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Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.

Bretscher P, Egger J, Shamshiev A, Trötzmüller M, Köfeler H, Carreira EM, Kopf M, Freigang S - EMBO Mol Med (2015)

Bottom Line: While the ability of OxPL to modulate biological processes is increasingly recognized, the nature of the biologically active OxPL species and the molecular mechanisms underlying their signaling remain largely unknown.Our study defines epoxycyclopentenones as potent anti-inflammatory lipid mediators that mimic the signaling of endogenous, pro-resolving prostanoids by activating the transcription factor nuclear factor E2-related factor 2 (Nrf2).Using a library of OxPL variants, we identified a synthetic OxPL derivative, which alleviated endotoxin-induced lung injury and inhibited development of pro-inflammatory T helper (Th) 1 cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

No MeSH data available.


Related in: MedlinePlus

Structure–function studies identify critical molecular determinants of the anti-inflammatory bioactivityDose–response curves showing the modulation of R837-induced (5 μg/ml; 18 h) IL-12 secretion by prior treatment of BMDCs with the indicated synthetic lipids for 1 h.Chemical structures and ΔEC50 values of the synthetic OxPL variant lipids analyzed in (A), presented relative to EC.Data information: Mean ± SEM of triplicate determinations are shown.
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fig06: Structure–function studies identify critical molecular determinants of the anti-inflammatory bioactivityDose–response curves showing the modulation of R837-induced (5 μg/ml; 18 h) IL-12 secretion by prior treatment of BMDCs with the indicated synthetic lipids for 1 h.Chemical structures and ΔEC50 values of the synthetic OxPL variant lipids analyzed in (A), presented relative to EC.Data information: Mean ± SEM of triplicate determinations are shown.

Mentions: These promising in vivo observations encouraged us to further investigate the structure–activity relationship of EC in order to elucidate key structural determinants mediating its potent bioactivity. We hypothesized a potential involvement of the epoxide group as well as the endocyclic and exocyclic enones and therefore evaluated the bioactivity of synthetic EC variants that selectively lacked these electrophilic sites (Fig6A and B). Our results revealed the cyclopentenone double bond as main driver of the overall bioactivity, since its removal in variant ‘MonoRed A’ completely abolished the anti-inflammatory property of EC. This notion was further supported by the fact that introduction of another electrophilic group, an epoxide, at this position into ‘MonoRed A’, which led to the variant ‘Bisepoxide’, restored its bioactivity. In addition, also the epoxide group and the extra-cyclic double bond in α,β position to the carbonyl group appeared to partially contribute to the overall bioactivity, as was illustrated by the reduced efficacy of the respective variants ‘No Epoxide’ and ‘MonoRed B’. However, additional removal of the double bond lacking in ‘MonoRed B’ from ‘MonoRed A’ did not further reduce the bioactivity of resulting variant ‘BisRed’, thus confirming the critical importance of the endocyclic enone for the overall bioactivity of the molecule. Moreover, the ability to trigger Nrf2 signaling and downstream anti-inflammatory effects appeared to be restricted to cyclopentenone-containing OxPL. For example, other prominent lipid mediators involved in the regulation of inflammation that lack a cyclopentenone moiety, such as the arachidonic acid-derived prostacyclin and lipoxin B4, or the omega-3 fatty acid-derived resolvin D2, neither affected the cytokine production nor triggered Nrf2 signaling in myeloid cells in our bioassay (Supplementary Figs S5 and S6). Taken together, these findings defined molecular determinants of the anti-inflammatory bioactivity of EC and provided a rationale to design customized EC variants as anti-inflammatory compounds with improved therapeutic potential.


Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.

Bretscher P, Egger J, Shamshiev A, Trötzmüller M, Köfeler H, Carreira EM, Kopf M, Freigang S - EMBO Mol Med (2015)

Structure–function studies identify critical molecular determinants of the anti-inflammatory bioactivityDose–response curves showing the modulation of R837-induced (5 μg/ml; 18 h) IL-12 secretion by prior treatment of BMDCs with the indicated synthetic lipids for 1 h.Chemical structures and ΔEC50 values of the synthetic OxPL variant lipids analyzed in (A), presented relative to EC.Data information: Mean ± SEM of triplicate determinations are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492819&req=5

fig06: Structure–function studies identify critical molecular determinants of the anti-inflammatory bioactivityDose–response curves showing the modulation of R837-induced (5 μg/ml; 18 h) IL-12 secretion by prior treatment of BMDCs with the indicated synthetic lipids for 1 h.Chemical structures and ΔEC50 values of the synthetic OxPL variant lipids analyzed in (A), presented relative to EC.Data information: Mean ± SEM of triplicate determinations are shown.
Mentions: These promising in vivo observations encouraged us to further investigate the structure–activity relationship of EC in order to elucidate key structural determinants mediating its potent bioactivity. We hypothesized a potential involvement of the epoxide group as well as the endocyclic and exocyclic enones and therefore evaluated the bioactivity of synthetic EC variants that selectively lacked these electrophilic sites (Fig6A and B). Our results revealed the cyclopentenone double bond as main driver of the overall bioactivity, since its removal in variant ‘MonoRed A’ completely abolished the anti-inflammatory property of EC. This notion was further supported by the fact that introduction of another electrophilic group, an epoxide, at this position into ‘MonoRed A’, which led to the variant ‘Bisepoxide’, restored its bioactivity. In addition, also the epoxide group and the extra-cyclic double bond in α,β position to the carbonyl group appeared to partially contribute to the overall bioactivity, as was illustrated by the reduced efficacy of the respective variants ‘No Epoxide’ and ‘MonoRed B’. However, additional removal of the double bond lacking in ‘MonoRed B’ from ‘MonoRed A’ did not further reduce the bioactivity of resulting variant ‘BisRed’, thus confirming the critical importance of the endocyclic enone for the overall bioactivity of the molecule. Moreover, the ability to trigger Nrf2 signaling and downstream anti-inflammatory effects appeared to be restricted to cyclopentenone-containing OxPL. For example, other prominent lipid mediators involved in the regulation of inflammation that lack a cyclopentenone moiety, such as the arachidonic acid-derived prostacyclin and lipoxin B4, or the omega-3 fatty acid-derived resolvin D2, neither affected the cytokine production nor triggered Nrf2 signaling in myeloid cells in our bioassay (Supplementary Figs S5 and S6). Taken together, these findings defined molecular determinants of the anti-inflammatory bioactivity of EC and provided a rationale to design customized EC variants as anti-inflammatory compounds with improved therapeutic potential.

Bottom Line: While the ability of OxPL to modulate biological processes is increasingly recognized, the nature of the biologically active OxPL species and the molecular mechanisms underlying their signaling remain largely unknown.Our study defines epoxycyclopentenones as potent anti-inflammatory lipid mediators that mimic the signaling of endogenous, pro-resolving prostanoids by activating the transcription factor nuclear factor E2-related factor 2 (Nrf2).Using a library of OxPL variants, we identified a synthetic OxPL derivative, which alleviated endotoxin-induced lung injury and inhibited development of pro-inflammatory T helper (Th) 1 cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

No MeSH data available.


Related in: MedlinePlus