Glucocorticoid Hormone Action Research Articles

SAT278 Thyroid Hormones Regulate 11bhsd Enzymes: A Novel Function In Glucocorticoid Hormone Metabolism

Abstract Disclosure: L. Bessiene: None. J. Perrot: None. S. Hescot: None. A. Bourdin-Pintueles: None. G. Vitellius: None. L.M. Sachs: None. P. Kamenicky: None. M. Lombes: None. E. Pussard: None. S. Viengchareun: None. L. Martinerie: None. Glucocorticoid hormone metabolism is regulated by 11-beta hydroxysteroid dehydrogenase enzymes: 11βHSD2, mostly expressed in the distal nephron, converts corticosterone into 11-dehydrocorticosterone in rodents, while 11βHSD1 catalyzes the opposite reaction in liver. Glucocorticoid hormone metabolism may be altered under pathophysiological conditions of hypothyroidism. However, direct functional relationship between glucocorticoid and thyroid hormones (T3) signaling pathways remains elusive. Identification of putative Thyroid Response Elements (TRE) in the promoter regions of hsd11b2 and hsd11b1 genes suggested that T3 might directly regulate expression and/or activity of these enzymes.We used human translational studies, a mouse model of hyperthyroidism and murine renal and hepatic cell lines to investigate the role of thyroid hormones in glucocorticoid hormone metabolism.In hypothyroid patients, the urinary [E]/[F] ratio measured by LC-MS/MS technology, showed a 60% decrease (P<0.05), compared to age- and sex- matched euthyroid controls, suggesting a regulation of glucocorticoid metabolism by T3. Similarly, a significant positive correlation was observed between the urinary [E]/[F] ratio and serum T4L concentration in hyperthyroid patients before and after normalization of T4L levels.Administration of T3 in drinking water, mimicking a mouse model of hyperthyroidism, led to significant increase in renal 11βHSD2 mRNA (P<0.05) and decrease in liver 11βHSD1 mRNA and protein levels (P<0.01), compared to control mice.Finally, T3 induced an increase in 11βHSD2 transcript levels in renal KC3AC1 cells (P<0.01) and a decrease in 11βHSD1 mRNA levels in hepatic HepG2 cells (P<0.01). 11βHSD2 activity increased by 20% (P<0.05). In HEK 293T cells, T3 transactivated hsd11b2 promoter via the Thyroid Receptor α1 (TRα1). ChIP experiments further demonstrated a T3-dependent specific recruitment of TRα1 onto hsd11b2 promoter. Altogether, these findings demonstrate that T3 directly regulate expression and activity of 11βHSD enzymes, thereby controlling glucocorticoid hormone metabolism and action. Presentation: Saturday, June 17, 2023

Genomic regulation of Krüppel-like-factor family members by corticosteroid receptors in the rat brain

Hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) mediate glucocorticoid hormone (GC) action in the hippocampus. These receptors bind to glucocorticoid responsive elements (GREs) within target genes, eliciting transcriptional effects in response to stress and circadian variation. Until recently, little was known about the genome-wide targets of hippocampal MRs and GRs under physiological conditions. Following on from our genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus, we investigated the Krüppel-like factors (KLFs) as targets of MRs and GRs throughout the brain under circadian variation and after acute stress. In particular, Klf2, Klf9 and Klf15 are known to be stress and/or GC responsive and play a role in neurobiological processes including synaptic plasticity and neuronal differentiation. We found increased binding of MR and GR to GREs within Klf2, Klf9 and Klf15 in the hippocampus, amygdala, prefrontal cortex, and neocortex after acute stress and resulting from circadian variation, which was accompanied by upregulation of corresponding hnRNA and mRNA levels. Adrenalectomy abolished transcriptional upregulation of specific Klf genes. These results show that MRs and GRs regulate Klf gene expression throughout the brain following exposure to acute stress or in response to circadian variation, likely alongside other transcription factors.

