Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis.
CO-Releasing molecules (CO-RMs)
Carbon monoxide (CO)
Heme oxygenase-1 (HO-1)
Hybrid molecules
Inflammation
Nrf2
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
13
03
2020
accepted:
23
03
2020
pubmed:
27
4
2020
medline:
22
6
2021
entrez:
27
4
2020
Statut:
ppublish
Résumé
Carbon monoxide (CO) produced by heme oxygenase-1 (HO-1) or delivered by CO-releasing molecules (CO-RMs) exerts anti-inflammatory action, a feature also exhibited by the nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the stress response. We have recently developed new hybrid molecules (HYCOs) consisting of CO-RMs conjugated to fumaric esters known to activate Nrf2/HO-1. Here we evaluated the biological activities of manganese (Mn) and ruthenium (Ru)-based HYCOs in human monocytes and keratinocytes in vitro as well as in vivo models of inflammation. The effects of HYCOs were compared to: a) dimethyl fumarate (DMF), a known fumaric ester used in the clinic; b) a CO-RM alone; or c) the combination of the two compounds. Mn-HYCOs donated CO and up-regulated Nrf2/HO-1 in vitro more efficiently than Ru-HYCOs. However, irrespective of the metal, a strong reduction in anti-inflammatory markers in monocytes stimulated by LPS was observed with specific HYCOs. This effect was not observed with DMF, CO-RM alone or the combination of the two, indicating the enhanced potency of HYCOs compared to the separate entities. Selected HYCOs given orally to mice accelerated skin wound closure, reduced psoriasis-mediated inflammation and disease symptoms equalling or surpassing the effect of DMF, and ameliorated motor dysfunction in a mouse model of multiple sclerosis. Thus, HYCOs have potent anti-inflammatory activities that are recapitulated in disease models in which inflammation is a prominent component. Prolonged daily administration of HYCOs (up to 40 days) is well tolerated in animals. Our results clearly confirm that HYCOs possess a dual mode of action highlighting the notion that simultaneous Nrf2 targeting and CO delivery could be a clinically relevant application to combat inflammation.
Identifiants
pubmed: 32335359
pii: S2213-2317(20)30432-8
doi: 10.1016/j.redox.2020.101521
pmc: PMC7184182
pii:
doi:
Substances chimiques
Membrane Proteins
0
NF-E2-Related Factor 2
0
Nfe2l2 protein, mouse
0
Heme Oxygenase-1
EC 1.14.14.18
Hmox1 protein, mouse
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
101521Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
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