Inhibitory Effects Of Glucocorticoids Research Articles

Differential regulation of hepatic SH3 domain binding kinase 1 (SBK1) expression in mouse and goldfish

SH3 domain binding kinase 1 (SBK1) is a serine/threonine kinase that belongs to the new kinase family (NFK) with limited information on its function. Previous studies reported that SBK1 plays a role in memory formation, lipid metabolism, and cancer cell progression. Nevertheless, the regulatory mechanism of Sbk1 expression in various tissues remains unknown. We report here that Sbk1 expression in mouse hepatocytes was downregulated by glucocorticoid, whereas saturated and unsaturated fatty acids were stimulators of Sbk1 expression. The regulatory role of glucocorticoid and fatty acid was further confirmed by the Sbk1 promoter assay, which aligned with the presence of several glucocorticoid-response elements (GRE) and peroxisome proliferator responsive elements (PPRE) in the mouse Sbk1 promoter. The inhibitory effect of glucocorticoids on hepatic Sbk1 expression and protein content could also be demonstrated in vivo after prednisolone injection. Moreover, the expression of SBK1 in goldfish (gfSBK1) was also sensitive to glucocorticoid suppression as their mouse orthologues. In contrast, insulin had a differential action on SBK1 expression that it promoted the expression of all SBK1 isoforms in the goldfish hepatocytes but inhibited Sbk1 expression in the mouse hepatocytes. Together, our findings indicate that SBK1 expression is hormone- and nutrient-sensitive with a species-specific response.

Embryonic exposure to hyper glucocorticoids suppresses brown fat development and thermogenesis via REDD1

Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids (GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue (BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone (DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates; such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1a transcription from the alternative promoter (Ppargc1a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1a-AP expression and mitochondrial biogenesis; and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate (cAMP) -responsive element-binding protein (CREB) binding to the cAMP regulatory element (CRE) in Ppargc1a-AP promoter, leading to Ppargc1a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.

Association between the circadian rhythm and the inhibitory effect of glucocorticoids on browning of adipocytes

Association between the circadian rhythm and the inhibitory effect of glucocorticoids on browning of adipocytes

Early transplantation of growth differentiation factor 11-silenced bone marrow stromal cells promotes osteogenesis in necrotic femoral head induced by steroid in rats

Objective To study the effect of growth differentiation factor (GDF) 11-silenced bone marrow stromal cells (BMSCs) on bone regeneration in early steroid-induced osteonecrosis of the femoral head in rats. Methods After GDF11 expression in BMSCs was inhibited by siRNA, the knockdown efficiency and transfection cytotoxicity were detected. The further experiments both in vitro (n=3) and in vivo (n=8) were divided into 4 groups respectively: blank control group (without any intervention), model group (glucocorticoid treatment), experimental group (siRNA transfection and glucocorticoid treatment) and negative control group (negative control transfection and glucocorticoid treatment). The BMSCs were induced into osteogenic differentiation. Alkaline phosphatase (ALP) staining and alizarin red staining were applied to evaluate the osteogenic differentiation ability of the cells while reverse transcription polymerase chain reaction (qRT-PCR) was employed to detect the relative expression levels of osteogenic markers. The osteogenesis in the necrotic femoral head was evaluated by microCT, H&E staining, immunohistochemistry staining and biomechanical test. Results No transfection cytotoxicity was found (P>0.05). The ALP staining and alizarin red staining showed that the osteogenic differentiation of BMSCs in the experimental group was better than that in the model group. At the level of mRNA, the relative expression of ALP, runt-related transcription factor (Runx) 2, osteocalcin (OCN) and type Ⅰ collagen (α1) (COL1A1) in the blank control group (1.00±0.09, 1.02±0.23, 1.03±0.30 and 1.02±0.25, respectively) were significantly higher than those in the model group (0.46±0.11, 0.50±0.11, 0.35±0.01 and 0.57±0.02, respectively) but significantly lower than those in the experimental group (1.97±0.30, 0.94±0.19, 1.50±0.18 and 1.28±0.37) (all P<0.05). MicroCT images and quantitative analysis showed that the bone mass in the experimental group was significantly increased compared with the model group (P<0.05). Histological examination showed better bone regeneration and higher expression of Runx2 and COL1 in the necrotic femoral head in the experimental group than in the model group. Improved biomechanical properties were shown in the experimental group compared with the model group (P<0.05). Conclusions Silence of GDF11 expression may alleviate the inhibitory effect of glucocorticoid on osteogenic differentiation of BMSCs. Early transplantation of GDF11-silenced BMSCs may promote osteogenesis in the necrotic femoral head in rats. Key words: Femoral head necrosis; Bone marrow cells; Growth differentiation factor 11; Glucocorticoids; Osteogenic differentiation

Asian Sand Dust Regulates IL-32 Production in Airway Epithelial Cells: Inhibitory Effect of Glucocorticoids.

