentiate between transrepression and transactivation mechanisms, remains an interesting approach, whole animal physiological studies have failed to confirm the predicted dissociation between antiinflammatory activity and adverse effects. Whether this indicates that homeostatic mechanisms present in the animal models override selectivity, which argues for biochemical redundancy in the mechanism, or merely reflect limitations of the prototypical tool, RU 24858, is unknown. Alternatively, these data suggest that some of the classical hormonal actions of GCs are a consequence of transrepression rather than transactivation. It is clear that research in this area should give us fundamental insights into the molecular physiology of steroid action. Given the possible therapeutic rewards of a dissociated steroid, the contradictory data generated to date should only serve as a spur to future research in this fascinating area.
|
|
|
|
|
|
|
|
|
|
Footnotes |
|---|
2 Abbreviations used in this paper: GC, glucocorticoid; ACP, acid phosphatase; ALP, alkaline phosphatase; GR, GC, receptor; GRE, GC response element; I-B, inhibitory protein that dissociates from NF-B; p.o., oral administration; TRAP, tartrate-resistant ACP.
3 Address correspondence and reprint requests to Dr. Maria G. Belvisi, Respiratory Pharmacology Group, Cardiothoracic Surgery, Imperial College School of Medicine at the National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, U.K.
4 Current address: Respiratory Pharmacology Group, Cardiothoracic Surgery, Imperial College School of Medicine at the National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, U.K.
5 Abbreviations used in this paper: GC, glucocorticoid; ACP, acid phosphatase; ALP, alkaline phosphatase; GR, GC, receptor; GRE, GC response element; I-B, inhibitory protein that dissociates from NF-B; p.o., ??; TRAP, tartrate-resistant ACP.
Received for publication June 26, 2000. Accepted for publication October 18, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B-dependent mechanism. Mol. Pharmacol. 56:797.B/c-myc-dependent survival pathway is targeted by corticosteroids in immature thymocytes. J. Immunol. 162:314.-galactoside binding protein, overexpressed during glucocorticoid-induced cell death. Biochem. Biophys. Res. Commun. 31:764.This article has been cited by other articles:
|
|
 |
|
  L. C. Hofbauer and M. Rauner Minireview: Live and Let Die: Molecular Effects of Glucocorticoids on Bone Cells Mol. Endocrinol., October 1, 2009; 23(10): 1525 - 1531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. De Bosscher and G. Haegeman Minireview: Latest Perspectives on Antiinflammatory Actions of Glucocorticoids Mol. Endocrinol., March 1, 2009; 23(3): 281 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dewint, V. Gossye, K. De Bosscher, W. Vanden Berghe, K. Van Beneden, D. Deforce, S. Van Calenbergh, U. Muller-Ladner, B. Vander Cruyssen, G. Verbruggen, et al. A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis J. Immunol., February 15, 2008; 180(4): 2608 - 2615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Newton and N. S. Holden Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor? Mol. Pharmacol., October 1, 2007; 72(4): 799 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. McMaster and D. W. Ray Modelling the glucocorticoid receptor and producing therapeutic agents with anti-inflammatory effects but reduced side-effects Exp Physiol, March 1, 2007; 92(2): 299 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Chivers, W. Gong, E. M. King, J. Seybold, J. C. Mak, L. E. Donnelly, N. S. Holden, and R. Newton Analysis of the Dissociated Steroid RU24858 Does Not Exclude a Role for Inducible Genes in the Anti-Inflammatory Actions of Glucocorticoids Mol. Pharmacol., December 1, 2006; 70(6): 2084 - 2095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Birrell, S. Wong, E. L. Hardaker, M. C. Catley, K. McCluskie, M. Collins, S. Haj-Yahia, and M. G. Belvisi I{kappa}B Kinase-2-Independent and -Dependent Inflammation in Airway Disease Models: Relevance of IKK-2 Inhibition to the Clinic Mol. Pharmacol., June 1, 2006; 69(6): 1791 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Barnes Corticosteroid effects on cell signalling Eur. Respir. J., February 1, 2006; 27(2): 413 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Belvisi, D. S. Bundschuh, M. Stoeck, S. Wicks, S. Underwood, C. H. Battram, E.