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At least 811 records · Page 45Linked to original sources
PubMed1995

Abnormalities in adrenal androgens, but not of glucocorticoids, in early Alzheimer's disease.

In an attempt to evaluate possible adrenal abnormalities in Alzheimer's disease (AD), prestimulus levels and ACTH-stimulated serum levels of steroid hormones, corticosteroid-binding globulin (CBG), and insulin-like growth factor I (IGF-I) were measured in 18 patients with early AD (8 men, 10 women; 74.6 +/- 6.5 years, mean +/- SD) and 19 healthy controls (10 men, 9 women; 74.2 +/- 7.6 years, mean +/- SD). Steroid hormone levels were measured before and after an intravenous bolus injection of 250 micrograms ACTH. AD per se had an independent influence on hormone levels when evaluated in MANOVA models. AD patients had significantly higher prestimulus levels of dehydroepiandrosterone and androstenedione (p = .04 and p = .003, respectively) with accentuated differences after ACTH (p = .02 and p < .001 for peak responses, respectively). Serum levels of cortisol, CBG, free cortisol, 17 alpha-hydroxyprogesterone (17 alpha-OHP), and IGF-I did not differ between groups. These abnormalities may have implications for neuronal degeneration as well as for behavioural symptoms in AD.

Adrenal Glands↗
PubMed1996

Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels.

Adult male and female rats were housed for 2 weeks in a Visible Burrow System resulting in the development of strong dominant-subordinate relationships among the male rats. Neuroendocrine measures indicated that the subordinate rats, and to a lesser extent dominant rats, experienced chronic HPA axis hyperstimulation during the 2 week experience. This paper focuses on the consequences of this chronic social stress on cytosolic type II corticosteroid receptor binding in the spleen. In the first study, rats were adrenalectomized 18 h prior to sacrifice in order to measure total cellular receptor protein levels in each animal. In spite of the severity of the social stress, there was no decrease in splenic type II corticosteroid receptor binding levels in these short-term adrenalectomized animals. In the second study, rats were left adrenal-intact. Corticosteroid receptor levels in these adrenal-intact animals reflect the level of receptors (available receptors) that were unoccupied by endogenous hormone at the time of sacrifice. Both subordinate and dominant rats had fewer available splenic type II receptors than control rats, suggesting that a greater proportion of receptors in subordinate and dominant rats were occupied and activated by endogenous hormone at the time of sacrifice than in control rats. The differences in available receptor levels were not a function of total plasma corticosterone levels at the time of sacrifice (mean corticosterone levels were the same for control and subordinate rats). Instead, the differences in available receptor levels may have been a function of plasma corticosteroid binding globulin (CBG) levels which regulate free corticosterone levels. There was a large reduction in plasma CBG levels of subordinate (-70%) and dominant (-40%) rats relative to control rats, and there was a significant correlation between plasma CBG level and available type II receptors in the spleen. These results suggest that a decrease in CBG levels as a result of chronic social stress led to greater access of free corticosterone hormone to type II receptors in the spleen than is typically present in rats under basal or acute stress conditions. This result illustrates one mechanism by which chronic stress may have a greater impact than acute stress on splenic immune function.

Animals↗
PubMed1994

Structure and chromosomal location of the gene encoding mouse corticosteroid-binding globulin: strain differences in coding sequence and steroid-binding activity.

Corticosteroid-binding globulin (CBG) is a member of the serine proteinase inhibitor superfamily and is responsible for the plasma transport of glucocorticoids. The mouse Cbg gene structure has been deduced from two non-overlapping DNA fragments of a lambda EMBL-3 genomic library, as well as PCR amplification of the approx. 2 kb of genomic DNA that lies between them. Mouse Cbg comprises five exons that span a region of approx. 10.5 kb, and has been localized in tight linkage with the Aat (alpha 1-antitrypsin) and Spi (serine proteinase inhibitor) gene complex on chromosome 12, in a region syntenic with this genetic locus on human chromosome 14. Intron-specific oligodeoxyribonucleotide primers were also used to PCR-amplify Cbg coding regions from several mouse strains. No differences were found in the Cbg coding sequences of BALB/c and C57BL/6J-cpk/cpk mice, while two mutations were found within RIIIS/J Cbg that result in Lys201-->Glu and Ala357-->Thr substitutions in the mature mouse CBG polypeptide. To assess what impact these substitutions might have on the steroid-binding activity of RIIIS/J CBG, these mutations were introduced separately or together into a BALB/c mouse Cbg cDNA. Expression of these mutants in the MDCK cell line indicated that the Lys201-->Glu substitution accounts for the abnormal steroid-binding affinity of CBG in RIIIS/J mice.

