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At least 451 records · Page 25Linked to original sources
PubMed2000

Synergistic antiinflammatory effect of NF-kappaB inhibitors and steroidal or non steroidal antiinflammatory drugs in the pleural inflammation induced by carrageenan in mice.

OBJECTIVES: Experiments were designed to determine whether or not inhibitors of NF-Kappa B (NF-kappaB) exhibit antiinflammatory effects when assessed in carrageenan-induced pleural inflammation in the mouse. MATERIAL AND METHODS: Adult mice of both sexes received pyrrolidine dithiocarbamate (PDTC) or sulfasalazine administered intraperitoneal by at several time points before intrapleural injection of carrageenan (1%) and the exudation and the total and differential cells were analysed. RESULTS: PDTC or sulfasalazine largely and almost completely inhibited the leukocyte infiltration and the exudation induced by intrapleural administration of carrageenan, when assessed 4 h (but not 48 h) after carrageenan injection. The combination of subliminal doses of PDTC or sulfasalazine with steroidal (dexamethasone) or non-steroidal (indomethacin, meloxicam, nabumetone, diacerein) antiinflammatory drugs, which alone had no antinflammatory action, greatly inhibited both the pleural cell infiltration and exudation induced by carrageenan. The highest inhibition of leukocyte infiltration was observed with the combination of PDTC or sulfasalazine with dexamethesone (84 and 75%, respectively). CONCLUSIONS: These results indicate that nuclear factor-kappaB might play an important role in the modulation of the early phase of the pleural inflammatory response induced by carrageenan in the mouse. Furthermore, our results demonstrate for the first time a marked synergistic interaction among dexamethasone--and to a lesser extent among nonsteroidal antiinflammatory drugs--and the NF-kappaB inhibitors, suggesting that this association may be of potential interest for the management of certain inflammatory processes, including asthma therapy.

Animals↗
PubMed1990

Affinity alkylation of human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase by 2 alpha-bromoacetoxyprogesterone: evidence for separate dehydrogenase and isomerase sites on one protein.

We have copurified human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase, which synthesize progesterone from pregnenolone and androstenedione from fetal dehydroepiandrosterone sulfate, from microsomes as a homogeneous protein based on electrophoretic and NH2-terminal sequencing data. The affinity alkylator, 2 alpha-bromoacetoxyprogesterone, simultaneously inactivates the pregnene and androstene dehydrogenase activities as well as the C21 and C19 isomerase activities in a time-dependent, irreversible manner following first order kinetics. At four concentrations (50/1-20/1 steroid/enzyme M ratios), the alkylator inactivates the dehydrogenase activity (t1/2 = 1.5-3.7 min) 2-fold faster than the isomerase activity. Pregnenolone and dehydroepiandrosterone protect the dehydrogenase activity, while 5-pregnene-3,20-dione, progesterone, and androstenedione protect isomerase activity from inactivation. The protection studies and competitive kinetics of inhibition demonstrate that the affinity alkylator is active site-directed. Kitz and Wilson analyses show that 2 alpha-bromoacetoxyprogesterone inactivates the dehydrogenase activity by a bimolecular mechanism (k3' = 160.9 l/mol.s), while the alkylator inactivates isomerase by a unimolecular mechanism (Ki = 0.14 mM, k3 = 0.013 s-1). Pregnenolone completely protects the dehydrogenase activity but does not slow the rate of isomerase inactivation by 2 alpha-bromoacetoxyprogesterone at all. NADH completely protects both activities from inactivation by the alkylator, while NAD+ protects neither. From Dixon analysis, NADH competitively inhibits NAD+ reduction by dehydrogenase activity. Mixed cofactor studies show that isomerase binds NAD+ and NADH at a common site. Therefore, NADH must not protect either activity by simply binding at the cofactor site. We postulate that NADH binding as an allosteric activator of isomerase protects both the dehydrogenase and isomerase activities from affinity alkylation by inducing a conformational change in the enzyme protein. The human placental enzyme appears to express the pregnene and androstene dehydrogenase activities at one site and the C21 and C19 isomerase activities at a second site on the same protein.

