Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids have previously have shown to decrease Type I collagen synthesis in vivo and in fibroblast cell culture. Several studies have demonstrated that glucocorticoids decrease Type I procollagen gene expression. These latter studies have included uridine incorporation into pro alpha 1 (I) and pro alpha 2 (I) mRNAs and nuclear run-off experiments. Using the ColCat 3.6 plasmid, which contains part of the 5' flanking region of the pro alpha 1 (I) collagen gene and the reporter gene, chloramphenicol acetyltransferase, the present studies demonstrate by stable transfection of fetal rat skin fibroblasts that dexamethasone down regulates the promoter activity of the pro alpha 1 (I) collagen gene. The glucocorticoid-mediated down-regulation of procollagen gene expression was demonstrated using the ColCat 3.6, 2.4, 1.7, or 0.9 plasmid. In addition, competitive oligonucleotide transfection experiments and site specific mutation of the glucocorticoid response element (GRE) in the whole ColCat 3.6 plasmid did not eliminate the effect. The possibility existed that another cis-element in the 5' flanking region of the pro alpha 1 (I) collagen gene was also required for the collagen glucocorticoid-mediated down-regulation of procollagen gene expression, since TGF-beta has been shown to stimulate in a decrease of transforming growth factor-beta (TGF-beta) secretion into the media. Gel mobility studies demonstrated that glucocorticoid treatment of rat skin fibroblasts decreased glucocorticoid receptor binding to the GRE and TGF-beta activator protein to the TGF-beta element which were brought back to control values by coordinate exogenous TGF-beta treatment. Thus the interaction of these TGF-beta molecules with cellular membrane receptors and subsequent transduction is dramatically decreased resulting in less signals to regulate collagen gene expression. These data indicate that glucocorticoids coordinately regulate procollagen gene expression through both the GRE and TGF-beta elements. Depression of procollagen gene expression by glucocorticoids through the TGF-beta element is mediated by decreased TGF-beta secretion, possibly involving a secondary effect on regulatory protein(s) encoded by noncollagenous protein gene(s). The present studies provide the basis for a novel mechanism of glucocorticoid-mediator regulation of eukaryotic genes containing the TGF-beta element.
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PMID:Glucocorticoids coordinately regulate type I collagen pro alpha 1 promoter activity through both the glucocorticoid and transforming growth factor beta response elements: a novel mechanism of glucocorticoid regulation of eukaryotic genes. 856 55

Impaired cognitive function and enhanced activity of the hypothalamic-pituitary-adrenocortical system are among the cardinal symptoms of major depression in humans that resolve after successful antidepressant treatment. We used a transgenic mouse model expressing antisense RNA complementary to that of glucocorticoid receptor (GR) mRNA to test the hypothesis that reduced GR function can cause these clinical disturbances. The transgenic mice show profound behavioural changes in a number of animal tests that are indicative of cognitive impairment. These mice also have elevated plasma corticotropin concentrations in response to stress. After long-term treatment with moclobemide, a reversible inhibitor of monoamine oxidase type A that acts clinically as an antidepressant, both the behavioural deficits and the hormonal alterations disappeared. These observations suggest that a transgenic mouse with GR dysfunction may be a useful model for investigation of drug effects on the cognitive and neuroendocrine aspects of depression.
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PMID:Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. 874 20

