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Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy.

ABSTRACT: Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Here, the first structure of serum albumin in complex with dexamethasone is reported. Dexamethasone binds to drug site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with an analysis of publicly available clinical data from Wuhan and suggests that an adjustment of the dexamethasone regimen should be further investigated as a strategy for patients affected by two major COVID-19 risk factors: low albumin levels and diabetes.

SUBMITTER: Shabalin IG

PROVIDER: S-EPMC7553145 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy.

Project description:Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Herein, we report the first structure of serum albumin in complex with dexamethasone. We show that it binds to Drug Site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with our analysis of publicly available clinical data from Wuhan and suggests that an adjustment of dexamethasone regimen should be considered for patients affected by two major COVID-19 risk-factors: low albumin levels and diabetes.

| S-EPMC7386489 | biostudies-literature

Inferring molecular mechanisms of dexamethasone therapy in severe COVID-19 from existing transcriptomic data.

Project description:Dexamethasone, a synthetic glucocorticoid, has previously shown mortality benefit in severe coronavirus disease 2019 (COVID-19) in a randomized controlled trial. As the illness is considered to reflect a hyperinflammatory state, this therapeutic effectiveness is presumably ascribed to broad anti-inflammatory activities of glucocorticoids. Here, an unbiased analysis of available transcriptomic data on lung and blood immune cells from severe COVID-19 patients and matching cellular models of dexamethasone treatment is presented that supports this presumption. Comparison of differentially expressed genes in severe COVID-19 with that in dexamethasone treated cells reveals a small set of genes that are regulated in opposite direction between the disease and the drug, and are enriched for genes and processes related to glucocorticoid pathway and receptor binding. This expression signature differentiates as a whole various cytokines from a set of anti-cytokine/anti-inflammatory agents, with the former resembling COVID-19 and the latter dexamethasone in gene regulation. The signature apparently relates to TNF- α, IL-1α, IL-1β, IFN-α, IFN-β, and IFN-γ signaling, but not IL-6 signaling, suggesting that therapeutic effect of dexamethasone in COVID-19 does not involve IL-6 pathway. However, as all these observations are purely based on bioinformatic analysis, experimental evidence will be required to validate the inferences drawn. In conclusion, the present analysis seems to provide a proof of concept for therapeutic mechanisms of dexamethasone in COVID-19.

| S-EPMC8054526 | biostudies-literature

Effects of Dexamethasone in COVID-19 patients

Project description:Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward in several centers in Greece and the Netherlands and whole blood transcriptomic analysis was performed before and after starting dexamethasone treatment. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and their transcriptome was assessed.

2023-07-26 | GSE227585 | GEO

Chemocentric Informatics Analysis: Dexamethasone <i>Versus</i> Combination Therapy for COVID-19.

Project description:COVID-19 is a biphasic infectious disease with no approved vaccine or pharmacotherapy. The first drug that has shown promise in reducing COVID-19 mortality in severely-ill patients is dexamethasone, a cheap, well-known anti-inflammatory glucocorticoid, approved for the treatment of inflammatory conditions including respiratory diseases such as asthma and tuberculosis. However, about 80% of COVID-19 patients requiring oxygenation, and about 67% of patients on ventilators, are not responsive to dexamethasone therapy mainly. Additionally, using higher doses of dexamethasone for prolonged periods of time can lead to severe side effects and some patients may develop corticosteroid resistance leading to treatment failure. In order to increase the therapeutic efficacy of dexamethasone in COVID-19 patients, while minimizing dexamethasone-related complications that could result from using higher doses of the drug, we applied a chemocentric informatics approach to identify combination therapies. Our results indicated that combining dexamethasone with fast long-acting beta-2 adrenergic agonists (LABAs), such as formoterol and salmeterol, can ease respiratory symptoms hastily, until dexamethasone's anti-inflammatory and immunosuppressant effects kick in. Our studies demonstrated that LABAs and dexamethasone (or other glucocorticoids) exert synergistic effects that will augment both anti-inflammatory and fibronectin-mediated anticoagulant effects. We also propose other alternatives to LABAs that are supported by sound systems biology evidence, such as nitric oxide. Other drugs such as sevoflurane and treprostinil interact with the SARS-CoV-2 interactome and deserve further exploration. Moreover, our chemocentric informatics approach provides systems biology evidence that combination therapies for COVID-19 will have higher chances of perturbing the SARS-CoV-2 human interactome, which may negatively impact COVID-19 disease pathways.

| S-EPMC7689662 | biostudies-literature

Molecular and functional resemblance of dexamethasone and quercetin: A paradigm worth exploring in dexamethasone-nonresponsive COVID-19 patients.

Project description: Not available

| S-EPMC7537236 | biostudies-literature

Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

Project description:While critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during COVID-19 ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using scRNA-seq and plasma proteomics, we discovered that compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin (PG) signalling. Dexamethasone during severe COVID-19 depleted circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated gene, and activated IL1R2+ve neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils, preferential steroid-induced immature neutrophil expansion, and possibly different effects on outcome. Our single-cell atlas (www.biernaskielab.ca/COVID_neutrophil) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.

2021-10-05 | GSE157789 | GEO

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-05 | GSE237180 | GEO

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19

Project description:Dexamethasone is the standard of care for critically ill patients with COVID-19, but its immunological effects in this setting and the mechanisms by which it decreases mortality are not understood. We performed bulk and single-cell RNA sequencing of the lower respiratory tract and blood, and plasma cytokine profiling to study the effect of dexamethasone on systemic and pulmonary immune cells. We find signatures of decreased viral injury, antigen presentation, and T cell recruitment in patients treated with dexamethasone. We identify compartment- and cell- specific differences in the effect of dexamethasone in patients with severe COVID that are reproducible in publicly available datasets. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.

2024-05-05 | GSE237109 | GEO

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19

2024-05-05 | GSE236030 | GEO

COVID-19, myocardial edema and dexamethasone.

Project description:Severe acute respiratory syndrome corona virus 2(SARS-CoV-2), the cause of coronavirus disease- 2019 (COVID-19) after emerging in china in late 2019 is spreading rapidly across the world. The most common cause of death in patient with COVID-19 is the rapid progression of acute respiratory distress syndrome (ARDS) shortly after the beginning of dyspnea and hypoxemia. Patients with severe COVID-19 may also develop acute cardiac, kidney and liver injury that are associated with poor prognosis and can lead to high mortality rate. Numerous randomized trials are ongoing to find an effective, safe and widely available treatment. Remdisivir is the only FDA -approved antiviral agent for treatment of severe COVID-19. Glucocorticoids (GCs) have been used for treatment of cytokine storm syndrome and respiratory failure in hospitalized patient with severe covid-19. One of the therapeutic effects of GCs is stability of vascular endothelial barrier and decreasing tissue edema. In our opinion, the decreasing vascular permeability effect of glucocorticoids in the injured myocardium might has an important additional factor in reducing mortality in severe, hospitalized COVID-19 patients.

| S-EPMC7834646 | biostudies-literature

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