3-Hydroxysteroid Dehydrogenases↗
PubMed1991

New steroid haptens for radioimmunoassay: synthesis of steroids substituted with thioether or ester linkages at the 2 alpha-position.

Haptens with bridge at the 2-position have not yet been explored. Radioimmunoassays with antibodies directed against 2 alpha-alkyl bridged steroid haptens are expected to be highly specific due to greater topographical exposure and similarity in conformation to the native steroid. The 2 alpha-alkyl bridged haptens were synthesized by first adding a cyclopropane ring to 2-methylene-4-en-3-one. Selective opening of the three-membered ring with trimethyl silyl iodide and transformation of the iodo group gave a carbocyclic acid, the desired analog for conjugation with protein.

Antibody Specificity↗
PubMed1985

Induction of steroid binding sites (receptors) and presence of steroid hormones in the unicellular Tetrahymena pyriformis.

The unicellular Tetrahymena does not normally possess a steroid hormone (dehydroepiandrosterone, DHEA) or a glucocorticoid (dexamethasone) receptor, but both kinds of receptor can be induced in it by pretreatment (imprinting) with the adequate hormone. The specific receptors which arise are demonstrable experimentally. Examination of Tetrahymena cells for endogenous steroids by the radioimmunoassay (RIA) technique detected an appreciable concentration of DHEA and DHEA sulphate, and lesser concentrations of testosterone and estradiol in this unicellular organism.

Androgens↗
PubMed1982

In vitro effects of sex steroids on LH-stimulated steroid accumulation by isolated rabbit ovarian follicles.

The in vitro effects of progesterone, testosterone and estradiol-17 beta on steroid accumulation by isolated rabbit follicles were examined. Progesterone had no effect on LH-stimulated androgen accumulation but inhibited LH-stimulated estrogen accumulation at 10(-7) M and 10(-6) M. Testosterone at 10(-5) M but not at 10(-6) M or 10(-7) M, inhibited LH-stimulated progesterone accumulation. LH-stimulated estrogen accumulation was inhibited at all dose levels of testosterone. Estradiol (10(-5) M) inhibited LH-stimulated androgen accumulation and had no effects on progesterone accumulation. It is concluded that the steroidal milieu of follicles can influence their response to LH.

Animals↗
PubMed1987

Effects of cadmium and zinc on steroid metabolism and steroid level in the sea star Asterias rubens L.

Steroid metabolism was studied in gonads and pyloric caeca of male and female sea stars which had been exposed to cadmium or zinc for 3 weeks. Steroid metabolism had increased in animals exposed to heavy metals. Significant increase of the enzyme activity was observed for 17 alpha-hydroxylase in the pyloric caeca of female animals exposed to zinc (pregnenolone----17 alpha-hydroxypregnenolone) or cadmium (progesterone----17 alpha-hydroxyprogesterone), for 17 beta-hydroxysteroiddehydrogenase in the gonads of female animals (dehydroepiandrosterone----androstenediol) and in pyloric caeca of male animals (androstenedione----testosterone) after exposure to cadmium, and for 5 alpha-reductase (progesterone----5 alpha-pregnane-3,20-dione) in ovaries of cadmium exposed sea star. There is some evidence that pregnenolone metabolism in male and female animals is affected by zinc in a different way. The effect of cadmium on the esterification of androstenedione differed highly significantly among male and female animals. It was concluded that the main way of entrance of cadmium into sea stars is via the surrounding medium and not via the food consumed. Testosterone and progesterone levels in, respectively, gonads of female and pyloric caeca of male sea stars which had been exposed to cadmium were significantly higher than the corresponding values in control animals. The effect of zinc exposure on testosterone level in pyloric caeca is significantly different for both sexes. Cadmium interacts directly with the esterification of testosterone, strongly stimulating this process. Cadmium stimulates the production of testosterone by action at the level of the biosynthesis of 17 beta-hydroxysteroiddehydrogenase.

17-Hydroxysteroid Dehydrogenases↗
PubMed1995

A putative step in steroid hormone action involves insertion of steroid ligands into DNA facilitated by receptor proteins.