Development of Insulin Resistance after Prolonged Exposure to Glucocorticoid Hormones as One of the Mechanisms of Transformation of Their Gastroprotective Effect into a Proulcerogenic Action

This work continues our studies of the mechanisms of transformation of the initial gastroprotective action of glucocorticoid hormones into a proulcerogenic action. Experiments on rats tested the suggestion that the development of insulin resistance after prolonged exposure to glucocorticoid hormones may be one of the mechanisms of this transformation. This was addressed by studying the effects of dexamethasone, corticosterone, and hydrocortisone on insulin sensitivity at different time points after single doses of pharmacological size. Insulin sensitivity was evaluated in terms of the decrease in the blood glucose level 1.5 h after administration of insulin (2 IU/kg, i.p.). Decreases in glucose levels were expressed as percentages of baseline (pre-insulin) glucose levels. The results indicated that at those time points at which these hormone had previously been found to have gastroprotective actions, insulin sensitivity remained unaltered from that in control animals. Administration of dexamethasone and hydrocortisone after prolonged exposure led to decreases in insulin sensitivity at those time points at which their proulcerogenic effects had been seen. Increases in the duration of exposure to corticosterone did not produce any changes in insulin sensitivity or transformation of its gastroprotective effect into a proulcerogenic action. These data support the suggestion that the development of insulin resistance after prolonged exposure to glucocorticoid hormones can be regarded as one of the mechanisms of the transformation of their gastroprotective effects into proulcerogenic actions.

OR10-1 Regulation of Glucocorticoid Metabolism: A Novel Function for Thyroid Hormones?

Glucocorticoid hormone metabolism and action are regulated by the 11-beta hydroxysteroid dehydrogenase (11βHSD) isozymes: the 11βHSD2, mostly expressed in the distal nephron, converts cortisol [F] into cortisone [E] in humans or corticosterone [B] into 11-dehydrocorticosterone [A] in rodents (11-dehydro derivatives being inactive compounds), and the 11βHSD1, ubiquitously expressed but abundant in the liver, catalyzes the opposite reaction. Under pathophysiological conditions of severe hypothyroidism, altered glucocorticoid metabolism has been observed, with decreased [F] to [E] conversion1,2. However, direct functional relationship between these two hormonal pathways has never been demonstrated to date. Using bioinformatics analyses, we identified five thyroid hormone response elements in the promoter region of the murine hsd11b2 gene. Therefore, we aimed at investigating whether thyroid hormones (T3) directly regulate expression and/or activity of the 11βHSD2 enzyme. We used three complementary models: human and mouse translational studies and molecular analyses in HEK293T cells and in fully differentiated KC3AC1 cortical collecting duct cells. Children and adults in hypo- or hyperthyroidism status were first compared either to age- and sex-matched euthyroid controls, or to themselves after reaching a euthyroid status. The urinary [E]/[F] ratio measured by LC-MS/MS method, was used as an index of renal 11βHSD2 activity. Interestingly, a 60% decrease in the [E]/[F] ratio was observed in hypothyroid patients, corroborating our hypothesis (p<0.05). Next, a mouse model of hyperthyroidism, generated by administrating T3 in drinking water, led to a significant 10% increase in renal 11βHSD2 mRNA and protein levels compared to wild type mice (n=10, p<0.05). Furthermore, we demonstrated in HEK293T cells that T3 transactivates the mouse hsd11b2 promoter cloned upstream the luciferase reporter gene via the Thyroid Receptor α1(TRα1). Finally, we showed that T3 exposure induces a 50% increase in 11βHSD2 mRNA levels in KC3AC1 cells, in a dose-dependent and time-dependent manner (as early as 6 h) (p<0.01). This induction was abrogated by Actinomycin D or DRB, two inhibitors of transcription, underlining a transcriptional regulatory mechanism. In addition, 11βHSD2 enzymatic activity, quantified by the [F] to [E] conversion ratio measured by LC-MS/MS in cell supernatants, increased significantly by 20% (p<0.05) after 24 h exposure to 100 nM T3. ChIP experiments further demonstrated a T3-dependent specific recruitment of the TRα1 onto the hsd11b2 promoter region. Altogether, our findings constitute the first demonstration that thyroid hormones directly regulate expression and activity of the renal 11βHSD2 enzyme, thereby controlling glucocorticoid metabolism and action.

