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Endogenous Generation and Signaling Actions of Omega-3 Fatty Acid Electrophilic Derivatives.

Cipollina C - Biomed Res Int (2015)

Bottom Line: Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects.Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop.The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Fondazione Ri.MED, Palermo, Italy ; Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche, 90146 Palermo, Italy.

ABSTRACT
Dietary omega-3 polyunsaturated fatty acids (PUFAs) are beneficial for a number of conditions ranging from cardiovascular disease to chronic airways disorders, neurodegeneration, and cancer. Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects. Electrophilic oxo-derivatives of omega-3 PUFAs represent a class of oxidized derivatives that can be generated via enzymatic and nonenzymatic pathways. Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop. Endogenous generation of electrophilic oxo-derivatives of omega-3 PUFAs has been observed in in vitro and ex vivo human models and dietary supplementation of omega-3 PUFAs has been reported to increase their formation. Due to the presence of an α,β-unsaturated ketone moiety, these compounds covalently and reversibly react with nucleophilic residues on target proteins triggering the activation of cytoprotective pathways, including the Nrf2 antioxidant response, the heat shock response, and the peroxisome proliferator activated receptor γ (PPARγ) and suppressing the NF-κB proinflammatory pathway. The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

No MeSH data available.


Related in: MedlinePlus

Enzymatic generation of electrophilic ketoderivatives of EPA (a), DHA (b), and DPA (c). Cox-2, cyclooxygenase-2; PGDS, prostaglandin D synthase; 5-LO, 5-lipoxygenase; 5-HEDH, 5-hydroxyeicosanoid dehydrogenase; deH, cellular dehydrogenases.
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fig2: Enzymatic generation of electrophilic ketoderivatives of EPA (a), DHA (b), and DPA (c). Cox-2, cyclooxygenase-2; PGDS, prostaglandin D synthase; 5-LO, 5-lipoxygenase; 5-HEDH, 5-hydroxyeicosanoid dehydrogenase; deH, cellular dehydrogenases.

Mentions: Endogenous generation of electrophilic α,β-unsaturated derivatives of omega-3 PUFAs has been reported in several cell types. In activated macrophages, 13-oxo-derivatives of DHA and DPA are formed in two enzymatic steps involving Cox-2 and a cellular dehydrogenase. In the presence of aspirin, Cox-2 converts DHA and DPA into 17-OH-derivatives which are then oxidized to 17-oxo-DHA and 17-oxo-DPA (Figure 2) [14]. Primary alveolar epithelial cells (AEC) supplemented with DHA generate the electrophilic 14-oxo-DHA via a 15-PGDH dependent mechanism [52]. These electrophilic compounds display anti-inflammatory and cytoprotective properties [12, 14]. When using EPA as substrate, Cox-2 catalyses the conversion of this omega-3 PUFA into PGH3 which is further metabolized to 3-series prostaglandins. In aqueous environment, PGD3 undergoes two nonenzymatic dehydration steps to give the electrophilic cyclopentenone-containing 15d-PGJ3 (Figure 2) [15, 16]. In human neutrophils, 5-LO-dependent generation of electrophilic 5-oxo-EPA, 7-oxo-DHA, and 7-oxo-DPA has been reported to be increased upon dietary supplementation with the precursors DHA and EPA (Figure 2) providing evidence that endogenous generation of electrophilic derivatives of omega-3 PUFAs can be effectively modulated through dietary interventions [9, 53].


Endogenous Generation and Signaling Actions of Omega-3 Fatty Acid Electrophilic Derivatives.

Cipollina C - Biomed Res Int (2015)

Enzymatic generation of electrophilic ketoderivatives of EPA (a), DHA (b), and DPA (c). Cox-2, cyclooxygenase-2; PGDS, prostaglandin D synthase; 5-LO, 5-lipoxygenase; 5-HEDH, 5-hydroxyeicosanoid dehydrogenase; deH, cellular dehydrogenases.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538325&req=5

fig2: Enzymatic generation of electrophilic ketoderivatives of EPA (a), DHA (b), and DPA (c). Cox-2, cyclooxygenase-2; PGDS, prostaglandin D synthase; 5-LO, 5-lipoxygenase; 5-HEDH, 5-hydroxyeicosanoid dehydrogenase; deH, cellular dehydrogenases.
Mentions: Endogenous generation of electrophilic α,β-unsaturated derivatives of omega-3 PUFAs has been reported in several cell types. In activated macrophages, 13-oxo-derivatives of DHA and DPA are formed in two enzymatic steps involving Cox-2 and a cellular dehydrogenase. In the presence of aspirin, Cox-2 converts DHA and DPA into 17-OH-derivatives which are then oxidized to 17-oxo-DHA and 17-oxo-DPA (Figure 2) [14]. Primary alveolar epithelial cells (AEC) supplemented with DHA generate the electrophilic 14-oxo-DHA via a 15-PGDH dependent mechanism [52]. These electrophilic compounds display anti-inflammatory and cytoprotective properties [12, 14]. When using EPA as substrate, Cox-2 catalyses the conversion of this omega-3 PUFA into PGH3 which is further metabolized to 3-series prostaglandins. In aqueous environment, PGD3 undergoes two nonenzymatic dehydration steps to give the electrophilic cyclopentenone-containing 15d-PGJ3 (Figure 2) [15, 16]. In human neutrophils, 5-LO-dependent generation of electrophilic 5-oxo-EPA, 7-oxo-DHA, and 7-oxo-DPA has been reported to be increased upon dietary supplementation with the precursors DHA and EPA (Figure 2) providing evidence that endogenous generation of electrophilic derivatives of omega-3 PUFAs can be effectively modulated through dietary interventions [9, 53].

Bottom Line: Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects.Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop.The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Fondazione Ri.MED, Palermo, Italy ; Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche, 90146 Palermo, Italy.

ABSTRACT
Dietary omega-3 polyunsaturated fatty acids (PUFAs) are beneficial for a number of conditions ranging from cardiovascular disease to chronic airways disorders, neurodegeneration, and cancer. Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects. Electrophilic oxo-derivatives of omega-3 PUFAs represent a class of oxidized derivatives that can be generated via enzymatic and nonenzymatic pathways. Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop. Endogenous generation of electrophilic oxo-derivatives of omega-3 PUFAs has been observed in in vitro and ex vivo human models and dietary supplementation of omega-3 PUFAs has been reported to increase their formation. Due to the presence of an α,β-unsaturated ketone moiety, these compounds covalently and reversibly react with nucleophilic residues on target proteins triggering the activation of cytoprotective pathways, including the Nrf2 antioxidant response, the heat shock response, and the peroxisome proliferator activated receptor γ (PPARγ) and suppressing the NF-κB proinflammatory pathway. The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

No MeSH data available.


Related in: MedlinePlus