Malabaricone C derived from nutmeg inhibits arachidonate 5-lipoxygenase activity and ameliorates psoriasis-like skin inflammation in mice.

As pro-inflammatory lipid mediators, leukotrienes have pathophysiological activities in several inflammatory diseases, including psoriasis. In the biosynthesis of leukotrienes from arachidonic acid, 5-lipoxygenase catalyzes the first two steps. In the present study, we showed that nutmeg (Myristica fragrans) strongly inhibited the catalytic activity of 5-lipoxygenase. To characterize the bioactive component(s) of nutmeg, we performed 5-lipoxygenase inhibitory activity-guided fractionation of aqueous ethanol extract of nutmeg, resulting in the isolation of malabaricone C having antioxidant activity. Malabaricone C exhibited potent competitive inhibition of 5-lipoxygenase with an IC50 value of 0.2 µM. In mice with imiquimod-induced psoriasis-like skin lesions, topical application of 2 mM malabaricone C significantly ameliorated hyperplasia and inflammatory cell infiltration, and suppressed the expression of the psoriasis-associated genes S100a9, Krt1, Il17a, and Il22. Lipid metabolome analysis of these psoriasis-like skin lesions showed that malabaricone C markedly decreased the level of leukotriene B4 but did not significantly increase the other pro-inflammatory lipid mediators. These findings suggest that malabaricone C decreases LTB4 by the 5-lipoxygenase inhibition and ameliorates the symptoms of psoriasis-like skin inflammation.

Lipid profiling reveals the presence of unique lipid mediators in human milk from healthy and mastitic subjects.

Milk lipids are an important energy source for infants, but the composition of milk lipids has not yet been clarified in detail. In this study, we analyzed free fatty acids and their metabolites in milk from humans and cows. In comparison to cow milk, human milk showed a higher content of free fatty acids including polyunsaturated fatty acids, especially ω-3 fatty acids and their metabolites. Polyunsaturated fatty acids were enriched at an early period of lactation, while saturated fatty acids did not change significantly over the period. Moreover, human milk contained high levels of ω-3 fatty acid metabolites, particularly 18-hydroxyeicosapentaenoic acid, an eicosapentaenoic acid-derived metabolite with anti-inflammatory activity. In comparison with human normal milk, thromboxane B2 and protectin D1 levels were significantly elevated in milk from individuals with mastitis, suggesting that these lipid mediators could be potential biomarkers of obstructive mastitis. Overall, the unique lipid profile of human milk supports the efficacy of breast-feeding for supply of more nutritional and bioactive lipids in comparison to artificial or cow milk to infants, in whom digestive and absorptive functions are still immature.

Segregated functions of two cytosolic phospholipase A2 isoforms (cPLA2α and cPLA2ε) in lipid mediator generation.

Among the phospholipase A2 (PLA2) superfamily, group IVA cytosolic PLA2 (cPLA2α) is currently attracting much attention as a central regulator of arachidonic acid (AA) metabolism linked to eicosanoid biosynthesis. Following cell activation, cPLA2α selectively releases AA, a precursor of a variety of eicosanoids, from phospholipids in perinuclear membrane compartments. cPLA2α-null mice display various phenotypes that could be largely explained by reduced eicosanoid signaling. In contrast, group IVE cPLA2ε, another member of the cPLA2 family, acts as a Ca2+-dependent N-acyltransferase rather than a PLA2, thereby regulating the biosynthesis of N-acylethanolamines (NAEs), a unique class of lipid mediators with an anti-inflammatory effect. In response to Ca2+ signaling, cPLA2ε translocates to phosphatidylserine-rich organelle membranes in the endocytic/recycling pathway. In vivo, cPLA2ε is induced in keratinocytes of psoriatic skin, and its genetic deletion exacerbates psoriatic inflammation due to a marked reduction of NAE-related lipids. cPLA2ε also contributes to NAE generation in several if not all mouse tissues. Thus, the two members of the cPLA2 family, cPLA2α and cPLA2ε, catalyze distinct enzymatic reactions to mobilize distinct sets of lipid mediators, thereby differently regulating pathophysiological events in health and disease. Such segregation of the cPLA2α-eicosanoid and cPLA2ε-NAE pathways represents a new paradigm of research on PLA2s and lipid mediators.

Red-kerneled rice proanthocyanidin inhibits arachidonate 5-lipoxygenase and decreases psoriasis-like skin inflammation.

5-lipoxygenase is a key enzyme in the synthesis of leukotrienes from arachidonic acid. The produced leukotrienes are involved in inflammatory diseases including psoriasis, asthma, and atherosclerosis. A suitable 5-lipoxygenase inhibitor might be useful for preventing and improving the symptoms of leukotriene-related inflammatory diseases. Here, we investigate the mechanism underlying the anti-inflammatory effect of a proanthocyanidin found in red-kerneled rice. Red-kerneled rice proanthocyanidin exhibited potent mixed noncompetitive inhibition of human and rat 5-lipoxygenases, with an IC50 values of 15.1 µM against human enzyme, and 7.0 µM against rat enzyme, respectively. This compound decreased leukotriene B4 production in rat basophilic leukemia-2H3 cells. In imiquimod-induced psoriasis-like mouse skin, topical application of the proanthocyanidin suppressed hyperplasia, decreased inflammatory cell infiltration, and down-regulated expression of the psoriasis-associated genes Il17a, Il22, S100a9, and Krt1. Lipid metabolome analysis by electrospray ionization mass spectrometry showed that red-kerneled rice proanthocyanidin treatment of psoriasis-like mouse skin dose-dependently decreased the production of leukotriene B4 but no other arachidonate metabolites. Red-kerneled rice proanthocyanidin inhibits 5-lipoxygenase, resulting in a decrease in leukotriene B4 production and psoriasis-like mouse skin inflammation. These results suggest that this proanthocyanidin may be therapeutically effective for treating leukotriene-related diseases.