International Journal of Molecular Sciences

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Open AccessEditorial

Glucocorticoid Signaling Pathway: From Bench to Bedside

by Nicolas C. Nicolaides and George P. Chrousos

Int. J. Mol. Sci. 2023, 24(13), 11030; https://doi.org/10.3390/ijms241311030 - 03 Jul 2023

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Abstract

Glucocorticoids were named by Hans Hugo Bruno Selye, the modern father of stress concepts, for their important role in glucose metabolism [...] Full article

(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)

Research

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14 pages, 2380 KiB

Open AccessArticle

Role of Glucocorticoid Signaling and HDAC4 Activation in Diaphragm and Gastrocnemius Proteolytic Activity in Septic Rats

by Álvaro Moreno-Rupérez, Teresa Priego, María Ángeles González-Nicolás, Asunción López-Calderón, Alberto Lázaro and Ana Isabel Martín

Int. J. Mol. Sci. 2022, 23(7), 3641; https://doi.org/10.3390/ijms23073641 - 26 Mar 2022

Cited by 7 | Viewed by 2487

Abstract

Sepsis increases glucocorticoid and decreases IGF-1, leading to skeletal muscle wasting and cachexia. Muscle atrophy mainly takes place in locomotor muscles rather than in respiratory ones. Our study aimed to elucidate the mechanism responsible for this difference in muscle proteolysis, focusing on local [...] Read more.

Sepsis increases glucocorticoid and decreases IGF-1, leading to skeletal muscle wasting and cachexia. Muscle atrophy mainly takes place in locomotor muscles rather than in respiratory ones. Our study aimed to elucidate the mechanism responsible for this difference in muscle proteolysis, focusing on local inflammation and IGF-1 as well as on their glucocorticoid response and HDAC4-myogenin activation. Sepsis was induced in adult male rats by lipopolysaccharide (LPS) injection (10 mg/kg), and 24 h afterwards, rats were euthanized. LPS increased TNFα and IL-10 expression in both muscles studied, the diaphragm and gastrocnemius, whereas IL-6 and SOCS3 mRNA increased only in diaphragm. In comparison with gastrocnemius, diaphragm showed a lower increase in proteolytic marker expression (atrogin-1 and LC3b) and in LC3b protein lipidation after LPS administration. LPS increased the expression of glucocorticoid induced factors, KLF15 and REDD1, and decreased that of IGF-1 in gastrocnemius but not in the diaphragm. In addition, an increase in HDAC4 and myogenin expression was induced by LPS in gastrocnemius, but not in the diaphragm. In conclusion, the lower activation of both glucocorticoid signaling and HDAC4-myogenin pathways by sepsis can be one of the causes of lower sepsis-induced proteolysis in the diaphragm compared to gastrocnemius. Full article

(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)

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18 pages, 14921 KiB

Open AccessArticle

Zebrafish Mutant Lines Reveal the Interplay between nr3c1 and nr3c2 in the GC-Dependent Regulation of Gene Transcription

by Alberto Dinarello, Annachiara Tesoriere, Paolo Martini, Camilla Maria Fontana, Davide Volpato, Lorenzo Badenetti, Francesca Terrin, Nicola Facchinello, Chiara Romualdi, Oliana Carnevali, Luisa Dalla Valle and Francesco Argenton

Int. J. Mol. Sci. 2022, 23(5), 2678; https://doi.org/10.3390/ijms23052678 - 28 Feb 2022

Cited by 7 | Viewed by 2441

Abstract

Glucocorticoids mainly exert their biological functions through their cognate receptor, encoded by the nr3c1 gene. Here, we analysed the glucocorticoids mechanism of action taking advantage of the availability of different zebrafish mutant lines for their receptor. The differences in gene expression patterns between [...] Read more.

Glucocorticoids mainly exert their biological functions through their cognate receptor, encoded by the nr3c1 gene. Here, we analysed the glucocorticoids mechanism of action taking advantage of the availability of different zebrafish mutant lines for their receptor. The differences in gene expression patterns between the zebrafish gr knock-out and the gr^s357 mutant line, in which a point mutation prevents binding of the receptor to the hormone-responsive elements, reveal an intricate network of GC-dependent transcription. Particularly, we show that Stat3 transcriptional activity mainly relies on glucocorticoid receptor GR tethering activity: several Stat3 target genes are induced upon glucocorticoid GC exposure both in wild type and in gr^s357/s357 larvae, but not in gr knock-out zebrafish. To understand the interplay between GC, their receptor, and the mineralocorticoid receptor, which is evolutionarily and structurally related to the GR, we generated an mr knock-out line and observed that several GC-target genes also need a functional mineralocorticoid receptor MR to be correctly transcribed. All in all, zebrafish mutants and transgenic models allow in vivo analysis of GR transcriptional activities and interactions with other transcription factors such as MR and Stat3 in an in-depth and rapid way. Full article

