Physiological Effects Of Glucocorticoids Research Articles

The effect of stress on liver function

«Psychosocial stress» is becoming an increasingly common concept in today’s complex and highly demanding society. Although the liver is one of the body’s most resilient organs, it is still vulnerable to the damaging effects of stress and aging, leading to liver disease, severe scarring and impaired function. Mental stress increases mortality from liver disease. Stressors activate macrophages and trigger an innate immune response, which then leads to the induction of inflammation and liver damage. In its diseases, symptoms such as low energy, fatigue, changes in employment status and functionality can also lead to the development of depression. The various physiological effects of glucocorticoids and catecholamines released into the bloodstream during stress lead to inflammation and oxidative stress in the liver. Research has explained the complex interactions that occur between stress system effectors and inflammation. Chronic psychological stress leads to an increase in serum glucocorticoid concentrations and the release of catecholamines, which increases the need for insulin. Insulin resistance leads to the development of metabolic-associated steatotic liver disease. The high prevalence of hepatogenic fatigue in chronic diffuse liver disease, its negative impact on the quality of life of patients, and the lack of effect of basic treatment lead to its aggravation due to stress. Sublingual S-adenosyl-L-methionine is effective in the treatment of hepatogenic stress fatigue, both in short-term and long-term use as part of the complex therapy of liver diseases.

Activity of the adrenocortical system in rats with experimental diabetes

Aim. To study the functional state of the adrenocortical system in experimental animals depending on severity of alloxan diabetes. Materials and methods. Diabetes in rats was induced by administering alloxan tetrahydrate at a dose of 17 mg/100 g b.w. Corticosteroids in plasma,adrenals, and 24-hr urine were measured by RIA, immunoenzyme assay, and HPLC. Hepatic aminotransferase activities were determined. Results. Durng the first week after induction of diabetes, the animals suffered metabolic disturbances and hypoinsulinemia the severity of which didnot significantly change up to day 30 Activation of adrenal glucocorticoid function (a rise in plasma corticosteron, urine and adrenal corticosteronand progesteron) occurred starting from days 8-9. Enhanced activity of hepatic aminotransferases confirmed physiological significance of elevatedblood corticosteron level. Conclusion. Physiological effects of glucocorticoids in the liver decreased by day 30 of experimental diabetes despite persisting disturbances in carbohydratemetabolism, probably due to reduced synthesis of corticosteron in adrenals and its concentration in blood.

Time of the day for 11β‐HSD1 inhibition plays a role in improving glucose homeostasis in DIO mice

The physiological effects of glucocorticoids in a given tissue are driven by the local level of the active glucocorticoid, which is determined by two sources: the plasma cortisol in human (or corticosterone in rodents) and the cortisol produced locally through 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. Because of the circadian variation of plasma glucocorticoids, the pharmacological efficacy of 11beta-HSD1 inhibition may depend on the time of the day for inhibitor administration. The circadian profile of corticosterone was established in lean and diet-induced obesity (DIO) C57BL/6 mice from blood collected at different time of the day. 11beta-HSD1 enzyme activity was also measured throughout the day in DIO mice. To determine the optimal timing for administration of an 11beta-HSD1 inhibitor to obtain maximum efficacy, we used a DIO mouse model and a small molecule inhibitor of 11beta-HSD1 from our thiazolinone series. Based on the circadian profile of corticosterone obtained, we administered the 11beta-HSD1 inhibitor to these animals at different times of the day and evaluated the effects on plasma glucose levels and glucose tolerance. We report that corticosterone circadian rhythm was similar between lean and DIO C57BL/6 mice, and 11beta-HSD1 enzyme activity undergoes minimal variations throughout the day. Interestingly, the compound exhibited maximum efficacy if dosed in the afternoon when plasma corticosterone is high; the morning dosing when plasma corticosterone is low did not lead to efficacy. These data suggest that because of the circadian rhythm of circulating glucocorticoids, the time of the day for 11beta-HSD1 inhibitor administration is important in achieving efficacy.

Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells

Phosphatidylinositol 3-kinase(PI3K) is a pivotal enzyme involved in the control of a variety of diverse metabolic functions. Glucocorticoids have been shown to attenuate PI3K signaling in some nonrenal cell types, raising the possibility that some physiological effects of glucocorticoids in renal cells may be achieved by a similar mechanism. Therefore, we tested whether glucocorticoids affect signaling through the insulin receptor substrate (IRS)-1/PI3K/Akt signaling cascade in LLC-PK1-GR101 renal epithelial cells. Treatment of cells with dexamethasone for 24 h: 1) suppressed IRS-1-associated PI3K activity and Akt phosphorylation, 2) increased the level of the PI3K p85 regulatory subunit but not the p110 catalytic subunit, and 3) induced the phosphorylation of IRS-1 on inhibitory Ser(307). We have previously reported that glucocorticoids increase branched-chain ketoacid dehydrogenase (BCKD) activity in LLC-PK1-GR101 cells. This response was achieved, in part, by alterations in the transcription of BCKD subunits and BCKD kinase, which inactivates the enzyme complex by phosphorylation. Therefore, we tested whether inhibition of PI3K signaling would mimick glucocorticoids by increasing branched-chain amino acid degradation. Expression of a dominant negative PI3K p85 regulatory subunit (Adp85DeltaiSH2) increased BCKD activity, and dexamethasone did not further stimulate enzyme activity. Inhibition of PI3K using LY-294002 increased the transcription of the BCKD E2 subunit but not the E1alpha subunit or BCKD kinase. Thus, glucocorticoids inhibit signaling through the IRS-1/PI3K/Akt pathway with a consequence of increased branched-chain amino acid catabolism.