-B. Haddad, S. E. Webber, and M. L. Foster Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 568 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rosen and J. N. Miner The Search for Safer Glucocorticoid Receptor Ligands Endocr. Rev., May 1, 2005; 26(3): 452 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-G. Bladh, J. Liden, K. Dahlman-Wright, M. Reimers, S. Nilsson, and S. Okret Identification of Endogenous Glucocorticoid Repressed Genes Differentially Regulated by a Glucocorticoid Receptor Mutant Able to Separate between Nuclear Factor-{kappa}B and Activator Protein-1 Repression Mol. Pharmacol., March 1, 2005; 67(3): 815 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Biggadike, I. Uings, and S. N. Farrow Designing Corticosteroid Drugs for Pulmonary Selectivity Proceedings of the ATS, December 1, 2004; 1(4): 352 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hochhaus New Developments in Corticosteroids Proceedings of the ATS, November 1, 2004; 1(3): 269 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Desmet, P. Gosset, B. Pajak, D. Cataldo, M. Bentires-Alj, P. Lekeux, and F. Bureau Selective Blockade of NF-{kappa}B Activity in Airway Immune Cells Inhibits the Effector Phase of Experimental Asthma J. Immunol., November 1, 2004; 173(9): 5766 - 5775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Schacke, A. Schottelius, W.-D. Docke, P. Strehlke, S. Jaroch, N. Schmees, H. Rehwinkel, H. Hennekes, and K. Asadullah Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects PNAS, January 6, 2004; 101(1): 227 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kurucz, S. Toth, K. Nemeth, K. Torok, V. Csillik-Perczel, A. Pataki, C. Salamon, Z. Nagy, J. I. Szekely, K. Horvath, et al. Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166) J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 83 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Barnes and I. M. Adcock How Do Corticosteroids Work in Asthma? Ann Intern Med, September 2, 2003; 139(5_Part_1): 359 - 370. [Full Text] [PDF]
|
|
|
|
|
|
K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Coghlan, P. B. Jacobson, B. Lane, M. Nakane, C. W. Lin, S. W. Elmore, P. R. Kym, J. R. Luly, G. W. Carter, R. Turner, et al. A Novel Antiinflammatory Maintains Glucocorticoid Efficacy with Reduced Side Effects Mol. Endocrinol., May 1, 2003; 17(5): 860 - 869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lasa, S. M. Abraham, C. Boucheron, J. Saklatvala, and A. R. Clark Dexamethasone Causes Sustained Expression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase 1 and Phosphatase-Mediated Inhibition of MAPK p38 Mol. Cell. Biol., November 15, 2002; 22(22): 7802 - 7811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.J. Vanacker, E. Palmans, R.A. Pauwels, and J.C. Kips Dose-related effect of inhaled fluticasone on allergen-induced airway changes in rats Eur. Respir. J., October 1, 2002; 20(4): 873 - 879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.-B. Haddad, S. L. Underwood, D. Dabrowski, M. A. Birrell, K. McCluskie, C. H. Battram, M. Pecoraro, M. L. Foster, and M. G. Belvisi Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification J. Immunol., March 15, 2002; 168(6): 3004 - 3016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Y. Almawi and O. K. Melemedjian Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor J. Leukoc. Biol., January 1, 2002; 71(1): 9 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Miura, R. Ouchida, N. Yoshikawa, K. Okamoto, Y. Makino, T. Nakamura, C. Morimoto, I. Makino, and H. Tanaka Functional Modulation of the Glucocorticoid Receptor and Suppression of NF-kappa B-dependent Transcription by Ursodeoxycholic Acid J. Biol. Chem., December 7, 2001; 276(50): 47371 - 47378. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