Amino Acid Sequence↗
PubMed1995

cis-regulatory elements within the proximal promoter of the rat gene encoding corticosteroid-binding globulin.

Corticosteroid-binding globulin (CBG) transports and modulates the bioavailability of glucocorticoids in blood plasma. It is produced predominantly by the liver, but is also produced in a complex spatial and temporal pattern during development and is regulated hormonally. The rat Cbg promoter (pCbg) has therefore been cloned to allow identification of cis-acting sequence elements that could contribute to its regulation. Five protein-binding sites (P1 to P5) were identified within 236 bp immediately 5' of the transcription start point by DNase I footprinting with rat liver nuclear extracts. These P1-P5 sites are highly conserved in the human pCbg, and resemble recognition sequences for HNF-1, CP-2, DBP, HNF-3 and C/EBP or NF-1L6, respectively. Electrophoretic mobility-shift assays indicted that the P1 element most likely binds HNF-1, and transient transfection assays with luciferase reporter plasmids demonstrated that P1-P5 represent a positive component of rat pCbg activity, whereas additional 5' sequences repressed promoter activity 2-4-fold in H4IIEC3 rat hepatoblastoma cells.

Animals↗
PubMed1981

Endocrinological and clinical investigations in post-menopausal women following administration of vaginal cream containing oestriol.

The maturation value (MV), cervical mucus parameters (ferning, Spinnbarkeit), oestrone (E1), oestradiol (E2), oestriol (E3), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyrotropin (TSH), growth hormone (GH), sex hormone binding globulin (SHBG), corticosteroid binding globulin (CBG) and thyroxin-binding globulin (TBG) were determined in 11 post-menopausal women presenting with vaginal atrophy prior to, and following, treatment with Ovestin vaginal cream containing 0.5 mg/day of E3 for 8 wk. In 6 of the patients E3 was measured during frequent plasma sampling on days 1, 21 and 56; in the same patients and on the same days TRH-stimulated PRL, TSH and GH levels were estimated. While the therapy induced a sharp rise in the MV, there was a moderate effect on ferning/Spinnbarkeit. Baseline E3 rose from undetectable levels to a mean value of 86.8 pmol/l at day 21. E3 levels achieved during frequent plasma sampling were higher on day 1 than on days 21 and 56 - a decline of the areas under the response curves being significant (P2-sided = 0.03). There was a slight suppression of FSH and LH. No changes in the circulating levels of E1, E2, SHBG, CBG, TBG, PRL, TSH and GH were seen. TRH-stimulated PRL, TSH and GH levels remained unaffected. Clinical effect was excellent and no untoward effects were reported.

Administration, Topical↗
PubMed1996

Interspecies variations of corticosteroid-binding globulin parameters.

In mammalian plasma, cortisol binds to a specific alpha 1-glycoprotein: corticosteroid-binding globulin (CBG). In this study, we measured the protein binding of cortisol by equilibrium dialysis in seven species in which plasma cortisol concentrations varied from 0.02 to 0.05 (ewe, dog, cow) to 0.1 to 0.6 (horse, human, cynomolgus monkey) to reach 1.6 microM (squirrel monkey). No binding of cortisol to CBG was discernible in plasma from squirrel monkey. In all other species examined, we showed that the CBG maximal capacity (Bmax) was 3 (1.7 to 5.2) times more than the plasma cortisol levels, with cow, dog, ewe exhibiting the lowest and cynomolgus monkey exhibiting the highest values. We also noted the existence of a linear relationship between Bmax and the corresponding dissociation constant (Kd), Bmax being systematically 10 (8.5 to 11.8) times more than Kd. The low binding affinity of cortisol assigned to albumin did not differ between species. The free (6 to 14%), CBG-bound (67 to 87%), and albumin-bound (7 to 19%) cortisol fractions calculated from the estimated binding parameters and measured plasma cortisol concentrations were similar within species, except for squirrel monkey, in which half of the cortisol was albumin bound, and the other half remained protein free. Our most appealing finding was that in most species, as much as 68% of plasma CBG remained free of cortisol under physiologic conditions. These results are discussed with respect to the theories concerning the role of CBG in plasma transport and the local delivery of cortisol and free CBG as a proper hormone.

Adolescent↗
PubMed1990

Characteristics of glucocorticoid-binding by inflammatory tissue of rats.