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14 pages, 2735 KiB

Open AccessArticle

Chronic Systemic Dexamethasone Regulates the Mineralocorticoid/Glucocorticoid Pathways Balance in Rat Ocular Tissues

by Marta Zola, Dan Mejlachowicz, Raquel Gregorio, Marie-Christine Naud, Frédéric Jaisser, Min Zhao and Francine Behar-Cohen

Int. J. Mol. Sci. 2022, 23(3), 1278; https://doi.org/10.3390/ijms23031278 - 24 Jan 2022

Cited by 8 | Viewed by 2940

Abstract

Central serous chorioretinopathy (CSCR) is a retinal disease affecting the retinal pigment epithelium (RPE) and the choroid. This is a recognized side-effect of glucocorticoids (GCs), administered through nasal, articular, oral and dermal routes. However, CSCR does not occur after intraocular GCs administration, suggesting [...] Read more.

Central serous chorioretinopathy (CSCR) is a retinal disease affecting the retinal pigment epithelium (RPE) and the choroid. This is a recognized side-effect of glucocorticoids (GCs), administered through nasal, articular, oral and dermal routes. However, CSCR does not occur after intraocular GCs administration, suggesting that a hypothalamic-pituitary-adrenal axis (HPA) brake could play a role in the mechanistic link between CSCR and GS. The aim of this study was to explore this hypothesis. To induce HPA brake, Lewis rats received a systemic injection of dexamethasone daily for five days. Control rats received saline injections. Baseline levels of corticosterone were measured by Elisa at baseline and at 5 days in the serum and the ocular media and dexamethasone levels were measured at 5 days in the serum and ocular media. The expression of genes encoding glucocorticoid receptor (GR), mineralocorticoid receptors (MR), and the 11 beta hydroxysteroid dehydrogenase (HSD) enzymes 1 and 2 were quantified in the neural retina and in RPE/ choroid. The expression of MR target genes was quantified in the retina (Scnn1A (encoding ENac-α, Kir4.1 and Aqp4) and in the RPE/choroid (Shroom 2, Ngal, Mmp9 and Omg, Ptx3, Plaur and Fosl-1). Only 10% of the corticosterone serum concentration was measured in the ocular media. Corticosterone levels in the serum and in the ocular media dropped after 5 days of dexamethasone systemic treatment, reflecting HPA axis brake. Whilst both GR and MR were downregulated in the retina without MR/GR imbalance, in the RPE/choroid, both MR/GR and 11β-hsd2/11β-hsd1 ratio increased, indicating MR pathway activation. MR-target genes were upregulated in the RPE/ choroid but not in the retina. The psychological stress induced by the repeated injection of saline also induced HPA axis brake with a trend towards MR pathway activation in RPE/ choroid. HPA axis brake causes an imbalance of corticoid receptors expression in the RPE/choroid towards overactivation of MR pathway, which could favor the occurrence of CSCR. Full article

(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)

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18 pages, 1047 KiB

Open AccessArticle

Wnt-Signaling Regulated by Glucocorticoid-Induced miRNAs

by Henriett Butz, Katalin Mészáros, István Likó and Attila Patocs

Int. J. Mol. Sci. 2021, 22(21), 11778; https://doi.org/10.3390/ijms222111778 - 29 Oct 2021

Cited by 6 | Viewed by 2029

Abstract

Glucocorticoids (GCs) are pleiotropic hormones which regulate innumerable physiological processes. Their comprehensive effects are due to the diversity of signaling mechanism networks. MiRNAs, small, non-coding RNAs contribute to the fine tuning of signaling pathways and reciprocal regulation between GCs and miRNAs has been [...] Read more.

Glucocorticoids (GCs) are pleiotropic hormones which regulate innumerable physiological processes. Their comprehensive effects are due to the diversity of signaling mechanism networks. MiRNAs, small, non-coding RNAs contribute to the fine tuning of signaling pathways and reciprocal regulation between GCs and miRNAs has been suggested. Our aim was to investigate the expressional change and potential function of GC mediated miRNAs. The miRNA expression profile was measured in three models: human adrenocortical adenoma vs. normal tissue, steroid-producing H295R cells and in hormonally inactive HeLa cells before and after dexamethasone treatment. The gene expression profile in 82 control and 57 GC-affected samples was evaluated in GC producing and six different GC target tissue types. Tissue-specific target prediction (TSTP) was applied to identify the most relevant miRNA−mRNA interactions. Glucocorticoid treatment resulted in cell type-dependent miRNA expression changes. However, 19.5% of the influenced signaling pathways were common in all three experiments, of which the Wnt-signaling pathway seemed to be the most affected. Transcriptome data and TSTP showed similar results, as the Wnt pathway was significantly altered in both the GC-producing adrenal gland and all investigated GC target tissue types. In different cell types, different miRNAs led to the regulation of similar pathways. Wnt signaling may be one of the most important signaling pathways affected by hypercortisolism. It is, at least in part, regulated by miRNAs that mediate the glucocorticoid effect. Our findings on GC producing and GC target tissues suggest that the alteration of Wnt signaling (together with other pathways) may be responsible for the leading symptoms observed in Cushing’s syndrome. Full article

