The severity of SARS-CoV-2 infection in K18-hACE2 mice is attenuated by a novel steroid-derivative in a gender-specific manner.
CD169+ macrophages
COVID-19
IBA-1 immunoreactive macrophage-dendritic cells
RNA scope
lung damage
mortality
survival
weight loss
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
18
05
2023
received:
29
11
2022
accepted:
19
05
2023
medline:
12
9
2023
pubmed:
1
6
2023
entrez:
31
5
2023
Statut:
ppublish
Résumé
COVID-19 infections caused by SARS-CoV-2 disseminated through human-to-human transmission can evoke severe inflammation. Treatments to reduce the SARS-CoV-2-associated inflammation are needed and are the focus of much research. In this study, we investigated the effect of N-ethyl-N'-[(3β,5α)-17-oxoandrostan-3-yl] urea (NEOU), a novel 17α-ketosteroid derivative, on the severity of COVID-19 infections. Studies were conducted in SARS-CoV-2-infected K18-hACE2 mice. SARS-CoV-2-infected K18-hACE2 mice developed severe inflammatory crises and immune responses along with up-regulation of genes in associated signalling pathways in male more than female mice. Notably, SARS-CoV-2 infection down-regulated genes encoding drug metabolizing cytochrome P450 enzymes in male but not female mice. Treatment with NEOU (1 mg·kg These findings demonstrate that SARS-CoV-2 exhibits gender bias by differentially regulating genes encoding inflammatory cytokines, immunogenic factors and drug-metabolizing enzymes, in male versus female mice. Most importantly, we identified a novel 17α-ketosteroid that reduces the severity of COVID-19 infection and could be beneficial for reducing impact of COVID-19.
Sections du résumé
BACKGROUND AND PURPOSE
COVID-19 infections caused by SARS-CoV-2 disseminated through human-to-human transmission can evoke severe inflammation. Treatments to reduce the SARS-CoV-2-associated inflammation are needed and are the focus of much research. In this study, we investigated the effect of N-ethyl-N'-[(3β,5α)-17-oxoandrostan-3-yl] urea (NEOU), a novel 17α-ketosteroid derivative, on the severity of COVID-19 infections.
EXPERIMENTAL APPROACH
Studies were conducted in SARS-CoV-2-infected K18-hACE2 mice.
KEY RESULTS
SARS-CoV-2-infected K18-hACE2 mice developed severe inflammatory crises and immune responses along with up-regulation of genes in associated signalling pathways in male more than female mice. Notably, SARS-CoV-2 infection down-regulated genes encoding drug metabolizing cytochrome P450 enzymes in male but not female mice. Treatment with NEOU (1 mg·kg
CONCLUSIONS AND IMPLICATIONS
These findings demonstrate that SARS-CoV-2 exhibits gender bias by differentially regulating genes encoding inflammatory cytokines, immunogenic factors and drug-metabolizing enzymes, in male versus female mice. Most importantly, we identified a novel 17α-ketosteroid that reduces the severity of COVID-19 infection and could be beneficial for reducing impact of COVID-19.
Substances chimiques
K-18 conjugate
0
Steroids
0
Ketosteroids
0
Cytokines
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2677-2693Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL085352
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132574
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL166546
Pays : United States
Informations de copyright
© 2023 British Pharmacological Society.
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