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Special Issue "Glucocorticoid Signaling Pathway: From Bench to Bedside"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: 30 November 2021.

Special Issue Editors

Prof. Dr. George P. Chrousos
E-Mail Website
Guest Editor
1. University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, 8 Livadias Street, Goudi, 11527 Athens, Greece
2. Center for Adolescent Medicine, UNESCO Chair on Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, 1 Thivon Street, Goudi, 11527 Athens, Greece
Interests: endocrinology; molecular endocrinology; pediatrics; pediatric endocrinology; genetics; epigenetics; stress; stress biology and medicine; human physiology
Special Issues and Collections in MDPI journals
Dr. Nicolas C. Nicolaides
E-Mail Website
Guest Editor
1. Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
2. First Department of Pediatrics, Aghia Sophia Children’s Hospital, School of Medicine, National and Kapodistrian University of Athens, 15773 Athens, Greece
Interests: endocrinology; molecular endocrinology; pediatrics; pediatric endocrinology; genetics; epigenetics; stress; stress biology and medicine; human physiology

Special Issue Information

Dear Colleagues,

Glucocorticoids are steroid hormones produced by the adrenal cortex and secreted into the systemic circulation in a circadian or stress-related fashion. Their secretion is under the complex control of the hypothalamic-pituitary-adrenal (HPA) axis, a major component of the stress system. Glucocorticoids play fundamental roles in the maintenance of resting and stress-related homeostasis. They regulate a broad spectrum of physiologic functions, including those of the central nervous, cardiovascular, metabolic, and immune systems. All pleiotropic actions of glucocorticoids are mediated by the ubiquitously expressed glucocorticoid receptor (hGR), which functions as a ligand-activated transcription factor influencing the transcription of approximately 20% of the human genome in a positive or negative fashion. In addition to their genomic actions, glucocorticoids may exert their effects within seconds or minutes through non-genomic actions, possibly mediated by membrane-bound hGRs.

Furthermore, glucocorticoid receptors are located within mitochondria where they may regulate cellular energy production. Either through genomic or non-genomic mechanisms, tissue glucocorticoid sensitivity is influenced by several factors, such as NR3C1 gene polymorphisms or mutations, presence of multiple hGR protein isoforms, an ever increasing number of interacting partners, including many proteins, as well as noncoding RNA molecules (microRNAs, long non-coding RNAs, etc.). Glucocorticoids have many epigenetic actions that can be stimulatory or inhibitory.  These are exerted especially strongly during critical periods of life, such as the prenatal period, the first 5 years of life, and the pubertal and young adult ages.   In this special issue, we aim to present the diverse and complex actions of glucocorticoids through their intracellular signaling pathways from bench to bedside.

Prof. Dr. George Panagiotis Chrousos
Dr. Nicolas C. Nicolaides
Guest Editors

Manuscript Submission Information

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Keywords

  • glucocorticoids
  • glucocorticoid receptor
  • glucocorticoid signaling
  • NR3C1 gene mutations
  • NR3C1 gene polymorphisms
  • synthetic glucocorticoids

Published Papers (9 papers)

