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At least 379 records · Page 21Linked to original sources
PubMed1994

6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase.

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

3-Hydroxysteroid Dehydrogenases↗
PubMed1975

Luteal 20alpha-hydroxy steroid dehydrogenase and the formation of delta4-3-oxo steroids in the rat after weaning or treatment with 2-bromo-alpha-ergocryptine during lactation.

Natural or early weaning of rat litters caused an increased activity of maternal luteal 20alpha-hydroxy steroid dehydrogenase and a decreased release of delta4-3-oxo steroids in vitro. 2. Compound CB-154 (2-bromo-alpha-ergocryptine) caused an increase of 20alpha-hydroxy steroid dehydrogenase activity in mid-lactation but not in early lactation. 3. Prolaction did not prevent these increases in enzyme activity.

Adrenalectomy↗
PubMed2004

The potential function of steroid sulphatase activity in steroid production and steroidogenic acute regulatory protein expression.

The first step in the biosynthesis of steroid hormones is conversion of cholesterol into pregnenolone. StAR (steroidogenic acute regulatory) protein plays a crucial role in the intra-mitochondrial movement of cholesterol. STS (steroid sulphatase), which is present ubiquitously in mammalian tissues, including the placenta, adrenal gland, testis and ovary, desulphates a number of 3beta-hydroxysteroid sulphates, including cholesterol sulphate. The present study was designed to examine the effect of STS on StAR protein synthesis and steroidogenesis in cells. Steroidogenic activities of COS-1 cells that had been co-transfected with a vector for the cholesterol P450scc (cytochrome P450 side-chain-cleavage enzyme) system, named F2, a StAR expression vector (pStAR), and an STS expression vector (pSTS) were assayed. Whole-cell extracts were subjected to SDS/PAGE and then to Western blot analysis. pSTS co-expressed in COS-1 cells with F2 and pStAR increased pregnenolone synthesis 2-fold compared with that of co-expression with F2 and pStAR. Western blot analysis using COS-1 cells that had been co-transfected with pSTS, F2 and pStAR revealed that StAR protein levels increased, whereas STS and P450scc protein levels did not change. The amount of StAR protein translation products increased when pSTS was added to an in vitro transcription-translation reaction mixture. Pulse-chase experiments demonstrated that the 37 kDa StAR pre-protein disappeared significantly ( P <0.01) more slowly in COS-1 cells that had been transfected with pSTS than in COS-1 cells that had not been transfected with pSTS. The increase in StAR protein level is not a result of an increase in StAR gene expression, but is a result of both an increase in translation and a longer half-life of the 37 kDa pre-StAR protein. In conclusion, STS increases StAR protein expression level and stimulates steroid production.

Animals↗
PubMed1996

Mesalamine in Crohn's disease with steroid-induced remission: effect on steroid withdrawal and remission maintenance, Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives.

BACKGROUND & AIMS: Steroid dependence and early relapse are frequent after a prednisolone-induces remission in Crohn's disease. The aim of this trial was to test whether mesalamine started at the onset of steroid tapering increases the rate of weaning from prednisolone and reduces the relapse rate after prednisolone cessation. METHODS: One hundred fifty patients with active Crohn's disease were administered oral prednisolone (1 mg.kg(-1). day(-1)) x 3-7 weeks; 129 patients went into clinical remission and were randomized to Pentasa (4 g . day(-1)) or placebo, administered until weaning and for 1 year thereafter. RESULTS: Groups were similar for clinical and biological items collected initially. Weaning failure rate was 30% and 12% in the placebo and mesalamine arms, respectively. At the end of the trial, 9 of 36 patients administered placebo and 14 of 48 administered mesalamine were in remission. Both groups had similar time to relapse curves in the postweaning year; after adjusting for risk factors (high Crohn's Disease Activity Index, white blood cell count of >9 x 10(9) /l-1 at weaning, and use of a medical treatment in the month before inclusion), Pentasa was found to be superior to placebo. CONCLUSIONS: After a prednisolone-induces remission in Crohn's disease, mesalamine facilitates steroid withdrawal and, during the postweaning year, may reduce the relapse rate in certain patient subgroups.