The hypothesis is advanced that hormonal ligands in the steroid/thyroid superfamily act through insertion between base pairs in partially unwound DNA. Using published X-ray coordinates of the complex of the glucocorticoid hormone response element (GRE) with the glucocorticoid receptor DNA binding domain, the interface between the protein and the gene was examined. The site 5'-TG-3'-5'-CA-3' previously shown to accommodate cortisol was found in the first two bases of the GRE half sites, 5'-TGTTCT-3'. These base pairs were sufficiently exposed at the receptor-gene interface to permit access by the steroid. Docking of cortisol into the receptor/DNA complex resulted in a favorable van der Waals energy. Given the general lack of correlation of receptor binding with hormonal activity, we propose that hormone action involves an additional step in which the receptor protein in concert with other transcription factors inserts the hormone into the DNA. This notion provides an explanation for earlier paradoxical observations including structural analogies between base pairs and steroid hormones. The insertion hypothesis suggests that receptor bound ligand facilitates DNA unwinding, stereospecific control of donor/acceptor functional groups on the DNA followed by insertion and release of the ligand between base pairs at 5'-TG-3'-5'-CA-3'.

Amino Acid Sequence↗
PubMed2005

An efficient one-pot synthesis generating 4-ene-3,6-dione functionalised steroids from steroidal 5-en-3beta-ols using a modified Jones oxidation methodology.

Steroids with 4-ene-3,6-dione functionality have application in natural product chemistry, as synthetic intermediates and as aromatase inhibitors. Here, we report a two-phase oxidation of a range of steroidal 5-en-3beta-ols into corresponding 4-ene-3,6-diones using a modified Jones oxidation. The new reaction affords high yields (77-89%) of product in relatively short reaction times (1-2h). The simplicity of this reaction gives significant advantages over previously reported methodologies.

Androstenedione↗
PubMed1991

Analysis of steroids. XLI. Ion-pair high-performance liquid chromatographic separation of quaternary ammonium steroids on silica.

A normal-phase ion-pair chromatographic system has been developed for the high-performance liquid chromatographic investigation of pipecuronium bromide (2 beta,16 beta-bis-(N'-dimethyl-l-piperazinyl)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide) and related quaternary ammonium steroids. The use of silica as the stationary phase and a 96:4 mixture of acetonitrile and water containing 0.1 mol/dm3 sodium perchlorate as the eluent with detection at 213 nm enable the potential impurities as well as the hydrolytic and oxidative degradation products of pipecuronium bromide to be separated and detected down to the 0.01% level. The above system is also applicable to the high-performance liquid chromatographic investigation of other quaternary ammonium steroids (pancuronium bromide, vecuronium bromide).

Chromatography, High Pressure Liquid↗
PubMed1984

Steroids. 2. Synthesis of C-18 functionalized steroids via the Smith-Hughes route.

The total synthesis of a series of racemic C-18 functionalized steroids was carried out in a search for novel estrogen-and/or progestin-receptor agonists or antagonists. The target compound 3,18-dihydroxyestra-1,3,5(10)-triene (2), 13-(2-oxopropyl)gona-4-en-3-one (3), 13-(1-hydroxy-1-prop-2-ynyl)gona-4-en-3-one (4a and 4b) and 13-(1-acetoxy-2-oxo-1-propyl)gona-4-en-3-one (5) are position isomers of the highly biologically active estradiol, progesterone, norethindrone, and 17-acetoxyprogesterone, respectively. Nevertheless the synthetic C-18 functionalized steroids 3-5 showed little activity in the Clauberg and anti-Clauberg assays. Compound 2 showed no antagonism in the postcoital assay despite the fact that it exhibited weak but measurable in vitro receptor-binding activity.

Animals↗
PubMed2005

Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors.

