Myriscagayanone C, a New Compound from the Fruit of Myristica Cagayanensis, Inhibits FMLP-induced Respiratory Bursts by Specifically Preventing Akt Translocation in Human Neutrophils

Neutrophils that are overactivated can cause inflammatory diseases. Neutrophils possess various surface receptors, including G-protein-coupled chemoattractant receptors, which assist in recognizing pathogen attacks and the inflammatory environment. Therefore, targeting G-protein-coupled chemoattractant receptors and their downstream molecules is important for preventing abnormal neutrophil activation. This study examines the effects and underlying mechanism of myriscagayanone C, a new compound obtained from the fruit of myristica cagayanensis, on neutrophil respiratory burst induced by fMLP. The immunoblotting assay was conducted to assess the mechanisms by which myriscagayanone C inhibits fMLP-induced respiratory burst by disrupting the translocation of Akt to the cellular membrane. Briefly, myriscagayanone C suppressed the production of superoxide anions induced by fMLP on human neutrophils in a concentration-dependent manner (IC: 4.73 ± 0.68 μM). Myriscagayanone C blocked fMLP-induced Akt translocation to the cell membrane, inhibiting Akt and Akt phosphorylation by PDK1 and mTOR, respectively. Myriscagayanone C inhibited fMLP-induced p47 phosphorylation and translocation. Myriscagayanone C did not inhibit the activity of PI3K, the amount of phosphatidylinositol (3, 4, 5)-trisphosphate, or the translocation of phosphorylated-PDK1 and -mTOR to the membrane. Myriscagayanone C did not inhibit fMLP-induced PKC, Src, ERK1/2, p38 phosphorylation, and intracellular calcium mobilization. Myriscagayanone C did not inhibit the chemotaxis and CD11b expression induced by fMLP. Myriscagayanone C did not inhibit PMA-induced superoxide anion production and neutrophil extracellular trap formation. According to this data, myriscagayanone C inhibits fMLP-induced neutrophil superoxide anion production by interrupting the translocation of Akt to the plasma membrane, which affects the NADPH oxidase activity by preventing p47 phosphorylation and translocation.