HYCO-3, a dual CO-releaser/Nrf2 activator, reduces tissue inflammation in mice challenged with lipopolysaccharide
| Autor: | Jayne Louise Wilson, Roberto Motterlini, Lucie Muchová, Thierry Martens, Aniket Nikam, Anthony Ollivier, Sylvie Manin, Roberta Foresti, Sabrina Djouadi, Michael Rivard |
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| Přispěvatelé: | Institut de Chimie et des Matériaux Paris-Est (ICMPE), Institut de Chimie du CNRS (INC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine Lipopolysaccharide NQO1 NAD(P)H:quinone oxidoreductase 1 Clinical Biochemistry Anti-Inflammatory Agents Gene Expression AST aspartate aminotransferase Pharmacology medicine.disease_cause Nrf2 nuclear factor erythroid 2-related factor 2 TNF-α tumor necrosis factor-α Biochemistry Antioxidants Dual-activity molecules Mice chemistry.chemical_compound ARG1 arginase 1 CO-RMs CO-releasing molecules 0302 clinical medicine LC-MS/MS liquid chromatography-tandem mass spectrometry EPF ethyl prop-2-yn-1-yl fumarate IL-6 interleukin-6 lcsh:QH301-705.5 Cells Cultured ComputingMilieux_MISCELLANEOUS Mice Knockout lcsh:R5-920 M2 anti-inflammatory macrophages Carbon Monoxide LDH lactate dehydrogenase Dimethyl fumarate IL-10 interleukin-10 [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences HMOX1 heme oxygenase-1 gene 3. Good health Nrf2 activators CO carbon monoxide iNOS inducible nitric oxide synthase LPS lipopolysaccharide Cytokines Microglia Inflammation Mediators medicine.symptom lcsh:Medicine (General) Research Paper M1 pro-inflammatory macrophages IL-1β interleukin-1β NF-E2-Related Factor 2 GCLC glutamate cysteine ligase C Carbon monoxide (CO) Inflammation HO-1 heme oxygenase-1 protein GCLM glutamate cysteine ligase M 03 medical and health sciences In vivo ALT alanine aminotransferase medicine Animals [CHIM.COOR]Chemical Sciences/Coordination chemistry ARG1 MCP-1/CCL2 monocyte chemoattractant protein-1 ALP alkaline phosphatase Macrophage phenotype Activator (genetics) Macrophages Organic Chemistry In vitro Disease Models Animal Oxidative Stress 030104 developmental biology lcsh:Biology (General) chemistry HYCOs HYbrid CO-releasing molecules COHb carbonmonoxy hemoglobin Heme Oxygenase-1 030217 neurology & neurosurgery Oxidative stress Hb hemoglobin |
| Zdroj: | Redox Biology Redox Biology, Elsevier, 2019, 20, pp.334-348. ⟨10.1016/j.redox.2018.10.020⟩ Redox Biology, Vol 20, Iss, Pp 334-348 (2019) |
| ISSN: | 2213-2317 |
| DOI: | 10.1016/j.redox.2018.10.020⟩ |
| Popis: | 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-/- mice, indicating that the CO-releasing part of this hybrid contributes to reduction of pro-inflammation and that this effect is organ-specific. These data demonstrate that the dual activity of HYCO-3 results in enhanced efficacy compared to the parent compounds indicating the potential exploitation of hybrid compounds in the development of effective anti-inflammatory therapies. Graphical abstract fx1 Highlights • HYCO-3 is a novel hybrid between an Nrf2 activator and a CO-releasing molecule. • HYCO-3 induces Nrf2 and simultaneously delivers CO in vitro and in vivo. • Oral administration of HYCO-3 reduces inflammation in mice challenged with LPS. • In Nrf2-/- mice, the anti-inflammatory action of HYCO-3 is organ specific. |
| Databáze: | OpenAIRE |
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