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Figure 6: Arachidonic acid metabolism as a provider of physiological PPAR ligands. The figure illustrates in a nonexhaustive way that arachidonic acid (AA) may generate various lipoxygenase (LOX) (hydroxyeicosatrienes, HETEs; hydroperoxyeicosatrienes; HPETEs, leucotrienes, LTs) and cyclooxygenase- (COX) (prostaglandins, PGs; thromboxanes, TXs) derived metabolites. Among these metabolites, LTB4, prostacyclin (PGI2), and 15-deoxy PGJ2 (PGJ2) represent ligands of each of the three PPAR isoforms, PPARα, β, and γ, respectively. Subsequent physiological activation of PPARs impacts the formation of such ligands via a negative feedback loop by increasing their degradation and lowering their formation. Indeed, PPARα activation stimulates microsomal ω-hydroxylase (in humans) and peroxisomal β-oxidation (in rodents, for instance but not in humans) and hence degradation of each of the precited PPAR ligands. Each of the PPARs may upregulate the activity of antioxidant enzymes and downregulate inflammatory proteins. Preventing induction of cyclooxygenase type 2 is a way to counteract inflammation-driven increase in arachidonic metabolites which are cyclooxygenase-dependent ligands of PPARs. The interest of a PPAR-based therapy in preventing the synergism between stromal cell inflammation and tumor development/invasion is explained in the text.