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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Squalamine is a novel aminosterol recently isolated from the dogfish shark, Squalus acanthias. This water-soluble steroid exhibits potent antibacterial activity against both gram-negative and gram-positive bacteria. In addition, squalamine is fungicidal and induces osmotic lysis of protozoa. We report here the structural determination of squalamine, 3 beta-N-1-[N(3-[4-aminobutyl])-1,3 diaminopropane]-7 alpha,24 zeta-dihydroxy-5 alpha-cholestane 24-sulfate, which was deduced from the analysis of fast atom bombardment spectra and a series of two-dimensional nuclear magnetic resonance (NMR) spectra. Squalamine is a cationic steroid characterized by a condensation of an anionic bile salt intermediate with the polyamine, spermidine. This molecule is a potential host-defense agent in the shark, and provides insight into a new class of vertebrate antimicrobial molecules.
Steroids 1993 Aug
PMID:Structure of the novel steroidal antibiotic squalamine determined by two-dimensional NMR spectroscopy. 821 87

Essential hypertensive patients often respond to treatments mitigating mineralocorticoid action, even though circulating levels of these steroids are within normal ranges. In addition to the kidney, mineralocorticoid or Type I receptors are found in the brain and vascular smooth muscle where they mediate effects associated with several forms of experimental hypertension. Studies in which discrete anatomic or functional areas of the brain have been ablated demonstrate that the periventricular areas of the hypothalamus and the central sympathetic and baroreceptor systems are crucial for the development of hypertension in the renoprival, DOCA salt, and Dahl salt-sensitive rat. Intracerebroventricular (i.c.v.) infusion of aldosterone in both rats and dogs at doses that do not raise serum levels above normal produce hypertension. The hypertension produced by systemic mineralocorticoid excess, adrenal regeneration, and i.c.v. or oral administration of glycyrrhetinic acid or carbenoxolone in genetically normotensive rats and by dietary salt in the Dahl salt-sensitive rat is inhibited by the i.c.v. infusion of a mineralocorticoid receptor antagonist or a Na+ channel-selective amiloride analog. Recent data demonstrate the extraadrenal synthesis of steroids in aortic endothelial cells, smooth muscle cells and the brain. The role of the extraadrenal synthesis of steroids raises new avenues for research into the causes of hypertension.
Steroids 1996 Apr
PMID:Mineralocorticoids, salt and high blood pressure. 873 97

Pseudohypoaldosteronism was first described in 1958 by Cheek and Perry, who reported an infant with severe salt wasting in the absence of any renal or adrenal defect. Since then several reports have described patients affected by symptoms consistent with resistance to mineralocorticoid action. The clinical picture is characterized by salt wasting and failure to thrive and is resistant to the administration of exogenous mineralocorticoids. Biological features are invariably high plasma and urinary aldosterone levels and elevated plasma renin activity associated with hyponatremia, hyperkalemia, and metabolic acidosis. The discovery of abnormal binding of aldosterone to the mineralocorticoid receptor (MR) in lymphocytes from affected patients, by analogy to findings in other syndromes of steroid hormone resistance, led to the hypothesis that the disease reflected a molecular defect in MR, which has prompted a series of molecular studies to characterize the defect. In this paper we review mechanisms of mineralocorticoid action, discuss the clinical features of mineralocorticoid resistance, overview the molecular characterization of the MR, and close with some pathophysiological hypotheses and questions.
Steroids 1996 Apr
PMID:Mineralocorticoid resistance. 873 98

In uninephrectomized rats on 1% NaCl solution to drink, aldosterone (0.75 micrograms/h subcutaneously for 8 weeks) raises blood pressure and causes marked interstitial and perivascular cardiac fibrosis, effects not seen in animals on a low salt intake. In extending these initial findings, we have shown that cardiac fibrosis (i) is not reversed by correction of mineralocorticoid-induced hypokalemia; (ii) appears not to involve the plasma or tissue renin-angiotensin systems, as fibrosis is largely unaffected by concurrent administration of Losartan or Perindopril; (iii) is independent of cardiac hypertrophy, in that it is equally seen in right and left ventricles, and in rats rendered hypertensive without cardiac hypertrophy by the administration of 9 alpha-fluorocortisol; (iv) is independent of elevated blood pressure, in that it is found in normotensive animals infused peripherally with aldosterone and intracerebroventricularly with the mineralocorticoid receptor (MR) antagonist RU28318; (v) is via classical MR, in that it is blocked by concurrent administration of the MR antagonist potassium canrenoate; and (vi) may or may not be a direct cardiac effect, inasmuch as data for in vivo effects on collagen formation by cardiac fibroblasts are conflicting. Although there is a high probability that the action of aldosterone to cause cardiac fibrosis in this experimental model is an effect via non-epithelial MR, the locus of aldosterone action remains to be established, as do the molecular mechanisms linking MR occupancy by aldosterone and collagen deposition. In addition, and in particular, the mechanisms underlying the crucial contribution of high salt intake in this model of mineralocorticoid excess await exploration.
Steroids 1996 Apr
PMID:Mineralocorticoids, salt, hypertension: effects on the heart. 873 7