We enrolled 25 patients with extensive, steroid-refractory chronic graft-versus-host disease (cGVHD) in a prospective trial evaluating the efficacy of extracorporeal photophoresis (ECP) in both skin and visceral cGVHD. The median time from transplant to initiation of ECP was 790 days. ECP was administered for 2 consecutive days every 2 weeks in 17 patients and once a week in eight patients until best response or stable disease. The median duration of therapy was 9 months (range 3-24 months). In all, 20 patients had improvement in cutaneous GVHD and six had healing of oral ulcerations. Steroid sparing or discontinuation of immunosuppressive medications was possible in 80% of patients. Response rates were similar between patients receiving treatment weekly vs every 2 weeks and in patients commencing ECP less than vs greater than 18 months from transplant (70 vs 66%). When patients were stratified based on the Akpek prognostic score, there was no difference in overall response between the favorable (Akpek score<2.5) and unfavorable risk groups, but patients with progressive onset cGVHD tended to have a higher response than those with de novo onset. In summary, we report improvement in skin and/or visceral cGVHD in 71% overall and 61% of high-risk patients.

Adolescent↗
PubMed2001

Effects of a non-steroidal (ketorolac tromethamine) and a steroidal (dexamethasone) anti-inflammatory drug on refractive state and ocular growth.

Topical steroidal anti-inflammatory drugs (SAID) and non-steroidal anti-inflammatory drugs (NSAID) are known to affect fluid balance. The effects of twice daily topical applications of Maxidex (dexamethasone, a SAID), Acular (ketorolac, a NSAID), and saline were examined biometrically on the development of refractive errors and eye growth in chicks raised from days 3-12 wearing either a monocular +10 D, 0 D, or -10 D lens. Biometric analysis showed that neither SAID nor NSAID nor saline affected refractive error compensation but that the anti-inflammatory drugs affected eye growth. In chicks reared with a +10 D lens, dexamethasone induced a decrease in axial length (AL), vitreous chamber (VC) and anterior chamber (AC) depth, while ketorolac only induced a decrease in AC. In -10 D lens chicks dexamethasone again induced a decrease in AL and VC, but did not affect AC depth, whereas ketorolac only induced an increase in AC depth. Taken together, these results suggest that anti-inflammatory drugs can induce changes in ocular size without affecting refractive state and, as such, have implications for the management of progressive myopia.

Administration, Topical↗
PubMed2002

Immunolocalization of sex steroid hormone receptors in canine vaginal and vulvar tissue and their relation to sex steroid hormone concentrations.

The aim of this immunohistochemical study was to describe the cellular distribution of the estrogen receptor-alpha (ERalpha), progesterone receptor (PR) and androgen receptor (AR) in canine vaginal and vulvar tissue. Samples were taken from dogs in different stages of the estrous cycle. Nuclear staining for ERalpha, PR and AR was observed in surface epithelium, stromal and smooth muscle cells. Receptors were also expressed in vulvar skin. Cytoplasmic staining for AR was observed in basal and parabasal cell layers of vulvar and vaginal epithelium. For all three receptors, staining intensity was generally higher in stromal cells compared with epithelial cells, suggesting that stromal cells may be more receptive to steroid hormone action. Therefore, as in other tissues of the female genital tract, stromal-epithelial interactions induced by sex steroid hormones may be of importance in canine vaginal and vulvar tissues. No cyclic changes in receptor immunostaining were observed. Significant positive correlations were found between receptor immunostaining in some vaginal and vulvar cell groups and the serum concentrations of estradiol-17beta and testosterone, but not with the serum progesterone concentration. Significant negative correlations were found between ERalpha immunostaining in epithelial and stromal cells of the vagina and the serum estradiol-17beta concentration, suggesting a negative feedback mechanism between estradiol-17beta and its receptor. Both cell types play a role in the differentiation of vaginal epithelium, under the influence of estradiol-17beta.

Animals↗
PubMed2002

Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA).

Steroid receptor RNA activator (SRA) is an RNA transcript that functions as a eukaryotic transcriptional coactivator for steroid hormone receptors. We report here the isolation and functional characterization of distinct RNA substructures within the SRA molecule that constitute its coactivation function. We used comparative sequence analysis and free energy calculations to systematically study SRA RNA subdomains for identification of structured regions and base pairings, and we used site-directed mutagenesis to assess their functional consequences. Together with genetic deletion analysis, this approach identified six RNA motifs in SRA important for coactivation. Because all nucleotide changes in the mutants that disrupted SRA function were silent mutations presumed not to alter deduced encoded amino acid sequence, our analysis provides strong evidence that SRA-mediated coactivation is executed by distinct RNA motifs and not by an encoded protein.

