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1.
Eur J Pharmacol ; 943: 175555, 2023 Mar 15.
Article in English | MEDLINE | ID: covidwho-2210224

ABSTRACT

The effect of corticosteroid therapy in COVID-19 patients is mediated by its suppressive effect on the regulations of inflammatory response. However, its clinical outcome is often unpredictable. This study aimed to explore the role of glucocorticoid receptors in corticosteroid response in Moderate-Severe COVID-19 patients. In this cross-sectional study, we attempted to find the relationship between the expression of the glucocorticoid receptor (encoded by NR3C1), the variation of glucocorticoid receptors isoform, and the mutations of glucocorticoid receptors exon with clinical response to corticosteroids. In addition, the relationship between glucocorticoid receptors expression and the expression of IκBα (encoded by NFKBIA) and glucocorticoid-induced leucine zipper protein (GILZ; encoded by TSC22D3) as steroid pathways was also evaluated. Thirty-four COVID-19 patients were studied. Blood was drawn before and on day 5 of corticosteroid treatment. Glucocorticoid receptors expression, isoform, and mutation were determined by RNA sequencing from white blood cells. Based on the improvement of clinical and oxygen status, patients were classified into responder and non-responder groups. Of thirty-four patients, 23 (67.6%) showed excellent responses to corticosteroids, and 11 (32.4%) were non-responders. The NR3C1 gene expression was significantly higher in the responsive group at baseline and after five days of glucocorticoid treatment. Isoform variant and mutation of glucocorticoid receptors did not correlate with clinical response. The expression of IκBα and GILZ correlated positively with glucocorticoid receptors expression. This study elucidates the relationship between glucocorticoid receptor expression with therapeutic responses to corticosteroids in moderate-severe COVID-19.


Subject(s)
COVID-19 , Glucocorticoids , Humans , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , NF-KappaB Inhibitor alpha , Cross-Sectional Studies , Adrenal Cortex Hormones , Steroids
2.
Transl Psychiatry ; 12(1): 386, 2022 09 16.
Article in English | MEDLINE | ID: covidwho-2036783

ABSTRACT

Stress exposure during pregnancy is critically linked with maternal mental health and child development. The effects might involve altered patterns of DNA methylation in specific stress-related genes (i.e., glucocorticoid receptor gene, NR3C1, and serotonin transporter gene, SLC6A4) and might be moderated by the gestational timing of stress exposure. In this study, we report on NR3C1 and SLC6A4 methylation status in Italian mothers and infants who were exposed to the COVID-19 pandemic lockdown during different trimesters of pregnancy. From May 2020 to February 2021, 283 mother-infant dyads were enrolled at delivery. Within 24 h from delivery, buccal cells were collected to assess NR3C1 (44 CpG sites) and SLC6A4 (13 CpG sites) methylation status. Principal component (PC) analyses were used to reduce methylation data dimension to one PC per maternal and infant gene methylation. Mother-infant dyads were split into three groups based on the pregnancy trimester (first, second, third), during which they were exposed to the COVID-19 lockdown. Mothers and infants who were exposed to the lockdown during the first trimester of pregnancy had lower NR3C1 and SLC6A4 methylation when compared to counterparts exposed during the second or third trimesters. The effect remained significant after controlling for confounders. Women who were pregnant during the pandemic and their infants might present altered epigenetic biomarkers of stress-related genes. As these epigenetic marks have been previously linked with a heightened risk of maternal psychiatric problems and less-than-optimal child development, mothers and infants should be adequately monitored for psychological health during and after the pandemic.


Subject(s)
COVID-19 , Epigenesis, Genetic , Quarantine , Receptors, Glucocorticoid , Serotonin Plasma Membrane Transport Proteins , COVID-19/epidemiology , COVID-19/prevention & control , Child , Communicable Disease Control , Epigenesis, Genetic/genetics , Female , Humans , Infant , Mouth Mucosa/metabolism , Pandemics/prevention & control , Pregnancy , Quarantine/psychology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism
3.
Front Immunol ; 13: 966522, 2022.
Article in English | MEDLINE | ID: covidwho-2022750

