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Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives.
PLoS One 2014; 9(4):e94836Plos

Abstract

Dietary ω-3 polyunsaturated fatty acids (PUFAs) decrease cardiovascular risk via suppression of inflammation. The generation of electrophilic α,β-unsaturated ketone derivatives of the ω-3 PUFAs docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) in activated human macrophages is catalyzed by cyclooxygenase-2 (Cox-2). These derivatives are potent pleiotropic anti-inflammatory signaling mediators that act via mechanisms including the activation of Nrf2-dependent phase 2 gene expression and suppression of pro-inflammatory NF-κB-driven gene expression. Herein, the endogenous generation of ω-3 PUFAs electrophilic ketone derivatives and their hydroxy precursors was evaluated in human neutrophils. In addition, their dietary modulation was assessed through a randomized clinical trial.

METHODS

Endogenous generation of electrophilic omega-3 PUFAs and their hydroxy precursors was evaluated by mass spectrometry in neutrophils isolated from healthy subjects, both at baseline and upon stimulation with calcium ionophore. For the clinical trial, participants were healthy adults 30-55 years of age with a reported EPA+DHA consumption of ≤300 mg/day randomly assigned to parallel groups receiving daily oil capsule supplements for a period of 4 months containing either 1.4 g of EPA+DHA (active condition, n = 24) or identical appearing soybean oil (control condition, n = 21). Participants and laboratory technicians remained blinded to treatment assignments.

RESULTS

5-lypoxygenase-dependent endogenous generation of 7-oxo-DHA, 7-oxo-DPA and 5-oxo-EPA and their hydroxy precursors is reported in human neutrophils stimulated with calcium ionophore and phorbol 12-myristate 13-acetate (PMA). Dietary EPA+DHA supplementation significantly increased the formation of 7-oxo-DHA and 5-oxo-EPA, with no significant modulation of arachidonic acid (AA) metabolite levels.

CONCLUSIONS

The endogenous detection of these electrophilic ω-3 fatty acid ketone derivatives supports the precept that the benefit of ω-3 PUFA-rich diets can be attributed to the generation of electrophilic oxygenated metabolites that transduce anti-inflammatory actions rather than the suppression of pro-inflammatory AA metabolites.

TRIAL REGISTRATION

ClinicalTrials.gov NCT00663871.

Authors+Show Affiliations

Fondazione Ri.Med, Palermo, Italy; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh Pennsylvania, United States of America.Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

24736647

Citation

Cipollina, Chiara, et al. "Generation and Dietary Modulation of Anti-inflammatory Electrophilic Omega-3 Fatty Acid Derivatives." PloS One, vol. 9, no. 4, 2014, pp. e94836.
Cipollina C, Salvatore SR, Muldoon MF, et al. Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. PLoS ONE. 2014;9(4):e94836.
Cipollina, C., Salvatore, S. R., Muldoon, M. F., Freeman, B. A., & Schopfer, F. J. (2014). Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. PloS One, 9(4), pp. e94836. doi:10.1371/journal.pone.0094836.
Cipollina C, et al. Generation and Dietary Modulation of Anti-inflammatory Electrophilic Omega-3 Fatty Acid Derivatives. PLoS ONE. 2014;9(4):e94836. PubMed PMID: 24736647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. AU - Cipollina,Chiara, AU - Salvatore,Sonia R, AU - Muldoon,Matthew F, AU - Freeman,Bruce A, AU - Schopfer,Francisco J, Y1 - 2014/04/15/ PY - 2013/09/27/received PY - 2014/03/19/accepted PY - 2014/4/17/entrez PY - 2014/4/17/pubmed PY - 2015/1/16/medline SP - e94836 EP - e94836 JF - PloS one JO - PLoS ONE VL - 9 IS - 4 N2 - UNLABELLED: Dietary ω-3 polyunsaturated fatty acids (PUFAs) decrease cardiovascular risk via suppression of inflammation. The generation of electrophilic α,β-unsaturated ketone derivatives of the ω-3 PUFAs docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) in activated human macrophages is catalyzed by cyclooxygenase-2 (Cox-2). These derivatives are potent pleiotropic anti-inflammatory signaling mediators that act via mechanisms including the activation of Nrf2-dependent phase 2 gene expression and suppression of pro-inflammatory NF-κB-driven gene expression. Herein, the endogenous generation of ω-3 PUFAs electrophilic ketone derivatives and their hydroxy precursors was evaluated in human neutrophils. In addition, their dietary modulation was assessed through a randomized clinical trial. METHODS: Endogenous generation of electrophilic omega-3 PUFAs and their hydroxy precursors was evaluated by mass spectrometry in neutrophils isolated from healthy subjects, both at baseline and upon stimulation with calcium ionophore. For the clinical trial, participants were healthy adults 30-55 years of age with a reported EPA+DHA consumption of ≤300 mg/day randomly assigned to parallel groups receiving daily oil capsule supplements for a period of 4 months containing either 1.4 g of EPA+DHA (active condition, n = 24) or identical appearing soybean oil (control condition, n = 21). Participants and laboratory technicians remained blinded to treatment assignments. RESULTS: 5-lypoxygenase-dependent endogenous generation of 7-oxo-DHA, 7-oxo-DPA and 5-oxo-EPA and their hydroxy precursors is reported in human neutrophils stimulated with calcium ionophore and phorbol 12-myristate 13-acetate (PMA). Dietary EPA+DHA supplementation significantly increased the formation of 7-oxo-DHA and 5-oxo-EPA, with no significant modulation of arachidonic acid (AA) metabolite levels. CONCLUSIONS: The endogenous detection of these electrophilic ω-3 fatty acid ketone derivatives supports the precept that the benefit of ω-3 PUFA-rich diets can be attributed to the generation of electrophilic oxygenated metabolites that transduce anti-inflammatory actions rather than the suppression of pro-inflammatory AA metabolites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00663871. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24736647/Generation_and_dietary_modulation_of_anti_inflammatory_electrophilic_omega_3_fatty_acid_derivatives_ L2 - http://dx.plos.org/10.1371/journal.pone.0094836 DB - PRIME DP - Unbound Medicine ER -