Electrospray ionization mass spectrometry (ESMS) of the estrogen receptor ligand binding domain (ER LBD) in its estradiol-binding form was performed. A dimeric ER LBD was observed, with a greatly reduced capacity for protonation (major charge state for dimer +16 vs. +23 for a monomer). Peak broadening (probably due to heterogeneity resulting from salt and water adduct formation) adversely affected our ability to distinguish between multiple discreet dimeric species and thus prevented us from establishing an accurate average mass for the dimerized domain. A mixture of species with molecular masses between 57,240 Da and 57,900 Da was observed, which would compare to 57,274 Da, 57,546 Da, and 57,818 Da for the calculated masses of the dimer without estradiol, or with one or two bound ligand molecules, respectively. Hence, nonliganded ER LBD dimer appeared to constitute the major species. The presence of low levels of a singly liganded ER LBD dimer cannot be ruled out, but the data argue against the possibility of the ER LBD dimer carrying two molecules of estradiol. Allowing for current limitations in the technology, our data demonstrate that ESMS on a quadrupole mass spectrometer of limited mass range (4000 Da for singly charged ions) has potential utility for studying ligand-binding proteins. In particular, in future it might be possible to compare spectra obtained from agonist- and antagonist-bound receptors and determine from subtle changes in protonation state possible differences in the higher order structure of those noncovalent protein complexes.
Steroids 1996 Jul
PMID:Intact noncovalent dimer of estrogen receptor ligand-binding domain can be detected by electrospray ionization mass spectrometry. 883 97

The novel 10 beta-(1'-azirinyl)estr-4-en-3,17-dione (10) has been synthesized from 19-methyl-19-methiodide salt intermediates 15 and 16 by a modified Neber reaction. Four other hitherto undescribed 10 beta-1'-azirinyl steroids 9, 12, 17, and 18 were also synthesized. Compound 10 inhibited human placental aromatase in vitro (IC50 value = 5.5 microM) but was not as potent as the related (19R)-10 beta-aziridine (1).
Steroids 1996 Mar
PMID:Synthesis of 10 beta-(1'-azirinyl)estr-4-en-3,17-dione as an aromatase inhibitor. 885 31

The transformation of delta 5-3 beta-hydroxysteroids into the corresponding delta 4-3-keto-steroids is an essential step for the biosynthesis of all classes of active steroids: progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. These steroid hormones play a crucial role in the differentiation, development, growth, and physiological function of most human tissues. The structures of several cDNAs encoding 3 beta-HSD isoenzymes have been characterized in human and several other vertebrate species: human types I and II; macaque; bovine; rat types I, II, III, and IV; mouse types I, II, III, IV, V and VI; hamster types I, II, and III; and rainbow trout. Their transient expression reveals that 3 beta-HSD and delta 5-delta 4-isomerase activities reside within a single protein. Distinct approaches have been used for a better understanding of the structure-function relationships of these 3 beta-HSD enzymes: i) affinity radiolabeling studies of the human type I 3 beta-HSD; ii) identification and the functional consequences of the human type-II 3 beta-HSD mutations detected in patients with 3 beta-HSD deficiency. Taken together, all of these data were examined to determine whether the relationship between the genotype and the phenotype of these patients were consistent with in vitro mutagenesis studies. 3 beta-HSD deficiency, transmitted in an autosomic recessive disorder, is characterized by varying degrees of salt wasting; in genetic males, fetal testicular 3 beta-HSD deficiency causes an undervirilized male genitalia (male pseudohermaphroditism); females exhibit either normal sexual differentiation or mild virilization. All mutations were detected in the type II 3 beta-HSD gene, which is expressed almost exclusively in the adrenals and gonads. No mutation was detected in the type I 3 beta-HSD gene, which is expressed in peripheral tissues. The finding of a normal type I 3 beta-HSD gene explains the elevated delta 5-steroids and mild virilization of affected girls at birth. To date, 24 mutations have been identified in 25 distinct families with 3 beta-HSD deficiencies. All nonsense and frameshift mutations introducing a premature termination codon were associated with the classical salt-losing form. The locations of these nonsense mutations suggest that at least the first 318 amino acids out of 371 are required for 3 beta-HSD activity. The consequences of the missense mutations on some domains of the 3 beta-enzyme, such as membrane-spanning domains, cofactor-binding site, and steroid-binding site, were reviewed. The future crystallization of the overexpressed normal and mutant-type II-3 beta-HSD enzymes should contribute to a better understanding of the structure-function relationships of this enzyme, especially for missense mutations located outside the putative functional regions.
Steroids 1997 Jan
PMID:Structure-function relationships of 3 beta-hydroxysteroid dehydrogenase: contribution made by the molecular genetics of 3 beta-hydroxysteroid dehydrogenase deficiency. 902 34