Increased glucocorticoid hormone actions induce skin-specific Na&lt;sup&gt;+&lt;/sup&gt; and water loss in melanocortin 3 receptor knockout mice

Increased glucocorticoid hormone actions induce skin-specific Na&lt;sup&gt;+&lt;/sup&gt; and water loss in melanocortin 3 receptor knockout mice

Increased glucocorticoid hormone actions induce skin-specific Na&lt;sup&gt;+&lt;/sup&gt; and water loss in melanocortin 3 receptor knockout mice

Increased glucocorticoid hormone actions induce skin-specific Na&lt;sup&gt;+&lt;/sup&gt; and water loss in melanocortin 3 receptor knockout mice

In Pursuit of Genes of Glucose Metabolism

If you don't know where you're going, you might wind up someplace else—Yogi Berra My professional journey, once I accepted the fact that I would not play first base for the Chicago Cubs, was not accomplished in a straight line. I entered medical school intending to become a family physician but soon became interested in research. I took an internal medicine residency at the University of California, San Francisco (UCSF), then a long research fellowship in the nascent field of molecular biology at the National Institutes of Health (NIH), and followed that with training in clinical endocrinology at the University of Wisconsin. I spent the next fifteen years dividing my time between the clinic and laboratory at the University of Iowa. Finally, I decided to concentrate on research and spent the next twenty-three years at Vanderbilt University. For the past eleven years, I have been at the University of Iowa, where I helped establish a new diabetes research center. My research journey also had several different directions. Upon reflection, I guess I ended up “someplace else” by choice, and it certainly has been an interesting trip. It is one I unreservedly recommend.

Glucocorticoids Increase Excitotoxic Injury and Inflammation in the Hippocampus of Adult Male Rats

Background/Aims: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. Methods: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether nonsteroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (1) chemokine production (CCL2 and CINC-1), (2) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-ß), and (3) NF-κB activity. Results: Concurrent treatment with minocycline, but not indomethacin, prevented GC endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-κB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus - factors that normally restrain inflammatory responses. Conclusions: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part by increasing the neurotoxicity of CNS inflammation.

From Gastroprotective to Ulcerogenic Effects of Glucocorticoids: Role of Long-Term Glucocorticoid Action

Glucocorticoids may have dual action on the gastric mucosa: gastroprotective and ulcerogenic. In this article, we review the data which suggested that an initial action of endogenous glucocorticoids, including stress-produced ones as well as exogenous glucocorticoids is gastroprotective and consider possible mechanisms of the conversion of physiological gastroprotective action of glucocorticoid hormones to their pathological ulcerogenic effect.

Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle

Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to the DNA-bound activator protein-1 and NF-κB and represses transcription of their target proinflammatory cytokine genes. However, these target genes fall into distinct classes depending on the step of the transcription cycle that is rate-limiting for their activation: Some are controlled through RNA polymerase II (PolII) recruitment and initiation, whereas others undergo signal-induced release of paused elongation complexes into productive RNA synthesis. Whether these genes are differentially regulated by GR is unknown. Here we report that, at the initiation-controlled inflammatory genes in primary macrophages, GR inhibited LPS-induced PolII occupancy. In contrast, at the elongation-controlled genes, GR did not affect PolII recruitment or transcription initiation but promoted, in a GRIP1-dependent manner, the accumulation of the pause-inducing negative elongation factor. Consistently, GR-dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages. Thus, GR:GRIP1 use distinct mechanisms to repress inflammatory genes at different stages of the transcription cycle.

High and low protein∶ carbohydrate dietary ratios during gestation alter maternal-fetal cortisol regulation in pigs.

