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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

Signaling pathways modulated by electrophilic lipids. (a) Nrf2-dependent antioxidant response. Under basal conditions, Keap1 binds to Nrf2, sending it to proteasomal degradation via cullin-3-dependent ubiquitination. Electrophilic lipids react with target cysteines on Keap1 inhibiting ubiquitination of Nrf2 and promoting nuclear accumulation of Nrf2 which leads to the activation of ARE-dependent genes; (b) Heat shock response. Under basal conditions, inert Hsf1 is found in the cytoplasm bound with Hsp72 and Hsp90. Electrophiles react with Hsp72 and Hsp90 and promote Hsf1 release, phosphorylation, trimerization, and translocation to the nucleus where Hsf1 activates the transcription of heat shock response genes. (c) NF-κB pathway. Under basal conditions, IKK phosphorylates IκB, causing the release of the heterodimer p50/p65 which translocates to the nucleus and activates a variety of proinflammatory mediators. Electrophiles react with IKK leading to kinase inhibition and blocking NF-κB activation. In addition, covalent reaction of electrophiles with target cysteines in the DNA-binding domain of p65 and p50 inhibits their binding to DNA.
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fig3: Signaling pathways modulated by electrophilic lipids. (a) Nrf2-dependent antioxidant response. Under basal conditions, Keap1 binds to Nrf2, sending it to proteasomal degradation via cullin-3-dependent ubiquitination. Electrophilic lipids react with target cysteines on Keap1 inhibiting ubiquitination of Nrf2 and promoting nuclear accumulation of Nrf2 which leads to the activation of ARE-dependent genes; (b) Heat shock response. Under basal conditions, inert Hsf1 is found in the cytoplasm bound with Hsp72 and Hsp90. Electrophiles react with Hsp72 and Hsp90 and promote Hsf1 release, phosphorylation, trimerization, and translocation to the nucleus where Hsf1 activates the transcription of heat shock response genes. (c) NF-κB pathway. Under basal conditions, IKK phosphorylates IκB, causing the release of the heterodimer p50/p65 which translocates to the nucleus and activates a variety of proinflammatory mediators. Electrophiles react with IKK leading to kinase inhibition and blocking NF-κB activation. In addition, covalent reaction of electrophiles with target cysteines in the DNA-binding domain of p65 and p50 inhibits their binding to DNA.

Mentions: Cells are equipped with highly efficient protective mechanisms to overcome chemical and oxidative insults. These include a large number of detoxification proteins such as phase II enzymes, like NAD(P)H:quinone oxidoreductase 1 (NQO1), the enzymes required for the synthesis and metabolism of glutathione, and the heme oxygenase 1 (HO-1). The expression of these proteins is controlled at their transcriptional level and depends on the presence of a cis-acting promoter element called the antioxidant or electrophile responsive element (ARE/EpRE) which is specifically recognized by the transcriptional factor Nrf2, the master regulator of the inducible antioxidant response [54]. Under basal conditions, Nrf2 binds to its negative regulator, Keap1, an adaptor for the ubiquitin ligase Cul3, which targets Nrf2 to ubiquitination and proteasomal degradation. In response to electrophilic inducers, Keap1-mediated ubiquitination of Nrf2 is inhibited and de novo synthesized Nrf2 protein accumulates in the nucleus [55, 56]. Upon nuclear translocation, Nrf2 forms heterodimers with small Maf proteins and recruits other transcriptional factors required for the activation of ARE elements thus starting its transcriptional program (Figure 3(a)). In human Keap1, Cys-273 and Cys-288 located in the intervening region (IVR) are crucial for basal turnover of Nrf2 [56, 57]. The highly reactive cysteine at position Cys-151, which is 100% conserved between species, appears to be critical for a subset of Nrf2 activators, including the electrophilic sulforaphane and 4-HNE [57, 58]. Cysteine 151 is located in the N-terminal BTB domain of Keap1 which is required for proper interaction with Cul3 [57, 59]. Covalent adduction of electrophiles to Cys-151 inhibits Keap1-mediated ubiquitination of Nrf2 leading to stabilization and nuclear accumulation of newly synthesized protein [56]. The electrophilic Nrf2-inducers 15d-PGJ2 and nitrofatty acids primarily form adducts with Cys-273 and Cys-288 on Keap1, displaying a much lower reactivity towards Cys-151, suggesting that different patterns of cysteine modification can lead to Keap1 inhibition and Nrf2 activation [60, 61]. Nuclear accumulation of Nrf2 and induction of its target genes have been reported in different experimental models in response to several omega-3 PUFAs derived electrophiles, including the DHA-derivatives 4-HHE and 17-oxo-DHA, the DPA-derivative 17-oxo-DPA, and the EPA-derivatives A3/J3-IsoPs [12–14, 62].