Glucocorticoid-binding activities of the granuloma cytosol were compared with those of the liver cytosol and of the serum in vitro. The granuloma cytosol bound cortisol (HC) about 4-fold higher than dexamethasone (DX) and triamcinolone acetonide (TA); the liver cytosol bound these two synthetic agonists more than HC. The kinetic parameters of the glucocorticoid-binding components of the granuloma and the liver cytosols were studied by the Scatchard method. The binding components of the granuloma cytosol had a single class of binding sites with high affinity for these three steroids, whereas the binding site of the liver cytosol had negative cooperativity or consisted of two distinct classes, because its Scatchard plot showed a hyperbolic curve. The granuloma glucocorticoid-binding components will be protein since their binding was prevented by a trypsin treatment and completely lost by heating at 60 C for 5 min. Heating at 25 or 37 degrees C for 30 min did not affect the HC-binding activity of the granuloma cytosol, regardless of prelabeling with the steroid. The binding activity for DX and TA were heat-labile and completely lost by heating the cytosol at 37 degrees C for 30 min without the respective steroid. The results of thermal inactivation and ammonium sulfate fractionation show the granuloma HC-binding protein closely resembles corticosteroid-binding globulin (CBG). From enzymatic determination of hemoglobin in tissue cytosols, attribution of the contaminating blood to the HC-binding activity of the cytosol is considered to be negligible.

Ammonium Sulfate↗
PubMed1990

Failure of glucocorticoid feedback during breeding in the male red-tailed phascogale Phascogale calura (Marsupialia: Dasyuridae).

An investigation was made into the factors which lead to an elevation in plasma free cortisol concentration during the last weeks of life of males in natural populations of the red-tailed phascogale Phascogale calura. The dexamethasone suppression-test was employed to examine the glucocorticoid feedback control of plasma cortisol both before and during the breeding season. In both sexes ACTH alone or in combination with dexamethasone caused an elevation in the plasma concentration of cortisol, corticosterone and free cortisol. Dexamethasone administration in both males and females resulted in significant decreases in the plasma concentration of each of the glucocorticoid groups both before and during the first week of the breeding season (June and early July), however during the last week of breeding (late July) dexamethasone decreased the plasma glucocorticoid concentration of females but not of males. Administration of ACTH caused a significant elevation in the plasma cortisol concentration in all groups. However, the magnitude of this response diminished with time in both sexes. Dexamethasone treatment resulted in a decrease in the plasma testosterone concentration in males before and early in the breeding season however toward the end of breeding this effect was abolished. It is apparent that towards the end of the breeding season and during the last week of life of the males, glucocorticoid feedback control of ACTH is almost abolished. These changes, which occur only in the males late in the breeding season and near the time of their disappearance from the population, are consistent with a condition known as end organ resistance to steroid hormones.

Adrenocorticotropic Hormone↗
PubMed1991

The release of corticosterone and a corticosterone-binding protein by incubated rat adrenal slices.

Stimulation of incubated rat adrenal slices with ACTH(1-24) resulted in an increase in the release of both corticosterone and specific corticosterone-binding protein into the incubation medium. The release of corticosterone and binding protein was dose and calcium dependent with adrenals from animals pretreated with betamethasone. While the secretion of corticosterone was continuous throughout the incubation period, there appeared to be a limit to the increase in binding capacity. The specificity of steroid binding to the adrenal protein showed a similar profile to that of corticosteroid-binding globulin (CBG) in rat serum. A Western blot analysis using anti-rat CBG as the primary antiserum, showed that the adrenal protein was not CBG. [3H]corticosterone binding with disc electrophoresis, run at 2 degrees C, gave a single peak with approximately the same Rf value for rat serum, purified CBG, and adrenal incubate; at 22 degrees C peaks were only seen for rat serum or purified CBG. The data presented provides further evidence for the existence of a specific corticosterone-binding protein of adrenal origin released in conjunction with corticosterone. The adrenal protein would appear to have a lower affinity for corticosterone than does CBG, and to be functionally more labile. It is possible that the adrenal protein may be CBG that has been internalized, modified and released with corticosterone.

Adrenal Glands↗
PubMed1991

Molecular studies of corticosteroid binding globulin structure, biosynthesis and function.