Imbalanced maternal nutrition during gestation can cause alterations of the hypothalamic-pituitary-adrenal (HPA) system in offspring. The present study investigated the effects of maternal low- and high-protein diets during gestation in pigs on the maternal-fetal HPA regulation and expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and 11β-HSD2) and c-fos mRNAs in the placenta and fetal brain. Twenty-seven German Landrace sows were fed diets with high (HP, 30%), low (LP, 6.5%) or adequate (AP, 12.1%) protein levels made isoenergetic by varying the carbohydrate levels. On gestational day 94, fetuses were recovered under general anesthesia for the collection of blood, brain and placenta samples. The LP diet in sows increased salivary cortisol levels during gestation compared to the HP and AP sows and caused an increase of placental GR and c-fos mRNA expression. However, the diurnal rhythm of plasma cortisol was disturbed in both LP and HP sows. Total plasma cortisol concentrations in the umbilical cord vessels were elevated in fetuses from HP sows, whereas corticosteroid-binding globulin levels were decreased in LP fetuses. In the hypothalamus, LP fetuses displayed an enhanced mRNA expression of 11β-HSD1 and a reduced expression of c-fos. Additionally, the 11β-HSD2 mRNA expression was decreased in both LP and HP fetuses. The present results suggest that both low and high protein∶carbohydrate dietary ratios during gestation may alter the expression of genes encoding key determinants of glucocorticoid hormone action in the fetus with potential long-lasting consequences for stress adaptation and health.

Circadian Rhythms of Glucocorticoid Hormone Actions in Target Tissues: Potential Clinical ImplicationsA Presentation from the European Society for Paediatric Endocrinology (ESPE) New Inroads to Child Health (NICHe) Conference on Stress Response and Child Health in Heraklion, Crete, Greece, 18 to 20 May 2012.

Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations--including obesity, metabolic syndrome, and cardiovascular disease--by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.

ZNF764Haploinsufficiency May Explain Partial Glucocorticoid, Androgen, and Thyroid Hormone Resistance Associated with 16p11.2 Microdeletion

Nuclear hormone receptors exert their transcriptional effects through shared cofactor molecules; thus, defects in such intermediate proteins may be associated with multiple hormone resistance. Microdeletion of small chromosomal segments results in hereditary or sporadic diseases by affecting expression of residing genes. We describe a 7-yr-old boy with partial resistance to glucocorticoids, thyroid hormones, and possibly androgens. He was diagnosed as being in the autism spectrum disorder and had developmental delay and several facial morphological manifestations. We explored genes responsible for multiple hormone resistance of this case. We found in this patient an approximately 1.1-Mb heterozygous 16p11.2 microdeletion, which included an approximately 500-kb unique deletion along with the common, previously reported approximately 600-kb 16p11.2 microdeletion. The small interfering RNA-based screening revealed that knockdown of ZNF764, which is located in the deleted segment unique to our case, significantly reduced glucocorticoid-, androgen-, and thyroid hormone-induced transcriptional activity of their responsive genes in HeLa cells, whereas its overexpression enhanced their transcriptional activity. The activities of the estrogen and progesterone receptors, cAMP response element-binding protein, and p53 were not affected in these cells. ZNF764 (zinc finger protein 764) expression was reduced in the patient's peripheral blood mononuclear cells, whereas exogenously supplemented ZNF764 recovered responsiveness to glucocorticoids in the patient's Epstein-Barr virus-transformed lymphocytes. The effect of ZNF764 on the glucocorticoid receptor transcriptional activity was mediated through cooperation with a general nuclear hormone receptor coactivator, transcriptional intermediary factor 1. ZNF764 haploinsufficiency caused by microdeletion may be responsible for the partial multiple hormone resistance observed in our patient. ZNF764 appears to be involved in glucocorticoid, androgen, and thyroid hormone action.

Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2–MSK1–Elk-1 signaling

Stressful events are known to have a long-term impact on future behavioral stress responses. Previous studies suggested that both glucocorticoid hormones and glutamate acting via glucocorticoid receptors (GRs) and N-methyl D-aspartate (NMDA) receptors, respectively, are of critical importance for the consolidation of these long-lasting behavioral responses at the dentate gyrus, the gateway of the hippocampal formation. We found that an acute psychologically stressful event resulted in ERK1/2 phosphorylation (pERK1/2), which within 15 min led to the activation of the nuclear kinases MSK1 and Elk-1 in granule neurons of the dentate gyrus. Next, MSK1 and Elk-1 activation evoked serine-10 phosphorylation and lysine-14 acetylation in histone H3, resulting in the induction of the neuroplasticity-associated immediate-early genes c-Fos and Egr-1 in these neurons. The pERK1/2-mediated activation of MSK1 and Elk-1 required a rapid protein-protein interaction between pERK1/2 and activated GRs. This is a unique nongenomic mechanism of glucocorticoid hormone action in dentate gyrus granule neurons on long-lasting behavioral responses to stress involving direct cross-talk of GRs with ERK1/2-MSK1-Elk-1 signaling to the nucleus.

Expression of glucocorticoid receptor and glucose transporter-1 during placental development in the diabetic rat

In various tissues, glucocorticoids (GCs) are known to downregulate glucose transport systems; however, their effects on glucose transporters (GLUTs) in the placenta of a diabetic rat are unknown. Glucocorticoid hormone action within the cell is regulated by the glucocorticoid receptor (GR). Thus, this study was designed to investigate the relationship between GR and glucose transporter expression in the placenta of the diabetic rat. Our immunohistochemical results indicated that GR and glucose transporter protein 1 (GLUT 1) are expressed ubiquitously in the trophoblast and endothelial cells of the labyrinthine zone, where maternal fetal transport takes place in the rat placenta. Expression of GR in the junctional zone of the rat placenta was detected in giant cells, and in some spongiotrophoblast cells, but not in the glycogen cells. GLUT 1 was present, especially in glycogen cells during early pregnancy, and in the spongiotrophoblast cells of the junctional zone during late pregnancy. Amounts of GR and GLUT 1 protein were increased towards the end of gestation both in the control and the diabetic placenta. However, at days 17 and 19 of gestation, only the placental GR protein was significantly increased in the streptozotocin-induced diabetic rats compared to control rats. Diabetes led to a significant decrease in placental weight at gestation day 15. In contrast, at gestational days 17 and 21, the weights of the diabetic placenta were significantly increased as compared with the controls. Moreover, diabetes induced fetus intrauterine growth retardation at gestational days 13, 17 and 21. In conclusion, the localization pattern of GR and GLUT 1 proteins in the same cell types led us to believe that there might be a relationship between GR and GLUT 1 expressions at the cellular level. GLUT 1 does not play a pivotal role in diabetic pregnancies. However, placental growth abnormalities during diabetic pregnancy may be related to the amount of GR.

Glucocorticoids, cytokines and brain abnormalities in depression

Major depression (MD) is a common psychiatric disorder with a complex and multifactor aetiology. Potential mechanisms associated with the pathogenesis of this disorder include monoamine deficits, hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, inflammatory and/or neurodegenerative alterations. An increased secretion and reactivity of cortisol together with an altered feedback inhibition are the most widely observed HPA abnormalities in MD patients. Glucocorticoids, such as cortisol, are vital hormones that are released in response to stress, and regulate metabolism and immunity but also neuronal survival and neurogenesis. Interestingly depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases and at the same time, depressed patients show higher levels of pro-inflammatory cytokines. Since communication occurs between the endocrine, immune and central nervous system, an activation of the inflammatory responses can affect neuroendocrine processes, and vice versa. Therefore, HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan-kynurenine pathway. Although the evidence for neurodegeneration in MD is controversial, depression is co-morbid with many other conditions where neurodegeneration is present. Since several systems seem to be involved interacting with each other, we cannot unequivocally accept the simple model that glucocorticoids induce neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders. Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. However, further studies are needed to clarify the relative contribution of glucocorticoids and inflammatory signals to MD and other disorders.

