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Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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of dystrophin protein weakens the sarcolemmal membrane and results in progressive replacement of muscle fibres by fat and fibrous tissue ( Deconinck & Dan 2007 ). Glucocorticoids (GC) are currently the mainstay of treatment in DMD and are an
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Introduction Response to neuroendocrine stress begins with the activation of the hypothalamic–pituitary–adrenal (HPA) axis leading to the increase in stress hormones glucocorticoids (GCs). These hormones mediate adaptation to stress and also
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SUMMARY
1. Fresh splenic tissue from pigs was extracted by the method of Swingle & Pfiffner for adrenocortical extracts, 1 ml. being equivalent to 100 g splenic tissue.
2. The material extracted was readily soluble in ethanol, benzene, acetone and water, but not in petroleum ether. It contained no protein, bile pigments, fat, fatty acids or cholesterol, and had marked reducing properties.
3. Administration of the extract to adrenalectomized male mice caused an increase, continuous with increasing dose of extract, in the glycogen content of liver and muscle. The increase in liver glycogen produced by 1·2 ml. extract was about the same as that caused by 2 mg cortisone.
4. In intact rats the extract caused an increase in blood sugar and in the glycogen content of liver and muscle. Cortisone had a similar effect.
5. Neither the splenic extract nor cortisone raised the glycogen content of the brain in adrenalectomized mice or intact rats.
6. Thus the spleen contains a substance which has a glucocorticoid-like effect on the carbohydrate metabolism of adrenalectomized and intact animals. In view of its chemical and biological properties, this substance is thought to be a glucocorticoid originating in the adrenal cortex. A substance with similar effects has been previously detected in liver, brain and muscle.
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SUMMARY
[7-3H]Pregnenolone was incubated with homogenates of adrenal glands from two 100-day-old sheep foetuses. Cortisol and corticosterone were isolated and identified by reverse isotope dilution and recrystallization to constant specific activity. Together these two compounds accounted for 12% and 17% of the substrate with the two tissue preparations. Other C21 and C19 metabolites which were sought were not present in appreciable quantities. Additional incubations were done with the adrenals of lamb foetuses ranging in age from 110 days of gestation to the immediate newborn period. Glucocorticoidogenic capacity similar to that of the 100-day-old foetuses was demonstrated throughout this period and no age-related change was evident. These results demonstrate that the lamb foetal adrenal has a substantial enzymic capacity for glucocorticoid synthesis throughout at least the last third of gestation. In conjunction with the observations of others, these experiments support the hypothesis that during this period of gestation the lamb foetal adrenal is actively synthesizing glucocorticoids in a manner which is similar to the lamb at term and the adult sheep.
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Glucocorticoid (GC) resistance is a phenomenon of major significance in a number of clinical situations, including the therapy of lymphoid malignancies. Resistance may concern all, or just selected, GC effects, it may be absolute or just reflect a state of reduced sensitivity and, clinically relevant, be reversible or irreversible. Numerous molecular mechanisms can be envisaged acting either 'upstream' in the GC-triggered signaling pathway, i.e. at the level of the GC receptor (GR), or 'downstream' at the level of the GC-regulated genes responsible for individual GC effects. In lymphoid malignancies, GCs have anti-leukemic effects through the induction of apoptosis and/or cell cycle arrest. In this condition evidence for only a small number of mechanisms for GC resistance has been provided, mostly at the level of the GR. Herein, we review reports and hypotheses regarding 'upstream' and 'downstream' mechanisms for GC resistance in lymphoblastic leukemia and present an in vitro GC resistance model that might allow identification of resistance mechanisms.
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Institut de Physiologie Générale, Université Louis Pasteur, Rue René Descartes, 67000 - Strasbourg, France
(Received 23 November 1976)
Studies on glucocorticoid binding to the anterior pituitary gland has revealed, in addition to a receptor binding both natural and synthetic steroids, the presence of a compound closely resembling plasma transcortin (Koch, Lutz, Briaud & Mialhe, 1975, 1976; DeKloet & McEwen, 1976). Whether this transcortin-like component, which is not a true receptor and has been shown not to be due to mere blood contamination, is intracellular or bound to the cell membrane is still unclear. In this study, using isolated cells and plasma membrane fractions, we present indirect evidence suggesting attachment of the transcortin-like material to the cellular membrane of the pituitary cells.
