| The nitric oxide-donating pravastatin, NCX 6550, inhibits cytokine release and NF-κB activation while enhancing PPARγ expression in human monocyte/macrophages. | |
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MedLine Citation:
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PMID: 20670683 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Previous studies have shown that NCX 6550 (NCX), a nitric oxide (NO)-donating pravastatin, induces anti-inflammatory effects in murine macrophage cell lines. Here, we have studied its activity in human monocyte/macrophages, by investigating cytokine release, NF-κB translocation and peroxisome proliferator-activated receptor γ (PPARγ) expression and function. For comparison, pravastatin, isosorbide-5-mononitrate (ISMN), sodium nitroprusside (SNP) and the PPARγ ligand 15-deoxy-Δ(12,14)-prostaglandin J(2) (PGJ) were also tested. Monocytes and macrophages (MDM: monocyte-derived macrophages) were isolated from healthy donors; cytokine release was measured by ELISA, NF-κB by electrophoretic mobility shift assay and PPARγ by Western blot and Real-Time PCR. NCX (1 nM-50 μM) dose-dependently inhibited phorbol 12-myristate 13-acetate (PMA)-induced TNF-α release from monocytes (IC(50)=240 nM) and MDM (IC(50)=52 nM). At 50 μM, it was more effective than pravastatin, ISMN and SNP (P<0.05), but less efficient than PGJ. Similar results were obtained for IL-6. Likewise, NCX was more effective than pravastatin and the other NO donors in inhibiting PMA-induced NF-κB translocation in both cell types, and, at the highest concentration, significantly (P<0.05) enhanced PPARγ protein expression in monocytes. We conclude that NCX 6550 exerts a significant anti-inflammatory activity in human monocyte/macrophages, that is also contributed by its NO donating properties, as the effects exerted by NCX are significantly higher than those evoked by pravastatin in many experimental assays. These data further indicate that the incorporation of a NO-donating moiety into a statin structure confers pharmacological properties which may translate into useful therapeutic benefits. |
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Authors:
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Angela Amoruso; Claudio Bardelli; Luigia Grazia Fresu; Elisa Poletti; Alessandra Palma; Donata Federici Canova; Hua Wu Zeng; Ennio Ongini; Sandra Brunelleschi |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-27 |
Journal Detail:
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Title: Pharmacological research : the official journal of the Italian Pharmacological Society Volume: 62 ISSN: 1096-1186 ISO Abbreviation: Pharmacol. Res. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-09-27 Completed Date: 2011-03-14 Revised Date: 2011-12-08 |
Medline Journal Info:
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Nlm Unique ID: 8907422 Medline TA: Pharmacol Res Country: England |
Other Details:
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Languages: eng Pagination: 391-9 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Medical Sciences, School of Medicine, University A. Avogadro, Via Solaroli 17, 28100 Novara, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents, Non-Steroidal / pharmacology Cytokines / metabolism* Dose-Response Relationship, Drug Humans Interleukin-6 / metabolism Macrophages / cytology, drug effects*, metabolism Mice Monocytes / drug effects*, metabolism NF-kappa B / antagonists & inhibitors, metabolism* Nitrates / pharmacology* Nitric Oxide / metabolism Nitric Oxide Donors / pharmacology PPAR gamma / metabolism* Pravastatin / analogs & derivatives*, pharmacology Superoxides / metabolism Tumor Necrosis Factor-alpha / metabolism |
| Chemical | |
Reg. No./Substance:
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0/1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid 4-(nitrooxy)butyl ester; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cytokines; 0/Interleukin-6; 0/NF-kappa B; 0/Nitrates; 0/Nitric Oxide Donors; 0/PPAR gamma; 0/Tumor Necrosis Factor-alpha; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 81093-37-0/Pravastatin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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