Purpose Epidemiologic studies have reported that Asian sand dust (ASD) is associated with chronic inflammatory diseases of the respiratory system. Glucocorticoids (GCs) have potent anti-inflammatory properties. The aims of this study were to evaluate the effects of GCs on ASD-induced interleukin-32 (IL-32) expression and to identify the underlying signaling pathways in airway epithelial cells. Methods A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cytotoxicity in A549 and human primary nasal epithelial cells. Expression levels of IL-32 messenger RNA and protein were measured by Western blot, real-time polymerase chain reaction, ELISA, and immunofluorescence staining. Signaling pathways were analyzed using specific inhibitors of Akt, MAPK, or NF- κB. The effects of GCs on the expression of ASD-induced IL-32 were confirmed with ex vivo organ cultures of the nasal interior turbinate. Results ASD (0–400 ng/mL) had no significant cytotoxic effects in A549 cells and human primary nasal epithelial cells. Expression levels of IL-32 were dose-dependently upregulated by ASD treatment in A549 cells. ASD induced phosphorylation of Akt, MAPK, and NF-κB, whereas GCs and specific inhibitors of Akt, MAPK, and NF-κB downregulated these activations and the expression of IL-32. These findings were further confirmed in human primary nasal epithelial cells and ex vivo organ cultures of the nasal interior turbinate. Conclusions GCs have an inhibitory effect on ASD-induced IL-32 expression via the Akt, MAPK, and NF- κB signaling pathways in airway epithelial cells.

Inhibitory effect of glucocorticoids on TGF-β1-mediated epithelial-to-mesenchymal transition of airway epithelium via MAPK and Snail/Slug signaling pathways

Inhibitory effect of glucocorticoids on TGF-β1-mediated epithelial-to-mesenchymal transition of airway epithelium via MAPK and Snail/Slug signaling pathways

A Remodeled Hsp90 Molecular Chaperone Ensemble with the Novel Cochaperone Aarsd1 Is Required for Muscle Differentiation.

Hsp90 is the ATP-consuming core component of a very abundant molecular chaperone machine that handles a substantial portion of the cytosolic proteome. Rather than one machine, it is in fact an ensemble of molecular machines, since most mammalian cells express two cytosolic isoforms of Hsp90 and a subset of up to 40 to 50 cochaperones and regulate their interactions and functions by a variety of posttranslational modifications. We demonstrate that the Hsp90 ensemble is fundamentally remodeled during muscle differentiation and that this remodeling is not just a consequence of muscle differentiation but possibly one of the drivers to accompany and to match the vast proteomic changes associated with this process. As myoblasts differentiate into myotubes, Hsp90α disappears and only Hsp90β remains, which is the only isoform capable of interacting with the novel muscle-specific Hsp90 cochaperone Aarsd1L. Artificially maintaining Hsp90α or knocking down Aarsd1L expression interferes with the differentiation of C2C12 myotubes. During muscle differentiation, Aarsd1L replaces the more ubiquitous cochaperone p23 and in doing so dampens the activity of the glucocorticoid receptor, one of the Hsp90 clients relevant to muscle functions. This cochaperone switch protects muscle cells against the inhibitory effects of glucocorticoids and may contribute to preventing muscle wasting induced by excess glucocorticoids.

Glucocorticoids impair bone formation of bone marrow stromal stem cells by reciprocally regulating microRNA-34a-5p.