Adolescent↗
PubMed2002

Immunolocalization of sex steroid hormone receptors in the canine uterine tube 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 uterine tubes. Samples of uterine tubes were taken from dogs in different stages of the estrous cycle, and dogs that were pregnant or had just delivered. Nuclear staining for sex steroid hormone receptors was observed in the surface epithelium, stromal cells and smooth muscle cells of the muscular layer. Only slight differences in staining pattern were observed between the ampulla and fimbriae. The staining for ERalpha and PR showed changes throughout the estrous cycle. Some of these changes were related to changing concentrations of sex steroid hormones. High staining scores for ERalpha and PR were found during proestrus and low scores during early metestrus. The staining for AR showed only minor cyclic changes. However, during proestrus and estrus, cytoplasmic staining for AR was observed in differentiated secretory epithelial cells, when nuclear staining in these cells was nearly absent. For the three hormone receptors, stromal cells generally stained with a higher intensity than epithelial cells. It is likely that many steroid hormone actions on the epithelium are mediated through stromal cells. During pregnancy, rather high staining scores were found for ERalpha and AR in the uterine tube. This is in contrast to observations in the canine pregnant uterus.

Anestrus↗
PubMed2004

Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant nephrotic syndrome (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes for end-stage renal disease (ESRD) in the first two decades of life. Sporadic mutations in the Wilms' tumor suppressor gene WT1 have been found to be present in patients with SRNS in association with Wilms' tumor (WT) and urinary or genital malformations, as well as in patients with isolated SRNS. METHODS: To further evaluate the incidence of WT1 mutations in patients with NS we performed mutational analysis in 115 sporadic cases of SRNS and in 110 sporadic cases of steroid-sensitive nephrotic syndrome (SSNS) as a control group. Sixty out of 115 (52%) patients with sporadic SRNS were male, 55/115 (48%) were female. Sex genotype was verified by haplotype analysis. Mutational analysis was performed by direct sequencing and by denaturing high-performance liquid chromatography (DHPLC). RESULTS: Mutations in WT1 were found in 3/60 (5%) male (sex genotype) cases and 5/55 (9%) female (sex genotype) cases of sporadic SRNS, and 0/110 (0%) sporadic cases of SSNS. One out of five female patients with mutations in WT1 developed a WT, 2/3 male patients presented with the association of urinary and genital malformations, 1/3 male patients presented with sexual reversal (female phenotype) and bilateral gonadoblastoma, and 4/5 female patients presented with isolated SRNS. CONCLUSION: According to the data acquired in this study, patients presenting with a female phenotype and SRNS and male patients presenting with genital abnormalities should especially be screened to take advantage of the important genetic information on potential Wilms' tumor risk and differential therapy. This will also help to provide more data on the phenotype/genotype correlation in this patient population.

Child↗
PubMed2005

Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1).

Steroid receptor coactivator 3 (SRC-3/AIB1) interacts with steroid receptors in a ligand-dependent manner to activate receptor-mediated transcription. A number of intracellular signaling pathways initiated by growth factors and hormones induce phosphorylation of SRC-3, regulating its function and contributing to its oncogenic potential. However, the range of mechanisms by which phosphorylation affects coactivator function remains largely undefined. We demonstrate here that peptidyl-prolyl isomerase 1 (Pin1), which catalyzes the isomerization of phosphorylated Ser/Thr-Pro peptide bonds to induce conformational changes of its target proteins, interacts selectively with phosphorylated SRC-3. In addition, Pin1 and SRC-3 activate nuclear-receptor-regulated transcription synergistically. Depletion of Pin1 by small interfering RNA (siRNA) reduces hormone-dependent transcription from both transfected reporters and an endogenous steroid receptor target gene. We present evidence that Pin1 modulates interactions between SRC-3 and CBP/p300. The interaction is enhanced in vitro and in vivo by Pin1 and diminished when cellular Pin1 is reduced by siRNA or in stable Pin1-depleted cell lines. Depletion of Pin1 in MCF-7 human breast cancer cells reduces the endogenous estrogen-dependent recruitment of p300 to the promoters of estrogen receptor-dependent genes. Pin1 overexpression enhanced SRC-3 cellular turnover, and depletion of Pin1 stabilized SRC-3. Our results suggest that Pin1 functions as a transcriptional coactivator of nuclear receptors by modulating SRC-3 coactivator protein-protein complex formation and ultimately by also promoting the turnover of the activated SRC-3 oncoprotein.