Through expression of a glucocorticoid receptor (GR) antisense RNA in brain, we have produced transgenic mice with an hyperactive hypothalamic-pituitary-adrenocortical (HPA) system similar to that seen in depressed patients. This model supports the hypothesis that disturbed corticosteroid receptor regulation could be the primary factor responsible for both the CRH/AVP hyperdrive that leads to increased activity of the HPA system, and the premature escape from the cortisol suppressant action of dexamethasone seen in affective disorders. Although normalisation of the hyperactive HPA system occurs during successful antidepressant therapy of depressive illness, these improvements do not correlate with changes in monoaminergic neurotransmitter systems, suggesting that unknown mechanisms of action may be operative. Work from my laboratory was the first to show that different types of antidepressants increased glucocorticoid receptor (GR) mRNA. We found increased GR mRNA levels irrespective of the preferential inhibitory action of antidepressant on the monoamine neurotransmitter re-uptake and showed increased GR gene transcription in antidepressant-treated mouse fibroblast cells that do not possess monoamine re-uptake mechanisms. We measured changes in glucocorticoid response in cells transfected with a glucocorticoid-sensitive reporter plasmid (MMTV-CAT) and observed increased glucocorticoid-stimulated CAT activity when the cells were treated with antidepressant. A different chimaeric gene construct consisting of a fragment of the GR gene promoter region fused to the CAT gene allowed more direct measurement of antidepressant action and increased CAT activity was also seen when cells transfected with this construct were treated with antidepressant. Finally, GR mRNA concentration and glucocorticoid binding activity were increased in brain tissues of animals chronically treated with antidepressant. The time course of antidepressant actions on corticosteroid receptors coincides with their long-term actions on HPA system activity and follows closely that of clinical improvement of depression. This suggests that antidepressant-induced changes in brain corticosteroid receptors may underlie the observed simultaneous decrease in circulating ACTH and corticosterone levels and the decreased adrenal size. Some of these effects may be mediated through CRH since, in antidepressant-treated transgenic mice hypothalamic CRH mRNA levels were decreased. From this work we have formulated the hypothesis that a primary action of antidepressants could be the stimulation of corticosteroid receptor gene expression that renders the HPA system more susceptible to feedback inhibition by cortisol. The resultant decrease in HPA system activity could induce secondary changes in glucocorticoid-sensitive gene expression and lead to redressment of neurotransmitter imbalance. This work opens up a completely new insight into antidepressant drug action and suggests a line of approach to the development of new drugs by focusing on this action.
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PMID:Modulation of glucocorticoid receptor gene expression by antidepressant drugs. 885 29

A review of the literature has been presented concerning pathogenetic role of limbic-hypothalamic-pituitary-adrenal axis (LHPA) in depression and the therapeutic possibility obtained by influencing this axis. Increased cortisol concentration has until now been the best documented biochemical abnormality in depression. Pathological results of the Dexamethasone Suppression Test pointing to hyperactivity of LHPA axis are found in about half of depressive patients. According to most recent research, primary disturbance of LHPA axis concerns hypothalamus (excessive secretion of corticotropin releasing factory) and limbic system (insufficiency of glucocorticoid receptor). An association was found between disturbances of LHPA axis in depression and immune system abnormalities in this illness. Disturbances of serotonergic and noradrenergic neurotransmission in depression may also partially result from LHPA axis dysfunction. In recent years, the attempts have been made to use drugs acting on LHPA axis for therapeutic purposes in depression, such as ketoconazole, within the framework of antiglucocorticoid strategy. Influencing LHPA axis may underlie the mechanism of new antidepressant drug, tianeptine. Recently, it was found that classical tricyclic antidepressant drugs as well as electroconvulsive may also act on LHPA in regulatory way.
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PMID:[Limbic-hypothalamic-pituitary-adrenal axis in depression: literature review]. 898 15

There is only sparse and ambiguous information about circadian and pulsatile secretion features of the hypothalamus-pituitary-adrenocortical system in depression. We studied 15 severely depressed (Hamilton Depression Scale 30.4 +/- 6.7) male patients (age 22-72 yr; mean, 47.7 +/- 14.8) and 22 age-matched male controls (age 23-85 yr; mean, 53.1 +/- 18.2). Twenty-four-hour blood sampling from 0800-0800 h with 30-min sampling intervals was performed; from 1800-2400 h, blood was drawn every 10 min. Multivariate analysis of covariance, with the covariate being age, revealed mean 24-h cortisol (315.9 +/- 58.5 vs. 188.2 +/- 27.3 nmol/L) and mean ACTH (7.82 +/- 1.94 vs. 5.79 +/- 1.28 pmol/L) to be significantly increased in depressed patients. The frequency of cortisol (2.6 +/- 0.7 vs. 1.3 +/- 1.0 pulses/6 h) and ACTH (2.6 +/- 1.6 vs. 1.6 +/- 1.4 pulses/6 h) pulses during the evening were higher in patients compared to controls. The flattened circadian cortisol variation and reduced time of quiescence of cortisol secretory activity (140 +/- 116 vs. 305 +/- 184 min) in patients suggest disturbances of circadian functions. We conclude that increased hypothalamus-pituitary-adrenocortical activity in depression is related to a greater frequency of episodic hormone release, and we hypothesize that the observed circadian changes might be partly due to altered mineralocorticoid and glucocorticoid receptor capacity and function.
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PMID:Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. 898 65