The inhibitory effects of glucocorticoids (GCs) on bone marrow stromal stem cell (BMSC) proliferation and osteoblastic differentiation are an important pathway through which GCs decrease bone formation. We found that microRNA-34a-5p was a critical player in dexamethasone (Dex)-inhibited BMSC proliferation and osteogenic differentiation. MicroRNA-34a-5p might be used as a therapeutic target for GC-impaired bone formation. The inhibitory effects of glucocorticoids (GCs) on bone marrow stromal stem cell (BMSC) proliferation and osteoblastic differentiation are an important pathway through which GCs decrease bone formation. The mechanisms of this process are still not completely understood. Recent studies implicated an important role of microRNAs in GC-mediated responses in various cellular processes, including cell proliferation and differentiation. Therefore, we hypothesized that these regulatory molecules might be implicated in the process of GC-decreased BMSC proliferation and osteoblastic differentiation. Western blot, quantitative real-time PCR, and cell proliferation and osteoblastic differentiation assays were employed to investigate the role of microRNAs in GC-inhibited BMSC proliferation and osteoblastic differentiation. We found that microRNA-34a-5p was reciprocally regulated by Dex during the process of BMSC proliferation and osteoblastic differentiation. Furthermore, we confirmed that microRNA-34a-5p was a critical player in Dex-inhibited BMSC proliferation and osteogenic differentiation. Mechanistic studies showed that Dex inhibited BMSC proliferation by microRNA-34a-5p targeting cell cycle factors, including CDK4, CDK6, and Cyclin D1. Furthermore, downregulation of microRNA-34a-5p by Dex leads to Notch signaling activation, resulting in inhibition of BMSC osteogenic differentiation. These results showed that microRNA-34a-5p, a crucial regulator for BMSC proliferation and osteogenic differentiation, might be used as a therapeutic target for GC-impaired bone formation.

Breed-specific expression of DROSHA, DICER and AGO2 is regulated by glucocorticoid-mediated miRNAs in the liver of newborn piglets.

MicroRNA (miRNA) biogenesis is determined mainly by Drosha, Dicer and Argonaute2 (Ago2). Different breeds of pigs with vast differences in serum cortisol level demonstrate distinct profiles of hepatic miRNA expression. As yet, little is known about whether glucocorticoid contributes to the breed differences in miRNA biogenesis. Here, we used newborn Large White (LW) and Erhualian (EHL) piglets to investigate the role of glucocorticoid in breed-specific hepatic miRNA biogenesis. Erhualian piglets showing significantly higher serum cortisol level, as compared to LW, demonstrated higher hepatic expression of Drosha, Dicer and Ago2 at the protein level, but not at the mRNA level. At the post-transcriptional level, miRNAs that are predicted to target these proteins may be involved in the regulation. Hepatic expression of miR-15b and miR-222 was significantly lower in EHL piglets and was associated with higher glucocorticoid receptor binding to the respective promoter regions of miR-15b and miR-222 genes. The inhibitory effect of glucocorticoid on miR-15b and miR-222 expression was further verified in HepG2 cells, in which dexamethasone significantly downregulated the expression of primary transcripts of miR-15b and miR-222 genes. In conclusion, the higher protein content of Drosha, Dicer and Ago2 in the liver of EHL piglets is post-transcriptionally regulated, at least in part, by glucocorticoid-mediated repression of miR-15b and miR-222.

Lack of Fpr2/Fpr3 receptors alters the structure and function of pituitary corticotrophs

Lack of Fpr2/Fpr3 receptors alters the structure and function of pituitary corticotrophs

The expression of IL-2 and IL-4 in CD4+ T cells from mouse lymph nodes and spleen during HSV-1-induced facial palsy

Herpes simplex virus 1 (HSV-1) is regarded as an important underlying cause of Bell's palsy, but the immunologic mechanism remains unknown. Here, we employed a mouse facial paralysis model to investigate the expressions of CD4(+) T lymphocytes and interleukin (IL)-2 and -4 in the left draining cervical lymph nodes (LCLN) and spleen, as well as the inhibitory effects of glucocorticoids (GCs). HSV-1 was inoculated into the surface of the posterior auricle to generate the facial paralysis model. The paralyzed mice were divided into three groups; in one group without any treatment, mice were killed at different time points, and those in the other two groups were injected with methylprednisolone sodium succinate (MPSS) or with a combination of MPSS and GC receptor blocker (RU486). The expression levels of CD4(+) T lymphocytes and CD4(+)-IL-2(+) and CD4(+)-IL-4(+) cells in the LCLN and spleen were detected by fluorescence-activated cell sorting. Expression levels of CD4(+), IL-2, and IL-4 first increased then decreased in LCLN and spleen and peaked 5 and 7days, respectively, after the manifestation of facial paralysis. All the data at the peak points were significantly different compared with control (p<0.05), and these effects were inhibited by MPSS. Our results suggest that CD4(+), IL-2, and IL-4 participate in the HSV-1-induced facial paralysis immune response. MPSS can effectively attenuate HSV-1-mediated nervous system damage, which is associated with its inhibitory effect on expression of these inflammatory markers.

