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Query: UNIPROT:P06889 (Mol)
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We studied the expression of messenger ribonucleic acids (mRNAs) for neurotrophins and neurotrophin receptors in the rat pituitary gland and examined the influence of adrenal hormones on their mRNA levels, using in situ hybridization and Northern blot analysis. The only neurotrophin present at detectable levels in the pituitary was brain-derived neurotrophic factor (BDNF), which was observed in the anterior and intermediate lobes. Several transcripts of the putative receptor for BDNF, trkB, were present in the anterior and posterior lobes of the pituitary. A low amount of trkC mRNA was found in both the anterior and the intermediate lobe. Dexamethasone treatment decreased both BDNF and trkB mRNA levels in the anterior lobe of the pituitary. Adrenalectomy had no effect on trkB expression, but it decreased BDNF mRNA levels in comparison to the control animals. This effect could not be reversed by dexamethasone substitution, suggesting that BDNF, mRNA levels may be regulated not only by glucocorticoids but also by other adrenal hormones. These results demonstrate that BDNF, trkB and trkC are expressed in the pituitary gland and that glucocorticoids and possibly other adrenal hormones may modulate pituitary functions by regulating the expression of neurotrophic factors and their receptors. Whether BDNF acts as a secreted hormone, a trophic factor, or has autocrine/paracrine functions within the pituitary through its receptor, trkB, remains to be studied.
Brain Res Mol Brain Res 1994 Dec
PMID:Neurotrophins and their receptors in the rat pituitary gland: regulation of BDNF and trkB mRNA levels by adrenal hormones. 789 23

This study was designed to test the hypothesis that ACTH from the fetal pituitary is a major regulator of adrenocortical steroid hydroxylase gene expression in the ovine fetus at 0.4 (60-70 days) of gestation. Pregnant ewes at 0.4 gestation received intravenous infusions of dexamethasone (0.76 mg/h, n = 13) for 48 h. The rationale for this regime was that some of the infused dexamethasone would cross the placenta and act on the fetal pituitary to suppress ACTH release. Control animals received infusions of saline (0.38 ml/h, n = 12) for 48 h. At the end of the infusion period, the animals were killed, umbilical vessel blood taken for ACTH and cortisol analyses, and the fetal adrenal glands taken for assessment of P-450scc, P-450(17 alpha) and P-450c21 levels using the techniques of hybridization histochemistry and RNase protection assay. Dexamethasone treatment decreased maternal and fetal concentrations of ACTH to 29 +/- 10 and < 20 pg/ml, respectively and cortisol concentrations to 3.5 +/- 0.6 and 3.2 +/- 0.8 nmol/l respectively. The adrenal glands from the dexamethasone-treated fetuses exhibited significantly lower levels of mRNA for P-450scc (11% of control) and P-450(17 alpha) (2% of control). These results suggest that ACTH is a major regulator of steroid hydroxylase gene expression and subsequent cortisol biosynthesis in vivo in the ovine fetus at 0.4 gestation.
Mol Cell Endocrinol 1994 Jul
PMID:Regulation of steroid hydroxylase gene expression in the ovine fetal adrenal gland at 0.4 gestation. 795 94

The goal of this investigation was to determine if administration of the synthetic glucocorticoid dexamethasone modulates rat brain AP-1 DNA binding activity. Treatment with the selective excitatory amino acid agonist kainate was used to activate AP-1 formation. Kainate (12 mg/kg) administration induced a biphasic activation of AP-1 in rat cerebral cortex and hippocampus with maximal levels observed at 1.5 h and 4.5 h and lower levels at 3 h and 6 h. Kainate also induced biphasic increases in the concentrations of some of the AP-1 constituent proteins (immediate early gene protein products), with initial increases of c-Jun, Fos, and Jun B occurring at 1.5 h and secondary larger increases at 4.5 h, but the level of Jun D was not altered by kainate treatment. Pretreatment with dexamethasone (1 mg/kg) reduced AP-1 activity at both 1.5 h and 4.5 h after kainate administration in both brain regions. Dexamethasone pretreatment did not modify the concentrations of the AP-1 constituent proteins obtained after kainate administration except for a reduction of Jun B levels 1.5 h after kainate. These results demonstrate that elevated glucocorticoid levels reduce the stimulation by kainate of AP-1 activity in rat cortex and hippocampus without causing corresponding decreases in the levels of immediate early gene proteins. Binding of the activated glucocorticoid receptor to c-Jun or Fos is likely to contribute to the decreased AP-1 DNA binding activity following dexamethasone treatment.
Brain Res Mol Brain Res 1994 Jul
PMID:Dexamethasone attenuates kainate-induced AP-1 activation in rat brain. 796 67

