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Active-Italia: (−)-Methyl-Oleocanthal, a New Oleocanthal Metabolite Reduces LPS-Induced Inflammatory and Oxidative Response: Molecular Signaling Pathways and Histones Epigenetic Modulation.

(−)-Methyl-Oleocanthal, a New Oleocanthal Metabolite Reduces LPS-Induced Inflammatory and Oxidative Response: Molecular Signaling Pathways and Histones Epigenetic Modulation.

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The antioxidant and anti-inflammatory responses of (−)-methyl-oleocanthal (met-OLE), a new metabolite of the extra virgin olive oil (EVOO) phenolic oleocanthal (OLE), were explored in lipopolysaccharide (LPS)-induced murine peritoneal macrophages. Possible signaling pathways and epigenetic modulation of histones were studied. Met-OLE inhibited LPS-induced intracellular reactive oxygen species (ROS) and nitrite (NO) production and decreased the overexpression of the pro-inflammatory enzymes COX-2, mPGES-1 and iNOS in murine macrophages. In addition, met-OLE was able to significantly decrease the activation of p38, JNK, and ERK mitogen-activated protein kinases (MAPKs) and blocked canonical and non-canonical inflammasome signaling pathways. On the contrary, met-OLE upregulated haem oxigenase 1 (HO-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) expression in treated cells. Finally, met-OLE pretreated spleen cells counteracted LPS induction, preventing H3K18 acetylation or H3K9 and H3K27 demethylation. Overall, these results provide novel mechanistic insights into the beneficial effects of met-OLE regarding the regulation of the immune–inflammatory response through epigenetic changes in histone markers. This revealing evidence suggests that the methylated metabolite of OLE may contribute significantly to the beneficial effects that are associated with the secoiridoid-related compound and the usual consumption of EVOO.
Macrophages are major components of the innate immune system and play a critical role in modulating inflammatory and immune responses. Extracellular bacterial lipopolysaccharide (LPS) acts as pathogen-associated molecular pattern and is recognized by the Toll-like receptor (TLR)-4, inducing macrophages to an activated state, producing pro-inflammatory cytokines and chemokines and enhancing the expression of inflammatory-related enzymes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1, which synthesize nitric oxide (NO) and prostaglandin (PG)E2, respectively. Additionally, LPS-stimulated macrophages disrupt the balance of the intracellular reduction–oxidation state, leading to oxidative stress, usually accompanied by damage that is mediated by reactive oxygen species (ROS). The process of gene expression of these pro-inflammatory mediators involves multiple signal transduction pathways, which are mainly through mitogen-activated protein kinases (MAPKs), nuclear transcription factor-kappa B (NF-κB), janus kinase/signal transducer and transcription activator of transcription (JAK/STAT) or inflammasome activation. Furthermore, the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2)/haem oxygenase-1 (HO-1) antioxidative axis, which exerts a regulative function on the activation of ROS, MAPKs, and inflammasome signaling pathways, is repressed in the event of the induction of the activated macrophages state.
Emerging evidence suggests that epigenetic processes that affect gene expression without causing changes in the nucleotide sequence occur after external stimuli exposure, and may contribute to the pathophysiology of inflammatory processes. In particular, histone H3 methylation at lysine 9 (H3K9), one of the most conserved epigenetic markers, is correlated with gene silencing and the modulation of immune cell differentiation and immune responses, and therefore, influences the outcome of inflammation. […]

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Montoya T, Alarcón-de-la-Lastra C, Castejón ML, Ortega-Vidal J, Altarejos J, Sánchez-Hidalgo M.

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