Emerging roles of glucocorticoid receptor phosphorylation in modulating glucocorticoid hormone action in health and disease

Glucocorticoids (GCs) are hormones naturally released when the body perceives stress and function to return homeostatic balance within various tissues. Synthetic GCs are widely prescribed therapeutics for the treatment of numerous inflammatory disorders and cancers. The effects of GCs are mediated by their binding and activation of the GC receptor (GR), a transcription factor that is subject to hormone-dependent and -independent phosphorylation on several serine and threonine residues. The GR is phosphorylated by kinases such as MAPKs, CDKs, and GSK-3beta, and these modifications modulate the transcriptional activity of the GR within cells. Here, we discuss the phosphorylation status of the GR as a mechanism to dictate how cells will ultimately respond to GCs. In doing so, we will review current knowledge about each phosphorylated residue within the GR and their contributions to modulating GC signaling in normal homeostatic physiology and during the progression of disease.

The role of phosphorylated glucocorticoid receptor in mitochondrial functions and apoptotic signalling in brain tissue of stressed Wistar rats

Mitochondrial dysfunction is increasingly recognized as a key component in compromised neuroendocrine stress response and, among other etiological causes, it may also involve action of glucocorticoid hormones. In the current study we followed glucocorticoid receptor and identified its mitochondrial phosphoisophorms in hippocampus and prefrontal brain cortex of Wistar male rats subjected to acute, chronic and combined neuroendocrine stresses. In both brain structures chronic social isolation caused marked increase in mitochondrial glucocorticoid receptor that was preferentially phosphorylated at serine 232 compared to serine 246 or serine 171. This increase corresponded with the decreased expression of mitochondrially encoded cytochrome oxidase subunits 1 and 3 in hippocampus, and with their increased expression in prefrontal brain cortex. Prefrontal brain cortex appeared to be more sensitive to chronic stress, since it exibited higher levels of mitochondrial Bax and cytoplasmic Bcl2 compared to hippocampus. Chronic stress also altered the response of both brain structures to subsequent acute stress according to the studied parameters. Therefore, prolonged social isolation may cause susceptibility to mitochondria triggered proapototic signalling, which at least in part may be mediated by the glucocorticoid receptor dependent mechanism.

Dual action of glucocorticoid hormones on the gastric mucosa: how the gastroprotective action can be transformed to the ulcerogenic one

Glucocorticoid hormones have dual action on the stomach: gastroprotective and ulcerogenic one. The present study was designed to investigate how physiological gastroprotective action of glucocorticoids can be transformed to pathological ulcerogenic effect. Dose- and time-dependent effects of single injection of dexamethasone on indomethacin-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in rats. Dexamethasone at the doses of 0.1, 1, 10 mg/kg decreased the gastric erosion area dose dependently in the case of its injection 1 h before indomethacin administration. Gastroprotective action of dexamethasone (at a dose of 1 mg/kg) was also observed in the case of its injection 6 and 12 h before indomethacin. However, the further increase in the time interval caused transformation of gastroprotective action of dexamethasone to ulcerogenic one. Accordingly to the data obtained short-term maintenance of blood glucose level provides the gastroprotective action of dexamethasone, while dexamethasone-induced long-lasting maintenance of blood glucose level accompanied with the signs of catabolic effects may be responsible at least partly for its ulcerogenic effect.

Glucocorticoid and Sex Hormone Receptors: Clinical Implications and Therapeutic Relevance

In general, steroid hormones exert their effects through intracellular receptors, the glucocorticoid (GR), mineralocorticoid (MR), androgen (AR), estrogen (ER), and progesterone (PR) receptors. In this brief review, we will focus on glucocorticoid and sex hormone actions in the skin through their distinct receptors and discuss their clinical relevance.