Progesterone receptors (PgR) of human breast cancer T47-D cells grown in an estrogenic environment (presence of phenol red, natural estrogens of foetal calf serum and insulin) were found to be present in considerable amounts (1-3 pmol/mg protein and 20 pmol/mg DNA), and to specifically bind progestins with a high affinity characterized by a Kd around 3 nM for ORG2058, and 4 nM for nomegestrol acetate (NOM; 17 alpha-acetoxy-6-methyl-19-nor-pregna-4,6-diene-3, 20-dione), when measured under equilibrium conditions. Both compounds formed an highly stable ligand-receptor complex with a dissociation constant (k-1) around 1 x 10(-5) s-1. At high pharmacological concentrations, NOM, ORG2058 and other synthetic progestins including promegestone (R5020), medroxy-progesterone acetate and norethindrone acetate (NOR), induced a dose-dependent inhibition of cell proliferation as measured by [3H]thymidine incorporation. Dexamethasone, which did not bind to PgR, did not reproduce this inhibitory effect. NOM, R5020 and NOR treatments of T47-D cells at concentrations around Kd resulted in an 80% decrease in PgR content. Our data on NOM as compared to other progestins are consistent with their antiproliferative effects on human breast cancer cells grown in estrogenic conditions.
J Steroid Biochem Mol Biol 1994 Jul
PMID:Inhibition by nomegestrol acetate and other synthetic progestins on proliferation and progesterone receptor content of T47-D human breast cancer cells. 804 31

Previous attempts to characterize the structural determinants required for binding of cortisol by the glucocorticoid receptor (GR) have proved difficult since almost all modifications of the ligand binding domain (LBD) of GRs either eliminate or greatly decrease steroid binding. The guinea pig, a New World hystricomorph with a phylogeny the subject of recent dispute, is corticoresistant due to a GR that has diminished affinity for dexamethasone. The guinea pig GR has been cloned, and sequencing has identified many unique amino acid substitutions in the LBD. Using a domain-swap approach, the cloned guinea pig GR LBD was substituted for the human GR LBD in a human GR expression vector. Dexamethasone response curves for these constructs show that the cortisol resistance observed in the guinea pig in vivo is conferred in vitro by the guinea pig GR LBD. In addition, the guinea pig GR LBD induces a high level of constitutive activity. This constitutive activity is not repressed by RU486 (1 microM) but is enhanced by the addition of 8-bromo-cAMP. One of the amino acid substitutions results in the loss of a cysteine, which in the human, rat, and mouse GR is the site of covalent attachment for dexamethasone-21-mesylate. This cysteine is replaced by a tryptophan residue in the guinea pig GR, the implications of which were examined by reciprocal mutation of the tryptophan to a cysteine in the guinea pig GR LBD, and the cysteine to a tryptophan in the human GR LBD.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1994 Apr
PMID:Unique sequences in the guinea pig glucocorticoid receptor induce constitutive transactivation and decrease steroid sensitivity. 805 64