Animals↗
PubMed1970

Steroidal free radicals as possible intermediates in the biosynthesis of C19-delta 16-steroids.

Treatment of deoxycorticosterone with reagents that abstract a hydrogen atom from the C-21-hydroxyl group leads to the formation of androsta-4,16-dien-3-one. In vitro incubations of [1,2-(3)H]deoxycorticosterone with homogenates of boar testis tissue produce the tritiated dienone. This reaction can be formulated as an abstraction of hydrogen from the C-21-hydroxyl group to form a C-21-alkoxy radical, followed by a 1,5-H.shift from the C-16 atom and beta-scission of the C-16-alkoxy radical leading to the loss of a C(2) fragment (C-20 and C-21) with the formation of the double bond between C-16 and C-17. Both the chemical model and the in vitro experiment support further the thesis [Lieberman, S., L. Bandy, V. Lippman, and K. D. Roberts, Biochem. Biophys. Res. Commun., 34, 367 (1969)] that biosynthetic reactions in which molecular oxygen reacts with steroids (for example, side-chain cleavage or hydroxylation) involve steroidal free radicals.

Androstanes↗
PubMed1991

Haplotypes of the steroid 21-hydroxylase gene region encoding mild steroid 21-hydroxylase deficiency.

Haplotypes of the complement 4 (C4) and steroid 21-hydroxylase [21-OHase; steroid hydrogen-donor: oxygen oxidoreductase (21-hydroxylating), EC 1.14.99.10] repeated gene complex were studied in nine families with at least one member affected with a mild form of 21-OHase deficiency. DNA probes from different parts of the repeated C4/21-OHase unit were used to follow the segregation of hybridization patterns in the families. Ten structurally distinct haplotypes of the C4/21-OHase gene region were identified, and the encoded phenotype was assigned to 34 of the 36 C4/21-OHase haplotypes. Four structurally different haplotypes with three C4/21-OHase repeat units were found. Eight of the nine haplotypes found with triplications of the C4/21-OHase repeat unit encoded the mild form of 21-OHase deficiency, whereas one particular triplicated haplotype encoded a severe form of the disease. In one case the mild form of 21-OHase deficiency was encoded by a haplotype with a single C4/21-OHase repeat unit. Mild 21-OHase deficiency was predicted in a patient by the presence of a triplicated haplotype. The finding of deranged 21-OHase genes on all triplicated C4/21-OHase haplotypes indicate that most of these common haplotypes carry mutated 21-OHase genes, and thus may cause functional polymorphism of general importance in the population.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium.

Steroid receptor coactivator-1 (SRC-1) family members interact with steroid receptors, including estrogen receptor alpha (ERalpha) and progesterone receptor (PR), to enhance ligand-dependent transcription. However, the expression of ERalpha and SRC-1 was found to be segregated in distinct subsets of cells within the epithelium of the estrogen-responsive rat mammary gland. This finding was in contrast to the finding for the stroma, where significant numbers of cells coexpressed ERalpha and SRC-1. Treatment of animals with estrogen induced PR expression in the ERalpha-expressing mammary epithelial cells in the absence of detectable SRC-1 and did not affect the segregated pattern of SRC-1 and ERalpha expression. PR was neither expressed nor induced by estrogen treatment in stroma, despite the coexpression of ERalpha and SRC-1. These results suggest that SRC-1 is not necessary for ERalpha-mediated induction of PR in mammary epithelial cells and is also not sufficient for PR induction in stromal cells expressing both ERalpha and SRC-1. Furthermore, the expression of SRC-1 in a subpopulation of mammary epithelial cells distinct from those expressing ERalpha or PR raises the possibility that SRC-1 has cell type-specific functions other than simply to act as coactivator for ERalpha or PR in the mammary epithelium.

Animals↗