ABSTRACT

Prenatal stress can affect pregnant women in an epigenetic way during the critical period of conception of their offspring. The study aims to investigate the relationship between peritraumatic distress, prenatal perceived stress, depression, and glucocorticoid receptor (NR3C1) DNA methylation among pregnant women who experienced COVID-19 lockdown in China. Study data were collected from 30 pregnant women in Wuhan and Huanggang, China. The Peritraumatic Distress Inventory was used to measure peritraumatic distress, the Edinburgh Postnatal Depression Scale was used to measure depressive symptoms, and the Perceived Stress Scale was used to measure perceived stress. DNA methylation in the exon 1F promoter region of NR3C1 gene from the venous blood mononuclear cell genome was characterized by bisulfite sequencing. Correlation and linear regression were used for data analysis. The mean level of peritraumatic distress, perceived stress, and depression was 6.30 (SD = 5.09), 6.50 (SD = 5.41), and 6.60 (SD = 4.85), respectively, with 23.33% of pregnant women being depressed. The mean NR3C1 methylation was 0.65 (SD = 0.22). Prenatal depression was positively correlated with the degree of methylation in venous blood from the mother (r = 0.59, p = 0.001), and depression predicted methylation of NR3C1 gene at the CpG 8 site (ß = 0.05, p = 0.03). No association was found between peritraumatic distress as well as perceived stress and methylation of NR3C1. NR3C1 gene was susceptible to epigenetic modification of DNA methylation in the context of prenatal stress, and maternal depression was associated with increased NR3C1 methylation among women who experienced COVID-19 lockdown.


Subject(s)
COVID-19 , Depression , Pregnancy Complications , Quarantine , Receptors, Glucocorticoid , Stress Disorders, Traumatic , COVID-19/epidemiology , COVID-19/genetics , COVID-19/prevention & control , COVID-19/psychology , China/epidemiology , Communicable Disease Control/methods , DNA Methylation/genetics , Depression/epidemiology , Depression/genetics , Depression/psychology , Female , Humans , Pregnancy , Pregnancy Complications/epidemiology , Pregnancy Complications/genetics , Pregnancy Complications/prevention & control , Pregnancy Complications/psychology , Pregnant Women , Quarantine/methods , Quarantine/psychology , Receptors, Glucocorticoid/genetics , Stress Disorders, Traumatic/epidemiology , Stress Disorders, Traumatic/genetics , Stress Disorders, Traumatic/psychology , Stress, Psychological/epidemiology , Stress, Psychological/genetics , Stress, Psychological/psychology
4.
Molecules ; 27(11)2022 May 26.
Article in English | MEDLINE | ID: covidwho-1892924

ABSTRACT

Excessive corticosterone (CORT), resulting from a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, is associated with cognitive impairment and behavioral changes, including depression. In Korean oriental medicine, Pedicularis resupinata is used for the treatment of inflammatory diseases such as rheumatoid arthritis. However, the antidepressant properties of P. resupinata have not been well characterized. Here, the antidepressant-like effects of P. resupinata extract (PRE) were evaluated in terms of CORT-induced depression using in vivo models. HPLC confirmed that acteoside, a phenylethanoid glycoside, was the main compound from PRE. Male ICR mice (8 weeks old) were injected with CORT (40 mg/kg, i.p.) and orally administered PRE daily (30, 100, and 300 mg/kg) for 21 consecutive days. Depressive-like behaviors were evaluated using the open-field test, sucrose preference test, passive avoidance test, tail suspension test, and forced swim test. Treatment with a high dose of PRE significantly alleviated CORT-induced, depressive-like behaviors in mice. Additionally, repeated CORT injection markedly reduced brain-derived neurotrophic factor levels, whereas total glucocorticoid receptor (GR) and GR phosphorylation at serine 211 were significantly increased in the mice hippocampus but improved by PRE treatment. Thus, our findings suggest that PRE has potential antidepressant-like effects in CORT-induced, depressive-like behavior in mice.


Subject(s)
Corticosterone , Pedicularis , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Behavior, Animal , Corticosterone/adverse effects , Depression/chemically induced , Depression/drug therapy , Depression/psychology , Disease Models, Animal , Hippocampus , Male , Mice , Mice, Inbred ICR , Pituitary-Adrenal System , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Receptors, Glucocorticoid
5.
EBioMedicine ; 80: 104057, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1867074