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

Cipollina C - Biomed Res Int (2015)

Signaling pathways modulated by electrophilic lipids. (a) Nrf2-dependent antioxidant response. Under basal conditions, Keap1 binds to Nrf2, sending it to proteasomal degradation via cullin-3-dependent ubiquitination. Electrophilic lipids react with target cysteines on Keap1 inhibiting ubiquitination of Nrf2 and promoting nuclear accumulation of Nrf2 which leads to the activation of ARE-dependent genes; (b) Heat shock response. Under basal conditions, inert Hsf1 is found in the cytoplasm bound with Hsp72 and Hsp90. Electrophiles react with Hsp72 and Hsp90 and promote Hsf1 release, phosphorylation, trimerization, and translocation to the nucleus where Hsf1 activates the transcription of heat shock response genes. (c) NF-κB pathway. Under basal conditions, IKK phosphorylates IκB, causing the release of the heterodimer p50/p65 which translocates to the nucleus and activates a variety of proinflammatory mediators. Electrophiles react with IKK leading to kinase inhibition and blocking NF-κB activation. In addition, covalent reaction of electrophiles with target cysteines in the DNA-binding domain of p65 and p50 inhibits their binding to DNA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: Signaling pathways modulated by electrophilic lipids. (a) Nrf2-dependent antioxidant response. Under basal conditions, Keap1 binds to Nrf2, sending it to proteasomal degradation via cullin-3-dependent ubiquitination. Electrophilic lipids react with target cysteines on Keap1 inhibiting ubiquitination of Nrf2 and promoting nuclear accumulation of Nrf2 which leads to the activation of ARE-dependent genes; (b) Heat shock response. Under basal conditions, inert Hsf1 is found in the cytoplasm bound with Hsp72 and Hsp90. Electrophiles react with Hsp72 and Hsp90 and promote Hsf1 release, phosphorylation, trimerization, and translocation to the nucleus where Hsf1 activates the transcription of heat shock response genes. (c) NF-κB pathway. Under basal conditions, IKK phosphorylates IκB, causing the release of the heterodimer p50/p65 which translocates to the nucleus and activates a variety of proinflammatory mediators. Electrophiles react with IKK leading to kinase inhibition and blocking NF-κB activation. In addition, covalent reaction of electrophiles with target cysteines in the DNA-binding domain of p65 and p50 inhibits their binding to DNA.
Mentions: Cells are equipped with highly efficient protective mechanisms to overcome chemical and oxidative insults. These include a large number of detoxification proteins such as phase II enzymes, like NAD(P)H:quinone oxidoreductase 1 (NQO1), the enzymes required for the synthesis and metabolism of glutathione, and the heme oxygenase 1 (HO-1). The expression of these proteins is controlled at their transcriptional level and depends on the presence of a cis-acting promoter element called the antioxidant or electrophile responsive element (ARE/EpRE) which is specifically recognized by the transcriptional factor Nrf2, the master regulator of the inducible antioxidant response [54]. Under basal conditions, Nrf2 binds to its negative regulator, Keap1, an adaptor for the ubiquitin ligase Cul3, which targets Nrf2 to ubiquitination and proteasomal degradation. In response to electrophilic inducers, Keap1-mediated ubiquitination of Nrf2 is inhibited and de novo synthesized Nrf2 protein accumulates in the nucleus [55, 56]. Upon nuclear translocation, Nrf2 forms heterodimers with small Maf proteins and recruits other transcriptional factors required for the activation of ARE elements thus starting its transcriptional program (Figure 3(a)). In human Keap1, Cys-273 and Cys-288 located in the intervening region (IVR) are crucial for basal turnover of Nrf2 [56, 57]. The highly reactive cysteine at position Cys-151, which is 100% conserved between species, appears to be critical for a subset of Nrf2 activators, including the electrophilic sulforaphane and 4-HNE [57, 58]. Cysteine 151 is located in the N-terminal BTB domain of Keap1 which is required for proper interaction with Cul3 [57, 59]. Covalent adduction of electrophiles to Cys-151 inhibits Keap1-mediated ubiquitination of Nrf2 leading to stabilization and nuclear accumulation of newly synthesized protein [56]. The electrophilic Nrf2-inducers 15d-PGJ2 and nitrofatty acids primarily form adducts with Cys-273 and Cys-288 on Keap1, displaying a much lower reactivity towards Cys-151, suggesting that different patterns of cysteine modification can lead to Keap1 inhibition and Nrf2 activation [60, 61]. Nuclear accumulation of Nrf2 and induction of its target genes have been reported in different experimental models in response to several omega-3 PUFAs derived electrophiles, including the DHA-derivatives 4-HHE and 17-oxo-DHA, the DPA-derivative 17-oxo-DPA, and the EPA-derivatives A3/J3-IsoPs [12–14, 62].

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