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1.
Front Immunol ; 13: 811430, 2022.
Article in English | MEDLINE | ID: covidwho-1731772

ABSTRACT

Despite significant research efforts, treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain limited. This is due in part to a lack of therapeutics that increase host defense to the virus. Replication of SARS-CoV-2 in lung tissue is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses that amplify tissue injury. Antagonists of the androgen (AR) and glucocorticoid (GR) receptors have shown efficacy in models of COVID-19 and in clinical studies because the cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2), are transcriptionally regulated by these receptors. We postulated that the GR and AR modulator, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID-19 by down-regulating expression of critical genes regulated through these receptors. Animals were infected intranasally with 2.5 × 104 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were examined at 3, 5 and 7 days post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the progression of SARS-CoV-2 infection. Results indicated that oral administration of PT150 caused a dose-dependent decrease in replication of SARS-CoV-2 in lung, as well as in expression of ACE2 and TMPRSS2. Lung hypercellularity and infiltration of macrophages and CD4+ T-cells were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular docking studies suggest that PT150 binds to the co-activator interface of the ligand-binding domain of both AR and GR, thereby acting as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR revealed a high degree of sequence identity maintained across multiple species, including humans, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID-19 across variants of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Glucocorticoids/metabolism , Immunity, Innate/drug effects , Inflammation/drug therapy , Receptors, Androgen/metabolism , Virus Internalization/drug effects , Animals , COVID-19/metabolism , Disease Models, Animal , Female , Inflammation/metabolism , Inflammation/virology , Lung/virology , Male , Mesocricetus , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Viral Load/drug effects
2.
Int J Mol Sci ; 22(16)2021 Aug 07.
Article in English | MEDLINE | ID: covidwho-1662667

ABSTRACT

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation. The multiple genomic and non-genomic pathways in GC signaling vary with exposure duration, location (adipose tissue depot), and species. Genomic effects occur directly through the cytosolic GC receptor (GR), regulating the expression of proteins related to lipid metabolism, such as ATGL and HSL. Non-genomic effects act through mechanisms often independent of the cytosolic GR and happen shortly after GC exposure. Studying the effects of GCs on adipose tissue breakdown and generation (lipolysis and adipogenesis) leads to insights for treatment of adipose-related diseases, such as obesity, coronary disease, and cancer, but has led to controversy among researchers, largely due to the complexity of the process. This paper reviews the recent literature on the genomic and non-genomic effects of GCs on WAT and BAT lipolysis and proposes research to address the many gaps in knowledge related to GC activity and its effects on disease.


Subject(s)
Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Genomics , Glucocorticoids , Lipogenesis , Lipolysis , Animals , Glucocorticoids/genetics , Glucocorticoids/metabolism , Humans
3.
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
4.
Cells ; 10(11)2021 10 28.
Article in English | MEDLINE | ID: covidwho-1512134

ABSTRACT

For more than 70 years, glucocorticoids (GCs) have been a powerful and affordable treatment option for inflammatory diseases. However, their benefits do not come without a cost, since GCs also cause side effects. Therefore, strong efforts are being made to improve their therapeutic index. In this review, we illustrate the mechanisms and target cells of GCs in the pathogenesis and treatment of some of the most frequent inflammatory disorders affecting the central nervous system, the gastrointestinal tract, the lung, and the joints, as well as graft-versus-host disease, which often develops after hematopoietic stem cell transplantation. In addition, an overview is provided of novel approaches aimed at improving GC therapy based on chemical modifications or GC delivery using nanoformulations. GCs remain a topic of highly active scientific research despite being one of the oldest class of drugs in medical use.


Subject(s)
Glucocorticoids/metabolism , Inflammation/metabolism , Animals , Disease Models, Animal , Humans , Inflammation/pathology , Models, Biological , Nanoparticles/chemistry , Phenotype
5.
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
6.
Int J Mol Sci ; 22(15)2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1344938

ABSTRACT

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.


Subject(s)
Disease Resistance , Glucocorticoids/metabolism , Hypothalamo-Hypophyseal System/metabolism , Hypoxia, Brain/metabolism , Ischemic Preconditioning , Pituitary-Adrenal System/metabolism , Signal Transduction , Animals , Humans , Hypothalamo-Hypophyseal System/pathology , Hypoxia, Brain/prevention & control , Pituitary-Adrenal System/pathology
7.
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 therapy , 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
9.
J Pharmacol Exp Ther ; 375(3): 398-405, 2020 12.
Article in English | MEDLINE | ID: covidwho-810772

ABSTRACT

Glucocorticoids are extensively used for a variety of conditions, including those associated with dysregulation of immune and inflammatory responses as primary etiopathogenic factors. Indeed, the proinflammatory cytokine storm of coronavirus disease 2019 (COVID-19) is the latest condition for which the use of a glucocorticoid has been advocated. Recognition of serious adverse effects of glucocorticoids has led to research aimed at unraveling molecular basis by which they impact immune and inflammatory events with the ultimate objective of devising novel therapies to circumvent glucocorticoids-related adverse outcomes. Consequently, glucocorticoid-induced leucine zipper (GILZ) protein was discovered and is increasingly recognized as the pivotal regulator of the effects of glucocorticoids on immune and inflammatory responses. Importantly, the advent of GILZ-based options raises the prospect of their eventual therapeutic use for a variety of conditions accompanied with dysregulation of immune and inflammatory responses and associated target organ complications. Thus, the objective of this minireview is to describe our current understanding of the role of GILZ in the cardiovascular system and the kidney along with outcome of GILZ-based interventions on associated disorders. This information is also of relevance for emerging complications of COVID-19. SIGNIFICANCE STATEMENT: Glucocorticoid-induced leucine zipper (GILZ) was initially discovered as the pivotal mediator of immune regulatory/suppressive effects of glucocorticoids. Since the use of glucocorticoids is associated with serious adverse effects, GILZ-based formulations could offer therapeutic advantages. Thus, this minireview will describe our current understanding of the role of GILZ in the kidney and the cardiovascular system, which is of relevance and significance for pathologies affecting them, including the multiorgan complications of coronavirus disease 2019.


Subject(s)
COVID-19/metabolism , Cardio-Renal Syndrome/complications , Cardiovascular System/metabolism , Coronavirus/metabolism , Kidney/metabolism , Transcription Factors/metabolism , Animals , COVID-19/complications , COVID-19/therapy , Gene Expression Regulation , Glucocorticoids/metabolism , Humans , Leucine Zippers , Macrophages/metabolism , Protein Transport , RNA, Messenger , Toll-Like Receptors/metabolism
11.
J Allergy Clin Immunol ; 146(2): 330-331, 2020 08.
Article in English | MEDLINE | ID: covidwho-597639
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