Both the unpredictability of side-effects and efficacy of glucocorticoid treatment can be problematic during clinical treatment. Here we discuss the evidence that exists for the hypothesis that individual glucocorticoid sensitivity underlies this problem. We suggest that glucocorticoid sensitivity is actually much more dynamic and common than previously thought. It is postulated that acquired tissue-specific glucocorticoid resistance could play a role in the origin and pathogenesis of depression, autoimmune disorders and AIDS. Moreover, recent genetic research has shown mutations in the glucocorticoid receptor (GR) gene and GR protein which are suggested to play a role in the pathogenesis of leukaemia, hereditary glucocorticoid resistance and Nelson's syndrome. These findings indicate that variations in the GR and in glucocorticoid resistance play a central role in a wide variety of diseases.
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PMID:Corticosteroid resistance and disease. 907 27

Decreased feedback control of the hypothalamic-pituitary-adrenocortical (HPA) system as revealed by the combined dexamethasone and corticotropin-releasing hormone (DEX-CRH) test has been documented in the vast majority of patients with affective disorders. This finding was interpreted as a failure at the level of the glucocorticoid receptor (GR)-mediated feedback action, which apparently fails to restrain HPA activity in the presence of elevated plasma corticosteroid levels. To test this hypothesis we conducted the DEX/CRH test using increasing doses of DEX in order to establish a dose-response relationship. We used three different DEX doses (0.75, 1.5, 3.0 mg) in three groups of depressed patients and controls. As expected, increasing DEX doses were associated with decreasing amounts of adrenocorticotropin (ACTH) and cortisol being released after CRH injection. However, dose-response curves for both plasma ACTH and cortisol concentrations were shifted to higher area under the curve (AUC) values among patients compared to controls. Pretreatment with 0.75 and 1.5 mg DEX produced significantly higher AUC values for both plasma ACTH and cortisol values among patients. These differences became less obvious with the higher DEX doses, indicating that the dose of 1.5 mg used in the majority of clinical studies so far is well suited to differentiate between healthy controls and patients. The reported data here are consistent with the hypothesis that an altered GR capacity or function underlies the exaggerated HPA activity in depression.
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PMID:Corticosteroid receptor function is decreased in depressed patients. 908 3

Abnormal interactions between serotonin (5-hydroxytryptamine) and glucocorticoids, notably in the hippocampus, may underpin neuroendocrine, affective and cognitive dysfunction in depression and ageing. Glucocorticoids act via intracellular glucocorticoid and mineralocorticoid receptors, whereas 5-hydroxytryptamine binds to a family of transmembrane sites; both cross- and auto-regulation have been proposed. To determine the roles of 5-hydroxytryptamine and corticosterone in the short-term control of hippocampal receptor gene expression, we used 3,4-methylenedioxymethamphetamine (20 mg/kg), which causes acute release of both 5-hydroxytryptamine and corticosterone. 3,4-methylenedioxymethamphetamine increased mineralocorticoid receptor messenger RNA expression throughout the hippocampus after 16 h. In rats with fixed glucocorticoid levels (adrenalectomy plus corticosterone pellets) this effect was lost in CA1-4, suggesting corticosterone-mediation, but maintained in the dentate gyrus, indicating 5-hydroxytryptamine involvement. In contrast, 3,4-methylenedioxymethamphetamine decreased glucocorticoid receptor messenger RNA expression in the dentate gyrus and CA1 within 4 h, but only in adrenal-intact rats, suggesting corticosterone control. 5-Hydroxytryptamine1A receptor messenger RNA expression was decreased in CA1 in both groups of rats, but increased in the dentate gyrus only in corticosterone-fixed rats, suggesting 5-hydroxytryptamine differentially regulates expression of this gene within hippocampal subfields. 5-hydroxytryptamine2C receptor messenger RNA was decreased in ventral CA1 only in adrenal-intact rats, suggesting a corticosterone effect, and decreased in the subiculum in both groups, indicating 5-hydroxytryptamine mediation. These results show the complexity and intricate subregional-specificity of 5-hydroxytryptamine and corticosterone interactions upon hippocampal corticosteroid and 5-hydroxytryptamine receptor gene expression. 3,4-Methylenedioxymethamphetamine-induced alterations in hippocampal receptor gene expression may play a role in the mood and behavioural changes associated with this drug of abuse.
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PMID:Site-specific regulation of corticosteroid and serotonin receptor subtype gene expression in the rat hippocampus following 3,4-methylenedioxymethamphetamine: role of corticosterone and serotonin. 913 93