Both Transient and Continuous Corticosterone Excess Inhibit Atherosclerotic Plaque Formation in APOE*3-Leiden.CETP Mice

IntroductionThe role of glucocorticoids in atherosclerosis development is not clearly established. Human studies show a clear association between glucocorticoid excess and cardiovascular disease, whereas most animal models indicate an inhibitory effect of glucocorticoids on atherosclerosis development. These animal models, however, neither reflect long-term glucocorticoid overexposure nor display human-like lipoprotein metabolism.AimTo investigate the effects of transient and continuous glucocorticoid excess on atherosclerosis development in a mouse model with human-like lipoprotein metabolism upon feeding a Western-type diet.MethodsPair-housed female APOE*3-Leiden.CETP (E3L.CETP) mice fed a Western-type containing 0.1% cholesterol for 20 weeks were given corticosterone (50 µg/ml) for either 5 (transient group) or 17 weeks (continuous group), or vehicle (control group) in the drinking water. At the end of the study, atherosclerosis severity, lesion area in the aortic root, the number of monocytes adhering to the endothelial wall and macrophage content of the plaque were measured.ResultsCorticosterone treatment increased body weight and food intake for the duration of the treatment and increased gonadal and subcutaneous white adipose tissue weight in transient group by +35% and +31%, and in the continuous group by +140% and 110%. Strikingly, both transient and continuous corticosterone treatment decreased total atherosclerotic lesion area by −39% without lowering plasma cholesterol levels. In addition, there was a decrease of −56% in macrophage content of the plaque with continuous corticosterone treatment, and a similar trend was present with the transient treatment.ConclusionIncreased corticosterone exposure in mice with human-like lipoprotein metabolism has beneficial, long-lasting effects on atherosclerosis, but negatively affects body fat distribution by promoting fat accumulation in the long-term. This indicates that the increased atherosclerosis observed in humans in states of glucocorticoid excess may not be related to cortisol per se, but might be the result of complex indirect effects of cortisol.

IL-25 Involved in Airway Inflammation of OVA-Induced Asthmatic Mice and the Inhibitory Effect of Glucocorticoid

Objective: To study the expression of IL-25 in airway inflammation of OVA-induced asthmatic mice and the effects of glucocorticoid. Methods: The asthmatic mice were induced by ovalbumin (OVA) sensitization and challenge. This model was confirmed by detecting airway responsiveness, serum levels of IgE and lung histopathology. We also detected the inflammatory cells by cell counting plate and cytokines by ELISA, respectively. We also detected the expression of IL-25 by quantitative real-time PCR and immunohistochemistry. Results: Compared with the mice in control group, the asthmatic mice showed elevated airway responsiveness and high serum levels of IgE. We also detected more inflammatory cells and high level of inflammatory cytokines in mice of OVA group. The expression of IL-25 was also significantly increased in both mRNA and protein levels in OVA group. Furthermore, treating mice with glucocorticoid could inhibit inflammatory cells and cytokines infiltration and reduce IL-25 expression. Conclusion: IL-25 level is increased in OVA-induced asthmatic airway inflammation and glucocorticoid is capable of inhibiting IL-25 expression as well as other Th2 cytokines, thus presents a promising strategy for the treatment of asthma.