We previously demonstrated that O-demethylation of the pendant dimethoxyphenol ring of epipodophyllotoxins to produce their respective catechol metabolites is catalyzed by cytochrome(s) P450 in human liver microsomes. Our objective was to identify the specific human cytochrome(s) P450 responsible for catechol formation. Using a panel of prototypical substrates and inhibitors for specific cytochromes P450, we identified substrates for CYP3A4 (midazolam, erythromycin, cyclosporin, and dexamethasone) as inhibitors of catechol formation from both etoposide and teniposide. Dexamethasone inhibition was competitive, with Ki values of 60 and 45 microM for etoposide and teniposide, respectively. In 58 human livers, the correlation coefficients for teniposide catechol formation versus 1'- and 4-hydroxymidazolam formation were 80% and 85%, respectively; for etoposide catechol formation versus 1'- and 4-hydroxymidazolam formation r2 was 83% and 79%, respectively. Teniposide and etoposide catechol formation rates were also significantly correlated with immunodetectable CYP3A (r2 = 49% and 51%, respectively) and not with immunodetectable CYP1A2, 2E1, or 2C8. Finally, cDNAs for human CYP3A4, 3A5, 2A6, 2B6, 2C8, and 2C9 were functionally expressed in HepG2 cells, using a vaccinia viral vector. Teniposide and etoposide catechol formation was catalyzed primarily by 3A4 (15.4 and 40.9 pmol/pmol/hr, respectively) and to a lesser degree by 3A5 (1.94 and 11.3 pmol/pmol/hr, respectively), whereas there was no detectable O-demethylation of epipodophyllotoxins by 2A6, 2B6, 2C8, 2C9, or the control virus alone. Moreover, the relative activities of midazolam hydroxylation, compared with O-demethylation of epipodophyllotoxins, were similar for heterologously expressed 3A4 and for human liver microsomes. We conclude that catechol formation from teniposide and etoposide is primarily mediated by human CYP3A4, making these reactions susceptible to inhibition by prototypical 3A substrates and inhibitors.
Mol Pharmacol 1994 Feb
PMID:O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. 811 83

The production of pulmonary surfactant protein D (SP-D) increases abruptly during late gestation, and the accumulation of this protein in lung tissue is increased following the exposure of fetal rats to glucocorticoids in utero. To examine the regulation of these events, we administered dexamethasone (Dex; 1 mg/kg/day intramuscularly for 3 days), or saline, to timed-pregnant rats and harvested the lungs on days 19 to 21 of gestation. Samples of pooled fetal lungs were analyzed for SP-D protein, mRNA, and gene transcription by immunoblot, Northern hybridization, and nuclear run-off transcription assays. Lungs from 19 day controls showed barely detectable levels of SP-D gene transcription and negligible accumulation of SP-D message. However, SP-D transcription and the accumulation of SP-D mRNA and protein were readily detected in lungs from 19 day Dex-treated rats. Dexamethasone also caused dose- and time-dependent increases in SP-D protein and mRNA accumulation in 19 day fetal lung explants. Immunohistochemistry of control 19 day lung using antibodies to rat SP-D showed only weak labeling of a small number of airway epithelial cells. By contrast, Dex-exposed rats showed strong staining of columnar and cuboidal epithelial cells lining airways and epithelial tubules and cuboidal cells lining primitive air sacs. In situ hybridization assays showed similar alterations in the number, intensity, and distribution of labeled epithelial cells in 19 day Dex-exposed lungs and demonstrated labeling of alveolar type II and nonciliated columnar cells in adult lung. These data indicate that the accelerated lung maturation accompanying glucocorticoid exposure in utero is associated with a precocious increase in SP-D gene transcription and protein production by pulmonary epithelial cells.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Modulation of surfactant protein D expression by glucocorticoids in fetal rat lung. 813 57