Phylogenetic comparisons of the primary structure of corticosteroid binding globulin (CBG) have revealed several conserved domains that include sites for N-glycosylation and a region which probably represents a portion of the steroid binding site. The major site of CBG biosynthesis in adults is clearly the liver, and the human CBG gene promoter contains sequence elements that interact with liver-specific transcription factors. Low levels of CBG gene expression have been detected in other tissues, and these may be important for fetal development during late gestation when hepatic CBG mRNA levels are low. Studies of the ontogeny of CBG biosynthesis in the rat have also indicated that plasma CBG levels may be influenced by a more rapid clearance of the protein during pubertal development. Analyses of the structural organization and chromosomal location of the human CBG gene have further confirmed its close relationship with the serine proteinase inhibitors, and suggests that CBG, alpha 1-proteinase inhibitor and alpha 1-antichymotrypsin evolved relatively recently by gene duplication. The functional significance of this relationship has been examined and our studies suggest that a specific interaction between CBG and elastase on the surface of neutrophils may represent a physiologically important event that promotes the delivery of glucocorticoids to these cells at sites of inflammation.

Amino Acid Sequence↗
PubMed1991

Interaction of human CBG with cell membranes.

Specific binding sites for corticosteroid-binding globulin (CBG) and its pregnancy-associated variant (pCBG), having a modified carbohydrate moiety, were found in the plasma membranes of human liver, decidual endometrium and placental syncytiotrophoblast. The membrane binding was influenced by the conformation of the glycoprotein molecules and structure of their carbohydrate chains. CBG receptor was solubilized from the endometrium membrane and partially characterized. It was found to have a subunit structure, with a homooligomeric sialoglycoprotein consisting of four 20 kDa protomeric species being involved in the recognition of the CBG molecules complexed with progesterone or cortisol. A kinetic study using membrane microvesicles derived from the syncytiotrophoblast brush border revealed that neither CBG nor pCBG restricted cortisol accumulation in the intravesicular space, whereas only normal CBG could penetrate the syncytiotrophoblast membrane. Action of the CBG-cortisol complex on trophoblast cells resulted in the activation of membrane adenylate cyclase and growth of the cAMP accumulation within these cells. Collectively, these findings suggest that both normal CBG and pCBG are involved in the guided transport of steroid hormones to the target cells and transmembrane transfer of hormones and/or hormonal signals.

Biological Transport↗
PubMed1992

Biosynthesis of hepatic corticosteroid-binding globulin: ontogeny and effect of thyroid hormone.

The present study reports on the ontogeny and the effect of thyroid hormones on liver corticosteroid-binding globulin (CBG) biosynthesis, in relation to plasma CBG binding capacity in the rat. We show that mRNACBG contents were high in liver of 18-day-old fetuses and decreased with age to reach almost undetectable levels by postnatal day 1. Interestingly, at the latter time point plasma CBG concentration remained elevated and disappeared thereafter from the circulation with a half-life of about 3 days. The messenger was localized in parenchymatous cells and not in hematopoietic ones, although the latter constitute the major cell population in fetal liver. It is not until after 10 days of age that mRNACBG and plasma CBG levels increased in concert, with a sex-difference being noticed by postnatal day 30. Treatment of rats with 3,3',5-triiodo-L-thyronine (T3), but not reverse T3 (rT3) (the predominant form present in fetal serum), enhanced CBG biosynthesis. These findings show that liver mRNACBG contents undergo dramatic changes during ontogeny and suggest the existence of a differential regulation of the messenger in fetal and neonatal rats.

Animals↗
PubMed1992

A Leu----His substitution at residue 93 in human corticosteroid binding globulin results in reduced affinity for cortisol.

A steroid binding capacity assay and a radioimmunoassay were both used to measure corticosteroid binding globulin (CBG) in serum samples from 22 patients with sepsis. An approximately 50% discordancy between the two values in one patient suggested the presence of a CBG variant with reduced affinity for cortisol, and this was confirmed by Scatchard analysis. We therefore used the polymerase chain reaction to amplify exons that encode for human CBG from the genomic DNA of this patient. This revealed two mutations within the coding sequences: one of which results in a Leu----His substitution at residue 93 and another which encodes a Ser----Ala substitution at residue 224 of the human CBG polypeptide. To assess the impact of each substitution on the steroid binding affinity of CBG, each mutation was introduced separately into a normal human CBG cDNA, and the normal and mutated cDNAs were expressed in Chinese hamster ovary cells. Scatchard analysis of the CBG produced in culture indicated that the His93 mutation (Kd = 2.24 +/- 1.75 nM) reduced the cortisol binding affinity of CBG (mean +/- SD) significantly (P less than 0.024) when compared to normal CBG (Kd = 0.64 +/- 0.31 nM), while the Ala224 mutation (Kd = 0.63 +/- 0.33 nM) did not influence cortisol binding affinity. We therefore conclude that residue 93 may play an important role in determining the structure of the CBG steroid binding site.