Erratum

Journal of NeurochemistryVolume 122, Issue s1 p. 37-37 Free Access Erratum This article corrects the following: Wednesday Session – 20 October 2010 Volume 115Issue s1Journal of Neurochemistry pages: 59-86 First Published online: September 12, 2010 First published: 10 September 2012 https://doi.org/10.1111/j.1471-4159.2012.7801.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstracts of the 10 th Biennial Meeting of the Asia-Pacific Society of Neurochemistry, Phuket, Thailand 18–20 October 2010 In the Wednesday Poster Session, the abstract for WE02-04 was inadvertently replaced with the abstract for WE04-04. Abstract for WE02-04 should read: WE02-04 GLUCOCORTICOID SUPPRESSES BDNF-TRIGGERED GLUTAMATE RELEASE VIA DECREASING INTERACTION BETWEEN GLUCOCORTICOID RECEPTOR AND TRKB Numakawa T., Adachi N., Kumamaru E., Yagasaki Y., Izumi A. and Kunugi H. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan Brain-derived neurotrophic factor, BDNF, is critical for synaptic plasticity in the CNS. Many reports indicate a decrease of BDNF expression in brain tissue from patients with mental disorders, including major depression, suggesting possible involvement of change of expression/function of BDNF in the pathophysiology. Glucocorticoids, stress-induced steroid hormones, may also contribute to the pathophysiology. Therefore, we investigated possible interaction between glucocorticoids- and BDNF-mediated functions in cortical neurons, and found the interaction of glucocorticoid receptor (GR) with TrkB (receptor for BDNF). The TrkB-GR interaction has a role in the BDNF-induced release of glutamate, an, excitatory neurotransmitter (Numakawa et al.PNAS. (2009) 106, 647-652). It was revealed that the BDNF-induced glutamate release was suppressed through reduction in the TrkB-GR interaction due to GR downregulation after glucocorticoids exposure. Thus, we are investigating the recovery effect of beneficial conditions, including co-application with other growth factors, from the inhibitory effect of glucocorticoids on BDNF action. Acknowledgements: This work was supported by a grant from the Core Research for Evolutional Science and Technology Program (CREST) Japan Science and Technology Agency (JST) (T. N., N. A., and H. K.), and a Grant-in-Aid for Young Scientists (A) (grant number 21680034) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (T. N.). Reference Abstracts of the 10th Biennial Meeting of the Asia-Pacific Society of Neurochemistry (2010) Wednesday Session – 20 October 2010. J. Neurochem. 115 (Suppl. 1), 59– 86. Volume122, Issues1Special Issue: Abstracts of the 5th Special Conference of the International Society for Neurochemistry, Synapses and Dendritic Spines in Health and Disease, Buenos Aires, Argentina, 12-15 September 2012September 2012Pages 37-37 ReferencesRelatedInformation

Implications of glucocorticoid therapy in idiopathic inflammatory myopathies

Glucocorticoids are the cornerstone of therapy in patients with idiopathic inflammatory myopathies (IIM), despite adverse effects and suboptimal therapy success rates. Glucocorticoids are used in patients with IIM to suppress inflammatory and immune responses implicated in the pathogenesis of these diseases. Nevertheless, potential inhibitory effects of glucocorticoids on skeletal muscle mass, myogenesis and immune responses that promote skeletal muscle regeneration after muscle injury warrant attention. Glucocorticoids lead to skeletal muscle catabolism by modulating major pathways involved in regulating muscle mass. Glucocorticoids also inhibit muscle regeneration by decreasing myogenic cell proliferation and differentiation. Finally, glucocorticoids might have inhibitory effects on immune cells that have been shown to be an important component of the muscle regenerative response. Better understanding of the signalling pathways involved in restorative versus adverse effects of glucocorticoids in IIM could yield additional insight into the aetiopathogenesis of persistent muscle weakness in patients with IIM after glucocorticoid treatment, and help in the development of novel, targeted treatment options with fewer adverse effects.

English

&nbsp; There are many evidences which indicate that calcium channel related voltage plays an important role on the mechanism of neuropathic pain, but no strong evidence has been found yet on the role played by type-L calcium channel. The aim of this study was to evaluate this role in using a properly designed experiment.&nbsp;This cohort study was carried out on seven groups (eight &nbsp;animals each) of male Wistar rats (200&nbsp;to300&nbsp;g). Chronic constriction nerve injury was performed on rats by loosely ligating their common sciatic nerve. The impact of corticosteron at 15&nbsp;mg/kg on neuropathic pain behaviors was assessed in the presence or absence of verapamil as an L-VSC channel blocker at 5, 10 or 20 mg/kg. Standard procedures were employed to evaluate the behavioral pain responses including the thermal hyperalgesia and the thermal and mechanical allodynia. Our findings indicate that peripheral administration of corticosterone suppressed both hyperalgesia, and thermal and mechanical allodynia; however, verapamil pretreatment attenuated the effects of corticosterone on both thermal hyperalgesia and mechanical allodynia. In addition, the administration of verapamil alone at high dose (20 mg) suppressed both thermal and mechanical allodynia. These findings show that the inhibitory effects of glucocorticoids on neuropathic pain behaviors, at least in part, may be mediated through L-type VSC channels; but our findings suggest a potential role for glucocorticoids receptors agonists in combination with L-type VSC channels antagonists in the clinical management of neuropathic pain. &nbsp; Key words:&nbsp;Corticosterone, L-type, calcium channel, mechanical allodynia, thermal allodynia, thermal hyperalgesia.