Acetyltransferases↗
PubMed2002

Steroid receptor coactivator SRC-1 exhibits high expression in steroid-sensitive brain areas regulating reproductive behaviors in the quail brain.

The steroid receptor coactivator SRC-1 modulates ligand-dependent transactivation of several nuclear receptors, including the receptors for sex steroid hormones. Reducing the expression of SRC-1 by injection of specific antisense oligonucleotides markedly inhibits the effects of estrogens of the sexual differentiation of brain and behavior in rats and inhibits the activation of female sexual behavior in adult female rats. SRC-1 thus appears to be involved in both the development and activation of sexual behavior. In the Japanese quail brain, we amplified by RT-PCR a 3,411-bp fragment extending from the HLH domain to the activating domain-2 of the protein. The quail SRC-1 is closely related to the mammalian (m) SRC-1 and contains a high proportion of GC nucleotides (62.5%). Its amino acid sequence presents 70% identity with mammalian SRC-1 and contains the three conserved LXXLL boxes involved in the interaction with nuclear receptors. In both males and females, RT-PCR demonstrates a similarly high level of expression in the telencephalon, diencephalon, optic lobes, brain stem, spinal cord, pituitary, liver, kidney, adrenal gland, heart, lung, gonads and gonoducts. Males express significantly higher levels of SRC-1 in the preoptic area-hypothalamus than females. In both sexes, lower levels of expression are observed in the cerebellum and muscles. In situ hybridization utilizing a mixture of four digoxigenin-labeled oligonucleotides confirms at the cellular level the widespread distribution of SRC-1 mRNA in the brain and a particularly dense expression in steroid-sensitive areas that play a key role in the control of male sexual behavior. These data confirm the presence and describe for the first time the SRC-1 distribution in the brain of an avian species. They confirm its broad, nearly ubiquitous, distribution in the entire body including the brain as could be expected for a coactivator that regulates to the action of many nuclear receptors. However this distribution is heterogeneous in the brain and sexually differentiated in at least some areas. The very dense expression of SRC-1 in limbic and mesencephalic nuclei that are associated with the control of male sexual behavior is consistent with the notion that this coactivator plays a significant role in the activation of this behavior.

Adrenal Glands↗
PubMed1980

Testicular steroid sulfotransferases: comparison to liver and adrenal steroid sulfotransferases of the mature rat.

Steroid sulfotransferase activity was investigated in cytosol fractions of whole testes, isolated seminiferous tubules, isolated interstitial tissue, livers, and adrenal glands of mature male rats. Enzyme activity was measured by incubating cytosol fractions with 3H-labeled pregnenolone, dehydroepiandrosterone, testosterone, or estradiol and the active sulfate donor 3'-phosphoadenosine-5'-phosphosulfate. Testicular steroid sulfotransferase activity was found in seminiferous tubules. 3 beta-Hydroxysteroid sulfotransferase activity of seminiferous tubules exhibited a pH optimum of 10 in contrast to a pH optimum of 5 reported for cytosol fractions of rat liver. Marked differences in substrate specificity were demonstrated in the three tissues. The preferred substrate for the 3 beta-hydroxysteroid sulfotransferase in seminiferous tubules was pregnenolone, and in liver it was dehydroepiandrosterone, No 3 beta-hydroxysteroid sulfotransferase activity could be detected in cytosol fractions of adrenal glands. Testosterone was sulfated only by hepatic cytosol fractions. All three tissues contained estrogen sulfotransferase activity. These data suggest that the 3 beta-hydroxysteroid sulfotransferase of seminiferous tubules is distinct from the 3 beta-hydroxysteroid sulfotransferase of liver. These differences may relate to different functions of steroid sulfates in liver and testes.