ABSTRACT

BACKGROUND: Reduced glucocorticoid-receptor (GR) expression in blood suggested that critically ill patients become glucocorticoid-resistant necessitating stress-doses of glucocorticoids. We hypothesised that critical illness evokes a tissue-specific, time-dependent expression of regulators of GR-action which adaptively guides glucocorticoid action to sites of need. METHODS: We performed a prospective, observational, cross-sectional human study and two translational mouse studies. In freshly-isolated neutrophils and monocytes and in skeletal muscle and subcutaneous adipose tissue of 137 critically ill patients and 20 healthy controls and in skeletal muscle and adipose tissue as well as in vital tissues (heart, lung, diaphragm, liver, kidney) of 88 septic and 26 healthy mice, we quantified gene expression of cortisone-reductase 11ß-HSD1, glucocorticoid-receptor-isoforms GRα and GRß, GRα-sensitivity-regulating-co-chaperone FKBP51, and GR-action-marker GILZ. Expression profiles were compared in relation to illness-duration and systemic-glucocorticoid-availability. FINDINGS: In patients' neutrophils, GRα and GILZ were substantially suppressed (p≤0·05) throughout intensive care unit (ICU)-stay, while in monocytes low/normal GRα coincided with increased GILZ (p≤0·05). FKBP51 was increased transiently (neutrophils) or always (monocytes,p≤0·05). In patients' muscle, 11ß-HSD1 and GRα were low-normal (p≤0·05) and substantially suppressed in adipose tissue (p≤0·05); FKBP51 and GILZ were increased in skeletal muscle (p≤0·05) but normal in adipose tissue. GRß was undetectable. Increasing systemic glucocorticoid availability in patients independently associated with further suppressed muscle 11ß-HSD1 and GRα, further increased FKBP51 and unaltered GILZ (p≤0·05). In septic mouse heart and lung, 11ß-HSD1, FKBP51 and GILZ were always high (p≤0·01). In heart, GRα was suppressed (p≤0·05), while normal or high in lung (all p≤0·05). In diaphragm, 11ß-HSD1 was high/normal, GRα low/normal and FKBP51 and GILZ high (p≤0·01). In kidney, 11ß-HSD1 transiently increased but decreased thereafter, GRα was normal and FKBP51 and GILZ high (p≤0·01). In liver, 11ß-HSD1 was suppressed (p≤0·01), GRα normal and FKBP51 high (p≤0·01) whereas GILZ was transiently decreased but elevated thereafter (p≤0·05). Only in lung and diaphragm, treatment with hydrocortisone further increased GILZ. INTERPRETATION: Tissue-specific, time-independent adaptations to critical illness guided GR-action predominantly to vital tissues such as lung, while (partially) protecting against collateral harm in other cells and tissues, such as neutrophils. These findings argue against maladaptive generalised glucocorticoid-resistance necessitating glucocorticoid-treatment. FUNDING: Research-Foundation-Flanders, Methusalem-Program-Flemish-Government, European-Research-Council, European-Respiratory-Society.


Subject(s)
Glucocorticoids , Receptors, Glucocorticoid , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Critical Illness , Cross-Sectional Studies , Gene Expression , Humans , Mice , Prospective Studies , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism
6.
Sci Adv ; 8(5): eabl8920, 2022 02 04.
Article in English | MEDLINE | ID: covidwho-1673337

ABSTRACT

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.


Subject(s)
Dexamethasone/pharmacology , Dipeptidases/genetics , Ferroptosis/drug effects , Ferroptosis/genetics , Gene Expression Regulation/drug effects , Glutathione/metabolism , Receptors, Glucocorticoid/metabolism , Carbolines/adverse effects , Carbolines/pharmacology , Cell Line , Dipeptidases/metabolism , Fluorescent Antibody Technique , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Gene Knockdown Techniques , Humans , Immunophenotyping , Oxidation-Reduction/drug effects , Piperazines/adverse effects , Piperazines/pharmacology
7.
Sci Rep ; 11(1): 22913, 2021 11 25.
Article in English | MEDLINE | ID: covidwho-1537333

ABSTRACT

Inflammation is a physiological process whose deregulation causes some diseases including cancer. Nuclear Factor kB (NF-kB) is a family of ubiquitous and inducible transcription factors, in which the p65/p50 heterodimer is the most abundant complex, that play critical roles mainly in inflammation. Glucocorticoid Receptor (GR) is a ligand-activated transcription factor and acts as an anti-inflammatory agent and immunosuppressant. Thus, NF-kB and GR are physiological antagonists in the inflammation process. Here we show that in mice and humans there is a spliced variant of p65, named p65 iso5, which binds the corticosteroid hormone dexamethasone amplifying the effect of the glucocorticoid receptor and is expressed in the liver of patients with hepatic cirrhosis and hepatocellular carcinoma (HCC). Furthermore, we have quantified the gene expression level of p65 and p65 iso5 in the PBMC of patients affected by SARS-CoV-2 disease. The results showed that in these patients the p65 and p65 iso5 mRNA levels are higher than in healthy subjects. The ability of p65 iso5 to bind dexamethasone and the regulation of the glucocorticoid (GC) response in the opposite way of the wild type improves our knowledge and understanding of the anti-inflammatory response and identifies it as a new therapeutic target to control inflammation and related diseases.