Effect of Intraperitoneal Administration of Bacterial Lipopolysaccharide on Synthesis of Pro-Opiomelanocortin mRNA in Rat Tanycytes

Intensity of pro-opiomelanocortin mRNA synthesis in tanycytes of adrenalectomied and sham-operated rats was studied by in situ hybridization 4 h after intraperitoneal injection of bacterial LPS. The results were compared with pro-opiomelanocortin mRNA expression in rats subjected to immobilization stress. Immobilization and LPS injection to adrenalectomied and sham-operated animals sharply reduced pro-opiomelanocortin mRNA expression in tanycytes. Injection of LPS to sham-operated animals and immobilization stress caused a significant increase in blood corticosterone level. On the other hand, LPS injection did not change low blood level of corticosterone in adrenalectomied rats. The data indicate a synergic inhibitory effect of glucocorticoids and LPS on synthetic activity of tanycytes.

The Hypothalamo–Pituitary–Adrenocortical Axis—An Overview of the Role of Glucocorticoids in the Pathophysiology of Endocrine Disorders and Perspectives for the Future

Glucocorticoids (GCs) are the end products of the hypothalamo–pituitary–adrenocortical axis (HPA) and, via activation of the ubiquitously expressed GC receptor, influence numerous physiological processes. GCs are also involved in the regulation of basal homeostasis as well as mediating adaptive responses to stress that act to restore homeostasis. This article discusses the various factors that are important in regulating plasma and intracellular GC concentrations and describes the genomic and non-genomic mechanisms used by GCs to influence cellular processes. We describe the concept of allostatic overload associated with chronic HPA activation and the subsequent development of tissue dysfunction and disease. While allostasis is associated with acute stress and a restoration of homeostasis, chronic stress is likely to induce allostatic overload owing to the sustained activation of adaptive processes. Increased wear and tear in GC-sensitive tissues can eventually lead to tissue dysfunction and disease. Chronic elevations in GCs can also induce dysfunction or disease associated with decreased tissue function owing to the prolonged inhibitory effects of GCs or the redistribution of metabolic resource away from physiological systems not involved in restoring homeostasis. Numerous endocrine-related disorders are associated with aberrant GC levels and in terms of pathophysiology may be linked with chronic tissue-specific alterations in GC actions.

The Use of Nanosized Cortisol-Polymer Complex for Analysis of Mechanisms of Regulation of Functional Activity of Skin Fibroblast

Cortisol in concentrations within the therapeutic range inhibits calcium response of fibroblast to angiotensin II. In physiological concentrations, cortisol potentiates the effects of angiotensin II via modulation of membrane mineralocorticoid receptors. The inhibitory effects of glucocorticoids on cell proliferation and collagen synthesis are manifestations of its genomic effects mediated by intracellular receptors. The use of glucocorticoid preparation based on nanosized polymer structure made it possible to distinguish between the genomic and nongenomic mechanisms of regulation of activity of target-cells.

The Hypothalamo–Pituitary–Adrenocortical Axis – An Overview of the Role of Glucocorticoids in the Pathophysiology of Endocrine Disorders and Perspectives for the Future

Glucocorticoids (GCs) are the end products of the hypothalamo–pituitary–adrenocortical axis (HPA) and, via activation of the ubiquitously expressed GC receptor, influence numerous physiological processes. GCs are also involved in the regulation of basal homeostasis as well as mediating adaptive responses to stress that act to restore homeostasis. This article discusses the various factors that are important in regulating plasma and intracellular GC concentrations and describes the genomic and non-genomic mechanisms used by GCs to influence cellular processes. We describe the concept of allostatic overload associated with chronic HPA activation and the subsequent development of tissue dysfunction and disease. While allostasis is associated with acute stress and a restoration of homeostasis, chronic stress is likely to induce allostatic overload owing to the sustained activation of adaptive processes. Increased wear and tear in GC-sensitive tissues can eventually lead to tissue dysfunction and disease. Chronic elevations in GCs can also induce dysfunction or disease associated with decreased tissue function owing to the prolonged inhibitory effects of GCs or the redistribution of metabolic resource away from physiological systems not involved in restoring homeostasis. Numerous endocrine-related disorders are associated with aberrant GC levels and in terms of pathophysiology may be linked with chronic tissue-specific alterations in GC actions.