A dysfunction in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, possibly attributed to a change in glucocorticoid receptor (GR) functionality, has been implicated in depression. We have measured both lymphocyte GR receptor binding parameters and plasma sialyltransferase activity, as a biochemical marker of GR function, in two groups of patients suffering from depression or schizophrenia and in a group of age- and sex-matched controls. While there was a significant increase in plasma cortisol levels in the depressed group, there were no changes in the lymphocyte GR binding parameters (K(m) and Bmax). There was, however, a significant decrease in the plasma sialyltransferase: cortisol ratio in the depressed group suggesting an inability of the raised cortisol levels to induce enzyme expression and this ratio may provide a useful biochemical marker of cortisol receptor function. Although there was an increase in the plasma activity of the alpha 2,6 sialyltransferase isozyme in the schizophrenic group, no other changes were determined. Therefore, while the total plasma sialyltransferase:cortisol ratio reflects HPA axis function, alterations in specific isozyme activity may also be associated with other CNS disease states.
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PMID:Plasma sialyltransferase levels in psychiatric disorders as a possible indicator of HPA axis function. 914 24

Both serotonergic dysfunction and glucocorticoid hypersecretion are implicated in affective and eating disorders. The adverse effects of serotonergic (5-HT)2C receptor activation on mood and food intake, the antidepressant efficacy of 5-HT2 receptor antagonists, and the hyperphagia observed in 5-HT2C receptor knockout mice all suggest a key role for increased 5-HT2C receptor-mediated neurotransmission. Glucocorticoids, however, downregulate 5-HT2C receptor mRNA in the hippocampus, and it is unclear how increased 5-HT2C receptor sensitivity is achieved in the presence of elevated glucocorticoid levels in depression. Here we show a monophasic diurnal rhythm of 5-HT2C receptor mRNA expression in the rat hippocampus that parallels time-dependent variations in 5-HT2C receptor agonist-induced behaviors in open field tests. Rats entrained to chronic food restriction show marked but intermittent corticosterone hypersecretion and maintain an unaltered 5-HT2C receptor mRNA rhythm. The 5-HT2C receptor mRNA rhythm, however, is suppressed by even modest constant elevations of corticosterone (adrenalectomy + pellet) or with elevated corticosterone during the daytime (8 A.M.), whereas a normal rhythm exists in animals that have the same dose of corticosterone in the evening (6 P.M.). Thus, animals showing even a transient daytime corticosterone nadir exhibit normal hippocampal 5-HT2C receptor mRNA rhythms, even in the presence of overt corticosterone hypersecretion. Chronic food restriction also abolishes the normal diurnal variation in hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor mRNAs and produces, unusually, both elevated corticosterone and increased GR. The mismatch between elevated glucocorticoids and maintained 5-HT2C receptor and increased GR gene expression in the hippocampus provides a new model to dissect mechanisms that may underlie affective and eating disorders.
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PMID:Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids. 915 22


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