Isolated pituitary cells were obtained as described by Portanova, Smith & Sayers (1970), using glands from 1-day adrenalectomized male rats, extensively perfused with ice-cold 0·9% saline through the heart.
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ABSTRACT
Granulosa cells from immature rats primed with diethylstilbestrol (DES) showed a fivefold rise in the activity of secreted plasminogen activator (PA) in response to human FSH. The dose giving 50% of the maximum response (ED50) was 10 ng/ml. Glucocorticoid hormones significantly suppressed PA activity in both control cells and cells stimulated with FSH (ED50 = 50 nmol dexamethasone/l; 1 μmol corticosterone/l). Cortexolone (2·5 μmol/l) significantly ameliorated this suppression, indicating that the response to glucocorticoids is receptor-mediated. These data, together with the time delay required for glucocorticoids to take effect (5 h), suggest that glucocorticoids induce the production of a specific PA inhibitor in granulosa cells.
J. Endocr. (1987) 114, 207–212
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ABSTRACT
Stress provokes a cohort of homeostatic reflexes by the central nervous, the immune as well as the metabolic control systems of the body. These powerful adaptive responses, which can cause a collapse of body homeostasis in the absence of feedback inhibition, are suppressed by adrenal glucocorticoid hormones. A prominent and physiologically significant early action of glucocorticoids that requires the induction of newly synthesized messenger RNA and protein is the suppression of ACTH release by anterior pituitary corticotroph cells. It is demonstrated here that glucocorticoids inhibit stimulated ACTH secretion in pituitary corticotroph tumour (AtT-20) cells by reducing stimulus-evoked intracellular free calcium transients. Thus, the data show for the first time that intracellular calcium signals may be modified by rapidly induced proteins. It is proposed that this is a general mechanism that underlies the early inhibitory effects of glucocorticoids during stress in various types of cell.
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The metabolic potential of cells with elevated heat shock protein 70 (hsp70) content was examined by measuring unstimulated and glucocorticoid-stimulated glucose release in trout hepatocytes maintained in primary culture. Exposure of hepatocytes to either heat shock (HS;+15 degrees C) or sodium arsenite (50 microM) did not affect cell viability, but resulted in significantly higher hsp70 levels over a 24 h recovery period. Hsp70 accumulation had no significant impact on unstimulated glucose release, but completely abolished cortisol-induced glucose release in trout hepatocytes. This lack of glucocorticoid responsiveness corresponded with lower glucocorticoid receptor protein levels. Together, our results suggest that stressor-induced hsp70 accumulation, while important for maintaining cellular homeostasis, may impair metabolic adjustments to subsequent stressors in animals, especially those that are glucocorticoid-dependent.
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This study was performed to assess the effect of glucocorticoids (dexamethasone) on insulin- and IGF-I-regulated muscle protein metabolism in adult and old rats. Muscle atrophy occurred more rapidly in old rats, and recovery of muscle mass was impaired when compared with adults. Muscle wasting resulted mainly from increased protein breakdown in adult rat but from depressed protein synthesis in the aged animal. Glucocorticoid treatment significantly decreased the stimulatory effect of insulin and IGF-I on muscle protein synthesis in adult rats by 25.9 and 58.1% respectively. In old rats, this effect was even greater, being 49.3 and 100% respectively. With regard to muscle proteolysis, glucocorticoids blunted the anti-proteolytic action of insulin and IGF-I in both age groups. During the recovery period, adult rats reversed the glucocorticoid-induced resistance of muscle protein metabolism within 3 days, at which time old rats still exhibited the decrease in insulin-regulated proteolysis. In conclusion, the higher sensitivity of old rat muscle to glucocorticoids may in part result from the greater modification of the effects of insulin and IGF-I on muscle protein metabolism. These responses to glucocorticoids in old rats may be associated with the emergence of muscle atrophy with advancing age.