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

• Published in: Free radical biology & medicine 2022-11, Vol.193 (Pt 1), p.1-8
• Main Authors: Tsukayama, Izumi, Kawakami, Yuki, Tamenobu, Asako, Toda, Keisuke, Maruoka, Saya, Nagasaki, Yuki, Mori, Yoshiko, Sawazumi, Risa, Okamoto, Kensuke, Kanzaki, Keita, Ito, Hideyuki, Takahashi, Yoshitaka, Miki, Yoshimi, Yamamoto, Kei, Murakami, Makoto, Suzuki-Yamamoto, Toshiko
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammation; Arachidonate 5-lipoxygenase; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Inflammation; Leukotriene B4; Leukotrienes; Malabaricone C; Mice; Myristica - metabolism; Platelet Activating Factor; Psoriasis; Psoriasis - chemically induced; Psoriasis - drug therapy; Psoriasis - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2022.09.028

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. [Display omitted] •5-LOX inhibitory activity-guided fractionation of nutmeg led to the isolation of MLB-C.•MLB-C competitively inhibited 5-LOX activity with an IC50 of 0.2 μM.•MLB-C markedly reduced LTB4 production in mouse psoriasis-like skin.•MLB-C markedly suppressed psoriasis-associated genes in the lesions.