Aged↗
PubMed1992

Comparison of the carbohydrate composition of rat and human corticosteroid-binding globulin: species specific glycosylation.

We have examined the carbohydrate composition of corticosteroid-binding globulin (CBG) obtained from rat and human serum. Rat CBG contained a carbohydrate composition that was strikingly different from that of human CBG. Like other glycoproteins that circulate in human plasma, human CBG had a carbohydrate composition that was consistent with the presence of biantennary and triantennary oligosaccharide structures. In contrast, the carbohydrate composition of rat CBG indicated the presence of more than one sialic acid residue per antenna. It is not clear whether rat CBG contains a carbohydrate structure with sialic acids attached to both galactose and N-acetylglucosamine on the same antenna, or a terminal disialylated structure (sialic acid linked alpha 2-8 to sialic acid). These structural variations may play a role in the interaction of CBG with its receptor.

Animals↗
PubMed1994

Substitutions of tryptophan residues in human corticosteroid-binding globulin: impact on steroid binding and glycosylation.

Human corticosteroid-binding globulin (CBG) contains four tryptophan residues at positions 141, 185, 266 and 371; one of which is thought to be located in the steroid-binding site. These residues were substituted by site-directed mutagenesis and expression of mutant CBG cDNAs in Chinese hamster ovary cells. Analyses of the resulting mutants indicate that Trp371 is most likely located in the steroid-binding site, and that hydrophobic interactions between Trp141 and the steroid molecule or other amino-acids in the CBG polypeptide may also contribute to high-affinity interactions between CBG and its steroid ligands. In addition, substitution of Trp266 resulted in altered glycosylation of CBG, and this supports the concept that it participates in intra-molecular carbohydrate-polypeptide interactions which may influence the conformation and secretion of this glycoprotein.

Binding Sites↗
PubMed1994

Antagonistic effects of retinoic acid and triiodothyronine in the expression of corticoid-binding globulin (CBG) by cultured fetal hepatocytes.

Cultures of rat fetal hepatocytes were used to investigate the effects and interplay of triiodothyronine (T3) and retinoic acid (RA) in the regulation of gene expression of CBG, compared to that of alpha-fetoprotein (AFP). The cultured cells showed cytological features typical to hepatocytes and actually synthesized CBG and AFP, as evidenced from in situ hybridization with specific radioactive probes. Time course studies indicated that CBG (but not AFP) binding capacity in culture medium and cell mRNA levels disappeared with a half-life of about 2 days, thereby reflecting the decrease previously seen in hepatic CBG mRNA contents during embryonic life. The Kd values for CBG binding were unchanged under these conditions. Culturing of hepatocytes in the presence of T3 resulted in dose-dependent stimulations of both medium CBG and cell mRNA levels, with an EC50 concentration of about 10(-9) M. In sharp contrast, RA caused a reduction in CBG biosynthesis (IC50 = 1.7 x 10(-7) M) and, in addition, antagonized the stimulatory influence of T3. Under the same experimental conditions, AFP synthesis failed to be affected in a similar fashion. We conclude that thyroid hormones and RA directly act on hepatocytes to specifically regulate the expression of CBG in an antagonistic way.

Animals↗
PubMed1994

Identification of the cysteine in the steroid-binding site of human corticosteroid binding globulin by site-directed mutagenesis and site-specific chemical modification.

Binding of corticosteroids by human corticosteroid binding globulin (hCBG) is thought to involve interaction with one of its two cysteine residues (Cys60 and Cys228). To identify which of the two cysteine residues mediates steroid binding, we have produced mutant hCBGs containing serine or alanine in place of Cys228 by site-directed mutagenesis. Alteration of Cys228 to serine or alanine does not change the steroid binding affinity of hCBG, demonstrating that Cys228 is not involved in the binding interaction. This finding strongly suggests that Cys60 is the functionally important cysteine. By modifying the wild-type and mutant hCBGs with the sulfhydryl-specific reagents N-ethylmaleimide, iodoacetamide, and sodium tetrathionate, we have demonstrated that Cys60 is present at the steroid binding site, and that it may be directly involved in steroid binding. This result also identifies Cys60 as the accessible cysteine reported in previous studies.

Base Sequence↗