Subject(s)
Inflammation/immunology , Receptors, Glucocorticoid/metabolism , Transcription Factor RelA/metabolism , Adrenal Cortex Hormones/metabolism , Adult , Alternative Splicing , Animals , COVID-19/immunology , Carcinoma, Hepatocellular/metabolism , Dexamethasone/metabolism , Female , Gene Expression/genetics , Gene Expression Regulation/genetics , Glucocorticoids/metabolism , Hepatitis/metabolism , Humans , Inflammation/metabolism , Leukocytes, Mononuclear/metabolism , Liver/metabolism , Liver Diseases/immunology , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , NF-kappa B/metabolism , Protein Isoforms , Receptors, Glucocorticoid/immunology , SARS-CoV-2/pathogenicity , Transcription Factor RelA/immunology , Transcription Factor RelA/physiology
9.
Crit Care Med ; 49(12): 2131-2136, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1522360

ABSTRACT

OBJECTIVES: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking. DESIGN: Prospective observational study. SETTING: One academic multidisciplinary ICU. SUBJECTS: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 µg/dL, p < 0.01) compared with the control group. CONCLUSIONS: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins.


Subject(s)
COVID-19/physiopathology , Hydrocortisone/blood , Leucine Zippers/physiology , Receptors, Glucocorticoid/biosynthesis , Academic Medical Centers , Adult , Aged , Comorbidity , Critical Illness , Female , Greece , Humans , Intensive Care Units , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Severity of Illness Index
10.
Int J Mol Sci ; 22(21)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1512373

ABSTRACT

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-ßhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.


Subject(s)
Cushing Syndrome/diagnosis , Cushing Syndrome/therapy , Adrenal Gland Neoplasms/complications , Cushing Syndrome/complications , Drug Development , Humans , Hydrocortisone/metabolism , Models, Biological , Receptors, Dopamine/drug effects , Receptors, Glucocorticoid/drug effects , Receptors, Somatostatin/drug effects , Steroids/biosynthesis
11.
Int J Mol Sci ; 22(21)2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1480799

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 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).


Subject(s)
COVID-19/metabolism , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/virology , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/virology , Receptors, Glucocorticoid/metabolism , Critical Illness , Glucocorticoids/metabolism , Humans , Stress, Physiological
12.
Essays Biochem ; 65(6): 1025-1038, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1334002

ABSTRACT

COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung - notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.


Subject(s)
COVID-19/metabolism , Lung/metabolism , Lung/virology , Receptors, Steroid/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Female , Hormone Antagonists/therapeutic use , Humans , Immunomodulation , Male , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/metabolism , Receptors, Progesterone/metabolism , SARS-CoV-2 , Serine Endopeptidases/metabolism , Sex Factors , COVID-19 Drug Treatment
14.
Cell Metab ; 33(8): 1592-1609.e7, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1300705

ABSTRACT

Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs.


Subject(s)
Epigenomics , Glucocorticoids , Adipocytes/metabolism , Anti-Inflammatory Agents , Dexamethasone/adverse effects , Glucocorticoids/adverse effects , Humans , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism
15.
Neurobiol Dis ; 156: 105422, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267874

ABSTRACT

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.


Subject(s)
Cerebellum/drug effects , Cerebral Cortex/drug effects , Glucocorticoids , Lung/drug effects , Pregnenediones/pharmacology , Prodrugs/pharmacology , Signal Transduction/drug effects , Animals , Animals, Newborn , Anti-Inflammatory Agents/pharmacology , Body Weight/drug effects , Brain/drug effects , Brain/growth & development , Dexamethasone/pharmacology , Female , Mice , Mice, Inbred C57BL , Myelin Basic Protein/biosynthesis , Organ Size/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/drug effects , COVID-19 Drug Treatment
16.
J Biol Chem ; 296: 100687, 2021.
Article in English | MEDLINE | ID: covidwho-1198855