Adrenal Glands↗
PubMed2006

Reduction of 1,4-dien-3-one steroids with LiAl2H4 or NaB2H4: stereospecific deuterium-labeling at the c-1alpha position of a 4-en-3-one steroid.

Reduction of a double bond at C-1 of 1,4-dien-3-one steroids 7 and 8 with LiAl2H4 in THF or NaB2H4 in MeOH and H2O gave stereospecifically [1alpha-2H]-labeled 4-en-3-one steroids 9 and 10, respectively. When the deuterated solvents, MeO2H and 2H2O, were used for the reaction of steroid 8 with NaB2H4, [1alpha,2xi-2H2]-labeled compound 10 was produced. This indicates that the reaction proceeds through the initial hydride attack at the C-1alpha position, followed by ketonization of the 2-en-3-ol intermediate.

Aluminum Compounds↗
PubMed2003

Effects of steroidal and non steroidal drugs on the neovascularization response induced by tumoral TA3 supernatant on CAM from chick embryo.

Angiogenesis, the development of new blood vessels from the existing vascular network, may result as a consequence of the increase or decrease of proangiogenic or antiangiogenic factors, respectively. The tumor itself could up-regulate the production of angiogenic factors. Recently, we established that the steroidal drug betamethasone in low concentration inhibit the neovascularization promoted by TA3 Ts on CAM of chick embryos. We describe here the effects of the non-steroidal drug ketoprofen, alone or in association with betamethasone, on the angiogenesis promoted by TA3 Ts on CAM. The main finding reported here is that the formation of new blood vessels is strongly inhibited by low concentrations of ketoprofen. The association of both drugs produced a synergistic effect, significantly decreasing tumoral supernatant angiogenesis. It is known that steroidal anti-inflammatory drugs inhibit the enzymes required for the production of prostaglandins through a nuclear GR mediated mechanism. This may operate as a general mechanism in endothelial cells as well. Considering that the induction of COX 1 and COX2 are inhibited by ketoprofen, and that these enzymes are located in the stromal compartment of the CAM, we propose that its antiangiogenic effect may occur via inhibition of the two COX isoforms. In fact, we found that ketoprofen induced apoptosis in both the stromal fibroblast and endothelial cells. The potentiated effect of the combination of betamethasone and ketoprofen may have some therapeutic projections in the control of pathological angiogenesis.

Animals↗
PubMed2005

[Skin cells as steroid target; the steroid action in some skin diseases and wound healing].

The paper is concerned with contemporary concepts on the role of androgens, estrogens, progesterone, mineralcorticosteroids, glucocorticoids and vitamin D3 and their signal transduction pathways in skin physiology, pathology and wound healing. The new therapeutic strategies based on mechanisms of steroid action have been presented. The classic, genomic pathway based on nuclear receptor activation is a well documented fact but less is known about indirect, nongenomic steroid effects. Steroids induced effects depend on their concentration, type of target cells and the receptors as well as accompanying side effects.

Androgens↗
PubMed1990

Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites.

The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3 alpha-OH-DHP, THDOC, 3 alpha-hydroxy-pregn-4-en-20-one, and pentobarbital enhancement of muscimol-stimulated 36Cl- uptake are biphasic, with Hill coefficients significantly less than 1.0. Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s). In contrast, the concentration-response curve for THDOC 21-mesylate is monophasic, with a smaller maximal response, and yields a Hill coefficients of 1.0. In addition to modulating GABA receptor-mediated 36Cl- uptake, THDOC enhanced the ability of the benzodiazepine clonazepam to potentiate muscimol-stimulated 36Cl- uptake. The central benzodiazepine antagonist Ro15-1788 failed to inhibit THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake, although it has been previously reported to inhibit some of the behavioral actions of THDOC. In contrast to the A ring-reduced metabolites and analogues of progesterone and deoxycorticosterone, glucocorticoids had no effect on muscimol-stimulated 36Cl- uptake in cerebral cortical synaptoneurosomes at concentrations between 20 nM and 5 microM.