Betaglycan (type III transforming growth factor-beta (TGF-beta) receptor) is a cell surface heparan/chondroitin sulfate proteoglycan that binds TGF-beta via its core protein and is abundantly expressed in osteoblastic cells. A previous report (Centrella et al., Mol. Cell. Biol. 11, 4490-4496, 1991) showed post-translational enhancement by glucocorticoid of TGF-beta binding to betaglycan. Upon the availability of the betaglycan cDNA, we investigated the effects of a glucocorticoid analogue, dexamethasone, on the regulation of betaglycan expression in osteoblast-like cells. Betaglycan mRNA was expressed as an approximately 6-kb band in MC3T3-E1 cells. The betaglycan mRNA level was enhanced severalfold by dexamethasone in these cells. The effect of dexamethasone on the betaglycan mRNA level was observed within 9 h and was sustained at least up to 48 h. The dexamethasone effect was dose-dependent, with a saturation concentration at 10(-7) M. Among the steroid hormones examined, dexamethasone exhibited the most potent effect on betaglycan mRNA expression, while retinoic acid also enhanced it moderately. Dexamethasone enhancement of betaglycan mRNA expression was blocked by actinomycin D, but it was not blocked by cycloheximide. Cross-linking experiments showed that dexamethasone treatment increased the binding of radiolabeled TGF-beta 1 to betaglycan, but did not affect binding to the type II receptor. A similar dexamethasone enhancement of betaglycan mRNA expression was also observed in a preosteoblast-like cell line, RCT1. These results suggest that dexamethasone enhances betaglycan expression at least in part via transcriptional events in osteoblasts and this would be one of the target points of glucocorticoid regulation of bone metabolism.
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PMID:Dexamethasone enhancement of betaglycan (TGF-beta type III receptor) gene expression in osteoblast-like cells. 814 77

Nerve growth factor (NGF) maintains cholinergic neurons in various animals models of neurodegeneration and is thus a potential treatment for certain neurodegenerative disorders such as Alzheimer's disease. Because NGF does not cross the blood-brain barrier, we have proposed elevating endogenous levels of NGF in the central nervous system with small molecules that induce NGF expression, as an alternative strategy. The present studies were conducted to determine whether pharmacologically elevated levels of NGF are sufficient to cause subsequent stimulation of its high affinity receptor, as measured by increased levels of Trk phosphorylation. Dexamethasone (0.5-20 mg/kg, intraperitoneally) caused a time- and dose-dependent increase in NGF mRNA and NGF protein in the hippocampus and septum of adult male Sprague-Dawley rats. Exogenously administered NGF (1 microgram, intracerebroventricularly) led to a rapid (30 min) and transient increase in Trk phosphorylation in the septum, which has high levels of NGF-specific TrkA. Similarly, dexamethasone led to an increase in Trk phosphorylation only within the septum. Dexamethasone-mediated Trk phosphorylation was dose and time dependent, with peak increases being observed 12 hr after injection, concurrently with peak increases in NGF protein. These data demonstrate an increase in activation of the high affinity NGF receptor with a compound that elevates levels of NGF in the central nervous system, and they support the strategy of discovering a pharmacological agent that induces NGF as a method for treating neurodegenerative disorders.
Mol Pharmacol 1994 Mar
PMID:Systemic dexamethasone administration increases septal Trk autophosphorylation in adult rats via an induction of nerve growth factor. 814 26

This study was designed to determine the contribution of elevated plasma ammonia levels to blood-brain barrier (BBB) abnormalities in the presence of intact liver. The permeability changes of the BBB were investigated grossly with Evans blue (EB) and quantitatively by measuring the blood-to-brain transfer content for alpha-aminoisobutyric acid (AIB) in normal rats and rats subjected to sublethal doses of ammonium acetate (NH4OAc) (750 and 600 mg/kg ip; at 30-min intervals). Some rats were pretreated with dexamethasone (DXN). Injection of NH4OAc increased both plasma and brain ammonia concentrations about 16-and 5-fold, respectively, above the control level. In rats receiving NH4OAc injection, the blood-to-brain transfer constant (Ki) for AIB was increased 3- to 11-fold. The elevated Ki values were limited to certain gray matter areas and less pronounced permeability changes were detected in white matter. Extravasation sites of EB were more restricted and were especially observed in thalamus and cerebellum, whereas cortex and white matter were unaffected. Dexamethasone pretreatment for 3 d reduced both leakage of EB and the Ki for AIB in NH4OAc injected animals, whereas acute treatment appeared ineffective. Dexamethasone did not prevent the development of coma but slightly decreased the ammonia concentration in plasma and brain. The results obtained indicate that hyperammonemia may disrupt BBB integrity not only to AIB and EB but also enhance the transport of other solutes.
Mol Chem Neuropathol 1993 Dec
PMID:Changes in the permeability of the blood-brain barrier in acute hyperammonemia. Effect of dexamethasone. 817 25


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