(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)

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29 pages, 5369 KiB

Open AccessArticle

Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium

by Jérémie Canonica, Min Zhao, Tatiana Favez, Emmanuelle Gelizé, Laurent Jonet, Laura Kowalczuk, Justine Guegan, Damien Le Menuet, Say Viengchareun, Marc Lombès, Eric Pussard, Yvan Arsenijevic and Francine Behar-Cohen

Int. J. Mol. Sci. 2021, 22(17), 9618; https://doi.org/10.3390/ijms22179618 - 05 Sep 2021

Cited by 11 | Viewed by 2778

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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9 pages, 6529 KiB

Open AccessArticle

Naturalistic Stress Hormone Levels Drive Cumulative Epigenomic Changes along the Cellular Lifespan

by Anthony S. Zannas

Int. J. Mol. Sci. 2021, 22(16), 8778; https://doi.org/10.3390/ijms22168778 - 16 Aug 2021

Cited by 7 | Viewed by 2035

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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22 pages, 9972 KiB

Open AccessArticle

Dexamethasone Inhibits the Pro-Angiogenic Potential of Primary Human Myoblasts

by Eva K. Langendorf, Pol M. Rommens, Philipp Drees and Ulrike Ritz

Int. J. Mol. Sci. 2021, 22(15), 7986; https://doi.org/10.3390/ijms22157986 - 26 Jul 2021

Cited by 7 | Viewed by 2617

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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12 pages, 17038 KiB

Open AccessArticle

Rapid Screening of Glucocorticoid Receptor (GR) Effectors Using Cortisol-Detecting Sensor Cells

by Jeahee Ryu, Euiyeon Lee, Chungwon Kang, Minhyeong Lee, Soyoun Kim, Seungil Park, Daeyeon Lee and Youngeun Kwon

Int. J. Mol. Sci. 2021, 22(9), 4747; https://doi.org/10.3390/ijms22094747 - 29 Apr 2021

Cited by 7 | Viewed by 3042

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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13 pages, 7126 KiB

Open AccessReview

Pituitary–Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19

by Dimitra A. Vassiliadi, Alice G. Vassiliou, Ioannis Ilias, Stylianos Tsagarakis, Anastasia Kotanidou and Ioanna Dimopoulou

Int. J. Mol. Sci. 2021, 22(21), 11473; https://doi.org/10.3390/ijms222111473 - 25 Oct 2021

Cited by 9 | Viewed by 4465

Abstract

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged [...] Read more.

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR). Full article

(This article belongs to the Special Issue Glucocorticoid Signaling Pathway: From Bench to Bedside)

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17 pages, 1452 KiB

Open AccessReview

Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update

by Nicolas C. Nicolaides and Evangelia Charmandari

Int. J. Mol. Sci. 2021, 22(19), 10839; https://doi.org/10.3390/ijms221910839 - 07 Oct 2021

Cited by 17 | Viewed by 3410

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

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22 pages, 1863 KiB

Open AccessReview

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

by Lisa M. Sevilla, Alba Jiménez-Panizo, Andrea Alegre-Martí, Eva Estébanez-Perpiñá, Carme Caelles and Paloma Pérez

Int. J. Mol. Sci. 2021, 22(18), 10049; https://doi.org/10.3390/ijms221810049 - 17 Sep 2021

Cited by 27 | Viewed by 6222

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

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18 pages, 1710 KiB

Open AccessReview

Dexamethasone for Severe COVID-19: How Does It Work at Cellular and Molecular Levels?

by Tomoshige Kino, Irina Burd and James H. Segars

Int. J. Mol. Sci. 2021, 22(13), 6764; https://doi.org/10.3390/ijms22136764 - 23 Jun 2021

Cited by 22 | Viewed by 6697

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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22 pages, 11281 KiB

Open AccessReview

Mitochondrial Glucocorticoid Receptors and Their Actions

by Ioanna Kokkinopoulou and Paraskevi Moutsatsou

Int. J. Mol. Sci. 2021, 22(11), 6054; https://doi.org/10.3390/ijms22116054 - 03 Jun 2021

Cited by 43 | Viewed by 6960

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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17 pages, 1259 KiB

Open AccessReview

Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

by Niki Mourtzi, Amalia Sertedaki and Evangelia Charmandari

Int. J. Mol. Sci. 2021, 22(11), 5964; https://doi.org/10.3390/ijms22115964 - 31 May 2021

Cited by 36 | Viewed by 6758

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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