3-Oxo-17 alpha-pregna-4,6-diene-21,17-carbolactone (canrenone, II) is produced from the potassium salt of 17-hydroxy-3-oxo-17 alpha-pregna-4,6-diene-21-carboxylic acid (I) by acid catalyzed lactonization. II reacts with acetic anhydride/nitric acid to give one main product (III) and some minor products. The structure of III was determined by chemical and spectral analysis to the 4-nitro derivative of canrenone. This result is in contrast to the known reactions of II with most other reagents that were found to add at delta(6), and also in contrast to the reactions of acetic anhydride/nitric acid with alkenes. Electrophilic substitution at the ambident C4 is discussed as the reaction path. The 4-nitro group enhances the inhibitory activity of II against Na+/K(+)-ATPase, the target enzyme of the cardioactive digitalis glycosides, which appears to indicate increased cardioactivity.
Steroids 1997 Dec
PMID:The nitration of canrenone with acetic anhydride/nitric acid. 943 41

Electrophoretic mobility shift assay was used to determine whether pregna-D'-pentaranes allow progesterone receptor (PR) from rat uterine cytosol to bind hormone response element (HRE)-containing oligonucleotide duplexes and to measure the affinity of this interaction. The formation of DNA-protein complexes in low salt medium was progesterone-related ligand-, temperature-, and PR-dependent, and specific for HRE. The highest affinity of PR to DNA (equilibrium K(a) = 0.420 +/- 0.185 nM(-1)) was found in the presence of the partial agonist/antagonist RU486, while the lowest affinity (K(a) = 0.074 +/- 0.013 nM(-1)) was demonstrated with the full agonist 6alpha-methyl-16alpha,17alpha-cyclohexanoprogesterone. With the exception of the strong full agonist R5020, there was a tendency toward correlation between the induced lower affinity of PR for DNA in the context of tyrosine aminotransferase HRE and the full agonistic activity of tested compounds.
Steroids 2002 Apr
PMID:Pregna-D'-pentarane structure influences progesterone receptor affinity for DNA. 1195 87

Studies from our laboratory have demonstrated rapid ( < 1 min) non-genomic activation of Na(+)-H(+) exchange, K(+) recycling, PKC activity and a PKC-dependent Ca(2+) entry through L-type Ca(2+) channels specifically by mineralocorticoids in distal colon. Aldosterone directly stimulates the activity of the PKC alpha isoform (but not PKC delta, PKC epsilon and PKC zeta) in a cell-free assay system containing only purified commercially available enzyme, appropriate substrate peptide, co-factors and lipid vesicles. The primary ion transport target of the non-genomic signal transduction cascade elicited by aldosterone in epithelia is the Na(+)-H(+) exchanger. In isolated colonic crypts, aldosterone produced a PKC alpha sensitive intracellular alkalinisation within 1 min of hormone addition. Intracellular alkalinisation upregulates an ATP-dependent K(+) channel, which is involved in K(+) recycling to maintain the electrical driving force for Na(+) absorption, while inhibiting a Ca(2+) -dependent K(+) channel, which generates the charge balance for Cl(-) secretion. The non-genomic response to aldosterone in distal colon appears to enhance the capacity for absorption while down-regulating the potential for secretion. We have also demonstrated rapid (< 1 min) non-genomic activation of Na(+)-H(+) exchange, K(+) recycling, PKC alpha activity, and a PKC delta- and PKA-dependent Ca(2+) entry through di-hydropyridine-blockable Ca(2+) channels specifically by 17beta-estradiol in distal colon. These rapid effects are female gender specific and are insensitive to inhibitors of the classical estrogen receptor (ER). 17 beta-Estradiol directly stimulated the activity of both PKC delta and PKC alpha (but not PKC epsilon or PKC zeta) in a cell-free assay system. E2 rapidly inhibited basolateral K(Ca) channel activity which would be expected to result in an acute inhibition of Cl(-) secretion. Physiological concentrations of E2 (0.1-10 nM) reduced both basal and secretagogue-induced Cl(-) secretion. This anti-secretory effect of E2 is sensitive to PKC inhibition, intracellular Ca(2+) chelation, and is female gender specific and insensitive to inhibitors of the classical ER. These observations link rapid non-genomic activation of second messengers with a rapid gender-specific physiological effect in the whole tissue. Aldosterone and E2 differ in their protein kinase signal transduction and both hormones stimulate specific PKC isoforms indicating both common and divergent signalling systems for salt-retaining steroid hormones. The physiological function of non-genomic effects of aldosterone and estradiol is to shift the balance from net secretion to net absorption in a pluripotential epithelium.
Steroids 2002 May
PMID:Non-genomic convergent and divergent signalling of rapid responses to aldosterone and estradiol in mammalian colon. 1196 Jun 25


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