Stylissatin A (SA) is a cyclic heptapeptide isolated from the marine sponge Stylissa massa. SA shows anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cells, but the detailed mechanism of action remains unclear. Here we report that D-Tyr1-tBuSA, a more potent SA derivative, inhibited production of the proinflammatory cytokines Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in LPS-stimulated RAW264.7 cells (EC50 = 1.4 and 5.9 μM, respectively). This compound also inhibited the LPS-stimulated expression of inducible nitric oxide synthase (iNOS) at 20 μM. Using a biotin derivative of SA, acyl-CoA dehydrogenase long chain (ACADL) was identified as a target protein of SA and its derivatives. It is proposed that SA and its derivatives might suppress the β-oxidation of fatty acids by ACADL, and the accumulation of fatty acids on macrophages would inhibit the nuclear factor-kappa B (NF-κB) signaling pathway and iNOS expression to show anti-inflammatory activity. Our research might provide a new mechanism of inflammation in macrophages, and contribute to the development of treatments for inflammatory diseases.

中文翻译：

---

酰基辅酶A脱氢酶长链（ACADL）是stylissatin A（一种抗炎性环状七肽）的靶蛋白。

Stylissatin A（SA）是从海生海绵Stylissa massa分离的环状七肽。SA对脂多糖（LPS）刺激的小鼠RAW264.7巨噬细胞具有抗炎活性，但具体的作用机理尚不清楚。在这里我们报道D-Tyr1-tBuSA，一种更有效的SA衍生物，在LPS刺激的RAW264.7细胞中抑制促炎细胞因子白介素6（IL-6）和肿瘤坏死因子α（TNF-α）的产生（EC50分别为1.4和5.9μM）。该化合物还以20μM抑制LPS刺激的诱导型一氧化氮合酶（iNOS）的表达。使用SA的生物素衍生物，酰基辅酶A脱氢酶长链（ACADL）被确定为SA及其衍生物的目标蛋白。有人提出SA及其衍生物可能通过ACADL抑制脂肪酸的β-氧化，脂肪酸在巨噬细胞上的积累会抑制核因子-κB（NF-κB）信号通路和iNOS表达，从而具有抗炎活性。我们的研究可能会提供巨噬细胞炎症的新机制，并有助于炎症性疾病治疗方法的发展。