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Research

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Article
Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
Int. J. Mol. Sci. 2021, 22(17), 9618; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179618 - 05 Sep 2021
Viewed by 595
Abstract
Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels [...] Read more.
Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Article
Naturalistic Stress Hormone Levels Drive Cumulative Epigenomic Changes along the Cellular Lifespan
Int. J. Mol. Sci. 2021, 22(16), 8778; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168778 - 16 Aug 2021
Viewed by 383
Abstract
Environmental stress is ubiquitous in modern societies and can exert a profound and cumulative impact on cell function and health phenotypes. This impact is thought to be in large part mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans. While [...] Read more.
Environmental stress is ubiquitous in modern societies and can exert a profound and cumulative impact on cell function and health phenotypes. This impact is thought to be in large part mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans. While the underlying molecular mechanisms are unclear, epigenetics—the chemical changes that regulate genomic function without altering the genetic code—has emerged as a key link between environmental exposures and phenotypic outcomes. The present study assessed genome-wide DNA (CpG) methylation, one of the key epigenetic mechanisms, at three timepoints during prolonged (51-day) exposure of cultured human fibroblasts to naturalistic cortisol levels, which can be reached in human tissues during in vivo stress. The findings support a spatiotemporal model of profound and widespread stress hormone-driven methylomic changes that emerge at selected CpG sites, are more likely to spread to nearby located CpGs, and quantitatively accrue at open sea, glucocorticoid receptor binding, and chromatin-accessible sites. Taken together, these findings provide novel insights into how prolonged stress may impact the epigenome, with potentially important implications for stress-related phenotypes. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Article
Dexamethasone Inhibits the Pro-Angiogenic Potential of Primary Human Myoblasts
Int. J. Mol. Sci. 2021, 22(15), 7986; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157986 - 26 Jul 2021
Viewed by 529
Abstract
Tissue regeneration depends on the complex processes of angiogenesis, inflammation and wound healing. Regarding muscle tissue, glucocorticoids (GCs) inhibit pro-inflammatory signalling and angiogenesis and lead to muscle atrophy. Our hypothesis is that the synthetic GC dexamethasone (dex) impairs angiogenesis leading to muscle atrophy [...] Read more.
Tissue regeneration depends on the complex processes of angiogenesis, inflammation and wound healing. Regarding muscle tissue, glucocorticoids (GCs) inhibit pro-inflammatory signalling and angiogenesis and lead to muscle atrophy. Our hypothesis is that the synthetic GC dexamethasone (dex) impairs angiogenesis leading to muscle atrophy or inhibited muscle regeneration. Therefore, this study aims to elucidate the effect of dexamethasone on HUVECs under different conditions in mono- and co-culture with myoblasts to evaluate growth behavior and dex impact with regard to muscle atrophy and muscle regeneration. Viability assays, qPCR, immunofluorescence as well as ELISAs were performed on HUVECs, and human primary myoblasts seeded under different culture conditions. Our results show that dex had a higher impact on the tube formation when HUVECs were maintained with VEGF. Gene expression was not influenced by dex and was independent of cells growing in a 2D or 3D matrix. In co-culture CD31 expression was suppressed after incubation with dex and gene expression analysis revealed that dex enhanced expression of myogenic transcription factors, but repressed angiogenic factors. Moreover, dex inhibited the VEGF mediated pro angiogenic effect of myoblasts and inhibited expression of angiogenic inducers in the co-culture model. This is the first study describing a co-culture of human primary myoblast and HUVECs maintained under different conditions. Our results indicate that dex affects angiogenesis via inhibition of VEGF release at least in myoblasts, which could be responsible not only for the development of muscle atrophy after dex administration, but also for inhibition of muscle regeneration after vascular damage. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Article
Rapid Screening of Glucocorticoid Receptor (GR) Effectors Using Cortisol-Detecting Sensor Cells
Int. J. Mol. Sci. 2021, 22(9), 4747; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094747 - 29 Apr 2021
Cited by 1 | Viewed by 720
Abstract
Cortisol, a stress hormone, plays key roles in mediating stress and anti-inflammatory responses. As abnormal cortisol levels can induce various adverse effects, screening cortisol and cortisol analogues is important for monitoring stress levels and for identifying drug candidates. A novel cell-based sensing system [...] Read more.
Cortisol, a stress hormone, plays key roles in mediating stress and anti-inflammatory responses. As abnormal cortisol levels can induce various adverse effects, screening cortisol and cortisol analogues is important for monitoring stress levels and for identifying drug candidates. A novel cell-based sensing system was adopted for rapid screening of cortisol and its functional analogues under complex cellular regulation. We used glucocorticoid receptor (GR) fused to a split intein which reconstituted with the counterpart to trigger conditional protein splicing (CPS) in the presence of targets. CPS generates functional signal peptides which promptly translocate the fluorescent cargo. The sensor cells exhibited exceptional performance in discriminating between the functional and structural analogues of cortisol with improved sensitivity. Essential oil extracts with stress relief activity were screened using the sensor cells to identify GR effectors. The sensor cells responded to peppermint oil, and L-limonene and L-menthol were identified as potential GR effectors from the major components of peppermint oil. Further analysis indicated L-limonene as a selective GR agonist (SEGRA) which is a potential anti-inflammatory agent as it attenuates proinflammatory responses without causing notable adverse effects of GR agonists. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Review

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Review
Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update
Int. J. Mol. Sci. 2021, 22(19), 10839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910839 - 07 Oct 2021
Viewed by 269
Abstract
Glucocorticoids are the final products of the neuroendocrine hypothalamic–pituitary—adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the [...] Read more.
Glucocorticoids are the final products of the neuroendocrine hypothalamic–pituitary—adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Review
Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways
Int. J. Mol. Sci. 2021, 22(18), 10049; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810049 - 17 Sep 2021
Viewed by 428
Abstract
Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. [...] Read more.
Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Review
Dexamethasone for Severe COVID-19: How Does It Work at Cellular and Molecular Levels?
Int. J. Mol. Sci. 2021, 22(13), 6764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136764 - 23 Jun 2021
Cited by 2 | Viewed by 1918
Abstract
The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious [...] Read more.
The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious diseases, such as bacterial sepsis and severe influenza pneumonia, which can develop respiratory failure and systemic inflammation similar to COVID-19. This apparent inconsistency suggests the presence of pathologic mechanism(s) unique to COVID-19 that renders this steroid effective. We review plausible mechanisms and advance the hypothesis that SARS-CoV-2 infection is accompanied by infected cell-specific glucocorticoid insensitivity as reported for some other viruses. This alteration in local glucocorticoid actions interferes with undesired glucocorticoid to facilitate viral replication but does not affect desired anti-inflammatory properties in non-infected organs/tissues. We postulate that the virus coincidentally causes glucocorticoid insensitivity in the process of modulating host cell activities for promoting its replication in infected cells. We explore this tenet focusing on SARS-CoV-2-encoding proteins and potential molecular mechanisms supporting this hypothetical glucocorticoid insensitivity unique to COVID-19 but not characteristic of other life-threatening viral diseases, probably due to a difference in specific virally-encoded molecules and host cell activities modulated by them. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Review
Mitochondrial Glucocorticoid Receptors and Their Actions
Int. J. Mol. Sci. 2021, 22(11), 6054; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116054 - 03 Jun 2021
Viewed by 1098
Abstract
Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid [...] Read more.
Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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Review
Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders
Int. J. Mol. Sci. 2021, 22(11), 5964; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115964 - 31 May 2021
Viewed by 953
Abstract
Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of [...] Read more.
Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders. Full article
(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)
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