ABSTRACT

Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocorticoid receptor (GR) monomers tether repressively to inflammatory transcription factors, thus abrogating inflammatory gene expression. However, newer data challenge this core concept and present an exciting opportunity to reframe our understanding of GR signaling. Here, we present an alternate, two-part model for transcriptional repression by glucocorticoids. First, widespread GR-mediated induction of transcription results in rapid, primary repression of inflammatory gene transcription and associated enhancers through competition-based mechanisms. Second, a subset of GR-induced genes, including targets that are regulated in coordination with inflammatory transcription factors such as NF-κB, exerts secondary repressive effects on inflammatory gene expression. Within this framework, emerging data indicate that the gene set regulated through the cooperative convergence of GR and NF-κB signaling is central to the broad clinical effectiveness of glucocorticoids in terminating inflammation and promoting tissue repair.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19 Drug Treatment , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , NF-kappa B/genetics , Receptors, Glucocorticoid/genetics , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Gene Expression Regulation , Genomics/methods , Humans , Inflammation/prevention & control , Models, Genetic , NF-kappa B/antagonists & inhibitors , NF-kappa B/immunology , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/immunology , SARS-CoV-2/growth & development , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction , Transcription, Genetic/drug effects , Transcription, Genetic/immunology
17.
J Chin Med Assoc ; 84(3): 245-247, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1132635

ABSTRACT

The rapid spread of coronavirus disease (COVID-19) in many countries has caused inconvenience in conducting daily life activities, and even deaths. Dexamethasone is a corticosteroid applied in clinical medicine since 1957, especially in immune therapy fields. Herein, we present the characteristics of Dexamethasone, from molecular mechanisms such as genomic and nongenomic pathways by cellular signal regulations, to clinical applications in various phases of the disease. During COVID-19 pandemic, Dexamethasone given to patients who required oxygen or ventilation therapy showed improved life efficacy.


Subject(s)
COVID-19 Drug Treatment , Dexamethasone/pharmacology , SARS-CoV-2 , Dexamethasone/therapeutic use , Humans , Receptors, Glucocorticoid/physiology , Signal Transduction/physiology
18.
Cell Cycle ; 19(24): 3632-3638, 2020 12.
Article in English | MEDLINE | ID: covidwho-1066164

ABSTRACT

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Receptors, Androgen/metabolism , Receptors, Glucocorticoid/metabolism , SARS-CoV-2/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , Cell Line , Disease Progression , Down-Regulation , Glucocorticoids/antagonists & inhibitors , Glucocorticoids/metabolism , Humans , Hydrocortisone/antagonists & inhibitors , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Middle East Respiratory Syndrome Coronavirus/drug effects , Receptors, Glucocorticoid/agonists , Serine Endopeptidases/metabolism
19.
Mol Psychiatry ; 26(9): 5087-5096, 2021 09.
Article in English | MEDLINE | ID: covidwho-1065838

ABSTRACT

The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.


Subject(s)
Depression/metabolism , NF-kappa B , Receptors, Glucocorticoid , Animals , Brain/metabolism , Hypothalamo-Hypophyseal System/metabolism , Mice , NF-kappa B/metabolism , Pituitary-Adrenal System/metabolism , Receptors, Glucocorticoid/metabolism
20.
Int J Mol Sci ; 21(23)2020 Dec 03.
Article in English | MEDLINE | ID: covidwho-965280

ABSTRACT

Glucocorticoids are drugs of choice in Duchenne muscular dystrophy (DMD), prolonging patients' ambulation. Their mode of action at the protein level is not completely understood. In DMD, muscle tissue is replaced by fibrotic tissue produced by fibroblasts, reducing mobility. Nuclear factor of activated T-cells 5 (NFAT5) is involved in fibroblast proliferation. By treating one DMD fibroblast cell culture and one of unaffected skeletal muscle fibroblasts with methylprednisolone (MP) or hydrocortisone (HC) for 24 h or 12 d, the antiproliferative properties of glucocorticoids could be unraveled. NFAT5 localization and expression was explored by immunocytochemistry (ICC), Western blotting (WB) and RT-qPCR. NFAT5 and glucocorticoid receptor (GR) colocalization was measured by ImageJ. GR siRNA was used, evaluating GR's influence on NFAT5 expression during MP and HC treatment. Cell proliferation was monitored by IncuCyte ZOOM. In DMD fibroblasts, treatment with MP for 24 h induced dots (ICC) positive for NFAT5 and colocalizing with GR. After 12 d of MP or HC in DMD fibroblasts, NFAT5 expression was decreased (RT-qPCR and WB) and growth arrest was observed (Incucyte ZOOM), whereas NFAT5 expression and cell growth remained unchanged in unaffected skeletal muscle fibroblasts. This study may help understand the antiproliferative properties of glucocorticoids in DMD fibroblasts.


Subject(s)
Fibroblasts/drug effects , Fibroblasts/metabolism , Glucocorticoids/pharmacology , Receptors, Glucocorticoid/metabolism , Transcription Factors/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Fluorescent Antibody Technique , Humans , Hydrocortisone/pharmacology , Methylprednisolone/pharmacology , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/metabolism , Protein Binding
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