20-alpha-Dihydroprogesterone↗
PubMed1989

An electron microscopic study of the steroid hormone receptor in uterine cells by the colloidal gold-labeled steroid hormone.

To study the localization of the progesterone and estradiol receptors by electron microscopy, the colloidal gold-labeled steroid hormones, intercalated with bovine serum albumin, were developed in the postembedding method. Among the tissues investigated in this study, receptors specifically distributed in the nuclei of the cells in the uterus and liver but not in the colon. Among the uterine smooth muscle cells in the estrus cycle, the frequency of the progesterone receptors in the nuclei indicated the highest level at a proestrus stage when the serum estradiol is maximum and the lowest level at a metestrus stage when the serum estradiol is minimum. On the other hand, the frequency of the estradiol receptor did not show significant changes among the stages of the estrus cycle. In the nuclei, the receptors specifically distributed on the euchromatin and on the peripheral regions of the heterochromatin, thought to be active regions of the transcription, and among the interchromatin granules. No receptors were observed within the nucleolus, the heterochromatin, the perinuclear chromatin, the nuclear sap, and the perichromatin granules. The colloidal gold-labeled steroids proved to be useful to study the microlocalization of the steroid hormone receptors in various target organs by electron microscopy.

Animals↗
PubMed1989

[Signs of steroid myopathy in a group of patients with asthma undergoing continuous steroid therapy].

The 35 patients with bronchial asthma undergoing continuous steroid therapy were examined in order to reveal any signs of steroid myopathy. More than 80% of patients complained of muscle weakness. In the physical examination the motor function was correct in the majority of patients. Muscular enzymes and blood electrolytes were normal. EMG has shown typical myopathic changes In over 80% of patients. The diagnosis of subclinical steroid myopathy was based mainly on EMG examination. This myopathy was independent of sex, age, dose an duration of therapy.

Adolescent↗
PubMed1976

Steroid phosphorus compounds. V--Mass spectrometry of phosphinic esters of monohydroxy steroids.

The mass spectra of the dimethylphosphinic, dimethylthiophosphinic and dimethylphosphinous ester derivatives of several monohydroxy steroids are reported. The fragmentations of the derivatized steroids largely depend on the nature of the phosphorus-containing ester group. Phenolic ester derivatives exhibit the base peak at the molecular ion, whereas the spectra of the secondary phosphinic esters are dominated by very intense protonated phosphinic acid ions [Me2P(XH)(OH)]+ at m/e 95 (X =O) or at m/e 111 (x = s). The present results also indicate the low ionization potential for the phosphinic ester group. Due to their good gas chromatographic properties, these steroid derivatives appear to be particularly suitable for gas chromatographic mass spectrometric analysis of biochemical materials.

Androsterone↗
PubMed1976

Steroids and hematopoiesis. I. The effect of steroids on in vitro erythroid colony growth: structure/activity relationships.

When substituted steroids of several classes are added to cultures of rat bone marrow cells in the presence of erythropoietin a consistent enhancement of the number of colonies of hemoglobin synthesizing cells is obtained. Maximum steroid effectiveness was found to be between 10(-6) and 10(-7) M. Representative compounds of several classes of steroids were examined for their ability to enhance colony growth, including delta 4-estrenes, delta 4-androstenes, 5alpha-H androstanes and estranes, 5beta-H estranes, pregnanes and androstanes. While testosterone and its 5alpha-H derivatives had little or no activity, many synthetic derivatives of testosterone were highly active in increasing erythroid colony growth. All 5beta-H androstanes, estranes, and all but one 5beta-H pregnane were active. Cortisol consistently inhibited colony growth and estradiol and progesterone had no significant effect.

Androstanes↗