The role of glucocorticoid action in the pathophysiology of the Metabolic Syndrome

Glucocorticoids are stress hormones that modulate a large number of physiological actions involved in metabolic, inflammatory, cardiovascular and behavioral processes. The molecular mechanisms and the physiological effects of glucocorticoids have been extensively studied. However, the involvement of glucocorticoid action in the etiology of the Metabolic Syndrome has not been well appreciated. Recently, accumulating clinical evidence and animal genetics studies have attracted growing interest in the role of glucocorticoid action in obesity and insulin resistance. This review will discuss the metabolic effects in the context of glucocorticoid metabolism and establish the association of glucocorticoid action with the features of the Metabolic Syndrome, especially obesity and insulin resistance. Special discussions will be focused on corticosteroid-binding globulin and 11β-hydroxysteroid dehydrogenase type 1, two proteins that mediate glucocorticoid action and have been implicated in the Metabolic Syndrome. Due to the complexities of the glucocorticoid biology and the Metabolic Syndrome and limited space, this review is only intended to provide a general link between the two areas with broad rather than in-depth discussions of clinical, pharmacological and genetic findings.

Abnormal expression of 11 beta-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation.

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11 beta-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11 beta-HSD2 was readily demonstrable. Here we have used real-time RT-PCR to quantify expression of mRNA for 11 beta-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11 beta-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11 beta-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11 beta-HSD2 activity (71.9+/-22.3 pmol/h/mg protein (mean+/-s.d.)) but no detectable 11 beta-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11 beta-HSD2 inhibitor) resulted in a 30.3+/-7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11 beta-HSDl to 11 beta-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11 beta-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.

Glucocorticoids: do we know how they work?

It is not known to what extent glucocorticoid hormones cause their anti-inflammatory actions and their undesirable side effects by the same or different molecular mechanisms. Glucocorticoids combine with a cytoplasmic receptor that alters gene expression in two ways. One way is dependent on the receptor's binding directly to DNA and acting (positively or negatively) as a transcription factor. The other is dependent on its binding to and interfering with other transcription factors. Both mechanisms could underlie suppression of inflammation. The liganded receptor binds and inhibits the inflammatory transcription factors activator protein-1 and NF-kappaB. It also directly induces anti-inflammatory genes such as that encoding the protein inhibitor of NF-kappaB. Recent work has shown that glucocorticoids inhibit signalling in the mitogen-activated protein kinase pathways that mediate the expression of inflammatory genes. This inhibition is dependent on de novo gene expression. It is important to establish the significance of these different mechanisms for the various physiological effects of glucocorticoids, because it may be possible to produce steroid-related drugs that selectively target the inflammatory process.

Perinatal expression of IGFBPs in rat lung and its hormonal regulation in fetal lung explants.

To gain more insight into the regulation of the expression of insulin-like growth factor (IGF) binding proteins (IGFBPs) in the lung, the developmental patterns of the abundance of the mRNAs encoding IGFBPs were measured in the perinatal rat lung and in explant cultures of fetal rat lung. In hormone-free explant cultures, the levels of the mRNAs encoding IGFBP-2 through -5 changed with a pattern similar to that occurring in vivo (although in the case of IGFBP-3 to -5 at a faster rate), indicating that the developmental regulation of the expression of these IGFBPs in perinatal lung is mimicked in the explants. For the IGFBP-6 mRNA level, the pattern in vitro differed from that in vivo. In the explant cultures, dexamethasone decreased the production of IGFBP-3 and -4 and decreased the abundance of the mRNAs encoding IGFBP-2 to -5 but increased the abundance of IGFBP-6 mRNA. These observations indicate that glucocorticoids may be involved in the developmental regulation of the expression of these components of the IGF system and that the IGF system may be involved in the physiological effects of glucocorticoids on lung development. No appreciable effects of 3,3',5-triiodothyronine on the expression of the IGFBPs were observed.

Review of the toxicology of beclomethasone dipropionate.

This paper reviews the published toxicity of beclomethasone dipropionate (BDP). BDP is a synthetic glucocorticosteroid which has a powerful local anti-inflammatory effect but little systemic action. It has been developed for both dermatological and inhaled applications. LD50 values and other acute studies indicated low toxicity. Findings published for repeat dose and reproductive toxicity studies embraced the known range of metabolic and physiological effects of glucocorticoids. For repeat dose studies, these included reduction in body weight gains, cushingoid syndrome in dogs, reductions in the numbers of lymphocytes and the weights of the tissues connected with the immune system, and hepatic glycogen deposition and fatty liver changes. In reproductive studies, there was an increase in the prevalence of cleft palate in mice and rabbits and in the number of dead foetuses, and ossification was retarded. Despite the route of administration, there was a general similarity of effects within and between species. All observations were characteristic of synthetic glucocorticoids and related to the intrinsic effects of these drugs.