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Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively hypersensitive to glucocorticoids, while 2.3% are relatively resistant. . These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even...
11β-hydroxysteroid dehydrogenase (11β-HSD), the enzyme that catalyzes the conversion of biologically active glucocorticoids to their inactive metabolites, was shown to be located exclusively in Leydig cells of the rat testis, and its appearance was associated with the developmental rise in testosterone. Thus, 11β-HSD was suggested to play an important role in maintaining steroidogenesis by inactivating...
Glucocorticoid excess carries the risk of inducing secondary osteoporosis. In endogenous Cushing's syndrome, osteoporosis may be the presenting symptom of the underlying disease. Bone loss may reverse after the condition is cured, but often active treatment of established osteoporosis is necessary. In long-term glucocorticoid treatment at therapeutic doses, bone loss is likely and should be prevented;...
Glucocorticoids are well-recognized modulators of immunocytes and osteoblasts via specific receptor-mediated mechanisms. We have evaluated the in vitro effect of interleukin 2 (IL-2) on the expression of glucocorticoid receptors (GRs) in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors and osteoblast-like Saos-2 cells. Aliquots of PBMC or Saos-2 cells were incubated for 20 h...
We have synthesized several halogenated steroids as potential glucocorticoid receptor mediated imaging agents. These compounds are analogs of aryl-pyrazolo steroids, similar to the potent glucocorticoid, cortivazol. Compounds containing the halogens, iodine, bromine, and fluorine, as well as the E- and Z-iodovinyl side chain at the para position of 2'-phenyl-11β,17,21-trihydroxy-16α-methyl-20-oxo-pregn-4-eno[3,2-c]...
The alpha isoform of the glucocorticoid receptor (GRα) binds glucocorticoids and functions as a ligand-dependent transcription factor. Although GRα is expressed in almost all tissues and cells, its subcellular distribution is controversial. Many studies have reported that GRα translocates from the cytoplasm to the nucleus in a hormone-dependent manner whereas others have concluded that GRα is constitutively...
Peripheral aromatization of androgens exerts estrogenic actions in many tissues. In this study, osteoarthritis synoviocytes were examined to clarify the possible action of adrenal androgen on synovial cell. Synoviocytes from postmenopausal women are able to express aromatase mRNA. By sequence analysis, the PCR fragment (485 bp) was determined to be 100% identical to that of human placental aromatase...
Glucocorticoids (GC's) are metabolized in vascular tissue by two isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD2 is unidirectional and metabolizes GC's to their respective inactive 11-dehydro derivatives. 11β-HSD1 is bi-directional, also possessing reductase activity and thus the ability to regenerate active GC from the 11-dehydro derivatives. In vascular tissue, GC's amplify the...
We examined fetal sheep adrenal glands from 99 to 130 days of gestational age (dGA) to see how connexin 43 (Cx43), the major if not the only adult adrenal gap junction protein, changes expression as the adrenal cortex emerges from the well-documented refractory period to participate in labor and delivery. Immunocytochemical technique and Western blot were used to examine changes in the quantity and...
In vitro models of bone cells are important for the study of bone biology, including the regulation of bone formation and resorption. In this study, we have validated an in vitro model of human osteoblastic cells obtained from bone marrow biopsies from healthy, young volunteers, aged 20-31 years. Osteoblast phenotypes were induced by either dexamethasone (Dex) or bone morphogenetic protein-2 (BMP-2)...
The anabolic steroid oxandrolone is increasingly used to preserve or restore muscle mass in those with HIV infection or serious burns. These effects are mediated, in part, by the androgen receptor (AR). Anti-glucocorticoid effects have also been reported for some anabolic steroids, and the goal of our studies was to determine whether oxandrolone had a similar mechanism of action. Studies with in vitro...
Traditionally, steroid hormone effects have been described as a result of the modulation of nuclear transcription, thus triggering genomic events that are responsible for physiological effects. Despite early observations of rapid steroid effects that were incompatible with this theory, nongenomic steroid effects have been widely recognized only recently. However, the nongenomic effect of glucocorticoid...
The outcome of aerial oxidation of the glucocortico-steroid side-chain (as exemplified by dexamethasone) has been shown to be subject to strict pH control. At pH 7.4 the glyoxal is the only product; at pH values of 8 and 9.2 the etioacid is formed, and at pH values of 13 or above the epimeric glycolic acids are produced. The glycolic acid epimer that predominates by a factor of 2 and is more stable...
The common disease asthma is characterized by the obstruction, inflammation and increased sensitivity of the airways. Glucocorticoids (GCs) are one of the most potent anti-inflammatory agents available for treating allergic disease. In this study, we report that the GC budesonide (BUD) can rapidly inhibit the histamine-induced contractions of airway smooth muscle in a process mediated by non-genomic...
Glucocorticoids are anti-inflammatory molecules classically described as acting through a genomic pathway. Similar to many steroid hormones, glucocorticoids also induce rapid non-genomic responses. The present paper provides a general overview of the rapid non-genomic effects of glucocorticoids in airway and will be mainly focused on a retrospective of the authors work on rapid effects of glucocorticoids...
Glucocorticoids (GC) by either up-regulating or down-regulating the expression of genes influence cellular processes in every tissue and organ of the body. The enzyme 11β-hydroxysteroid dehydrogenase Type-1 (11β-HSD-1) confers bioactivity upon the inactive GC cortisone (E) and prednisone (P) by converting them to cortisol (F) and prednisolone (L), respectively. We sought to investigate whether gene...
In the ovary cortisol-cortisone inter-conversion is catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD). Its role in carcinomas of human ovary is unknown. The majority of ovarian cancers are derived from ovarian surface epithelium and the inflammation caused by successive ovulation seems to a play a role in the development of cancer. Cortisol is known to act as anti-inflammatory agent...
Glucocorticoids act through glucocorticoid receptor (GR) and are used for the treatment of several diseases. Ligand-induced recruitment of coregulator protein(s), coactivator/corepressor, to GR is an initial step in transcriptional activation/inhibition of GR. We describe herein genetically encoded fluorescent probes for screening of glucocorticoids, natural and synthetic, in single living cells....
Peri-operative immunosuppression in cardiac transplantation includes the use of intravenous methylprednisolone. During a national shortage, intravenous dexamethasone was substituted for methylprednisolone at standard equivalencies. Methylprednisolone and dexamethasone are used interchangeably in many clinical settings; however, their equivalency has not been demonstrated.Forty-two consecutive cardiac...
Stress-mediated elevations in circulating glucocorticoid levels lead to corresponding rapid declines in testosterone production by Leydig cells in the testis. In previous studies we have established that glucocorticoids act on Leydig cells directly, through the classic glucocorticoid receptor (GR), and that access to the GR is controlled prior to the GR by a metabolizing pathway mediated by the type...
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