HYCO-3, a dual CO-releaser/Nrf2 activator, reduces tissue inflammation in mice challenged with lipopolysaccharide.
Animals
Anti-Inflammatory Agents
/ pharmacology
Antioxidants
/ metabolism
Carbon Monoxide
/ metabolism
Cells, Cultured
Cytokines
/ genetics
Disease Models, Animal
Gene Expression
Heme Oxygenase-1
/ genetics
Inflammation
/ drug therapy
Inflammation Mediators
/ metabolism
Lipopolysaccharides
/ adverse effects
Macrophages
/ drug effects
Male
Mice
Mice, Knockout
Microglia
/ drug effects
NF-E2-Related Factor 2
/ genetics
Oxidative Stress
/ drug effects
Carbon monoxide (CO)
Dual-activity molecules
Inflammation
Macrophage phenotype
Nrf2 activators
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
21
09
2018
revised:
12
10
2018
accepted:
23
10
2018
pubmed:
6
11
2018
medline:
22
3
2019
entrez:
5
11
2018
Statut:
ppublish
Résumé
Oxidative stress and inflammation are predominant features of several chronic diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a major arbiter in counteracting these insults via up-regulation of several defensive proteins, including heme oxygenase-1 (HO-1). HO-1-derived carbon monoxide (CO) exhibits anti-inflammatory actions and can be delivered to tissues by CO-releasing agents. In this study we assessed the pharmacological and anti-inflammatory properties of HYCO-3, a dual activity compound obtained by conjugating analogues of the CO-releasing molecule CORM-401 and dimethyl fumarate (DMF), an immunomodulatory drug known to activate Nrf2. HYCO-3 induced Nrf2-dependent genes and delivered CO to cells in vitro and tissues in vivo, confirming that the two expected pharmacological properties of this agent are achieved. In mice challenged with lipopolysaccharide, orally administered HYCO-3 reduced the mRNA levels of pro-inflammatory markers (TNF-α, IL-1β and IL-6) while increasing the expression of the anti-inflammatory genes ARG1 and IL-10 in brain, liver, lung and heart. In contrast, DMF or CORM-401 alone or their combination decreased the expression of pro-inflammatory genes but had limited influence on anti-inflammatory markers. Furthermore, HYCO-3 diminished TNF-α and IL-1β in brain and liver but not in lung and heart of Nrf2
Identifiants
pubmed: 30391826
pii: S2213-2317(18)30869-3
doi: 10.1016/j.redox.2018.10.020
pmc: PMC6223233
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Antioxidants
0
Cytokines
0
Inflammation Mediators
0
Lipopolysaccharides
0
NF-E2-Related Factor 2
0
Carbon Monoxide
7U1EE4V452
Heme Oxygenase-1
EC 1.14.14.18
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
334-348Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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