Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, Jena 07743, Germany.
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, Jena 07743, Germany; Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria.
Biochem Pharmacol. 2022 Jan;195:114825. doi: 10.1016/j.bcp.2021.114825. Epub 2021 Nov 8.
Specialized pro-resolving mediators (SPMs) comprise lipid mediators (LMs) produced from polyunsaturated fatty acids (PUFAs) via stereoselective oxygenation particularly involving 12/15-lipoxygenases (LOXs). In contrast to pro-inflammatory LMs such as leukotrienes formed by 5-LOX and prostaglandins formed by cyclooxygenases, the SPMs have anti-inflammatory and inflammation-resolving properties. Although glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) that block prostaglandin production are still prime therapeutics for inflammation-related diseases despite severe side effects, novel concepts focus on SPMs as immunoresolvents for anti-inflammatory pharmacotherapy. Here, we studied the natural chalcone MF-14 and the corresponding dihydrochalcone MF-15 from Melodorum fruticosum, for modulating the biosynthesis of LM including leukotrienes, prostaglandins, SPM and their 12/15-LOX-derived precursors in human monocyte-derived macrophage (MDM) M1- and M2-like phenotypes. In MDM challenged with Staphylococcus aureus-derived exotoxins both compounds (10 µM) significantly suppressed 5-LOX product formation but increased the biosynthesis of 12/15-LOX products, especially in M2-MDM. Intriguingly, in resting M2-MDM, MF-14 and MF-15 strikingly evoked generation of 12/15-LOX products and of SPMs from liberated PUFAs, along with translocation of 15-LOX-1 to membranous compartments. Enhanced 12/15-LOX product formation by the chalcones was evident also when exogenous PUFAs were supplied, excluding increased substrate supply as sole underlying mechanism. Rather, MF-14 and MF-15 stimulate the activity of 15-LOX-1, supported by experiments with HEK293 cells transfected with either 5-LOX, 15-LOX-1 or 15-LOX-2. Together, the natural chalcone MF-14 and the dihydrochalcone MF-15 favorably modulate LM biosynthesis in human macrophages by suppressing pro-inflammatory leukotrienes but stimulating formation of SPMs by differential interference with 5-LOX and 15-LOX-1.
特殊的促分解介质（SPMs）包括通过立体选择性氧化产生的多不饱和脂肪酸（PUFAs）衍生的脂质介质（LMs），特别是涉及 12/15-脂氧合酶（LOXs）。与通过 5-LOX 形成的促炎 LMs 如白三烯和通过环加氧酶形成的前列腺素不同，SPMs 具有抗炎和炎症分解特性。尽管糖皮质激素和阻断前列腺素产生的非甾体抗炎药（NSAIDs）仍然是炎症相关疾病的主要治疗药物，但尽管存在严重的副作用，新的概念还是侧重于 SPM 作为抗炎药物治疗的免疫调节剂。在这里，我们研究了来自 Melodorum fruticosum 的天然查尔酮 MF-14 和相应的二氢查尔酮 MF-15，以调节包括白三烯、前列腺素、SPM 及其 12/15-LOX 衍生前体在内的 LM 生物合成，在人单核细胞衍生的巨噬细胞（MDM）M1-和 M2 样表型中。在金黄色葡萄球菌衍生的外毒素刺激的 MDM 中，两种化合物（10µM）均显著抑制 5-LOX 产物的形成，但增加了 12/15-LOX 产物的生物合成，特别是在 M2-MDM 中。有趣的是，在静止的 M2-MDM 中，MF-14 和 MF-15 惊人地引发了从游离 PUFAs 中生成 12/15-LOX 产物和 SPMs 的生成，同时 15-LOX-1 易位到膜隔间。当提供外源性 PUFAs 时，查尔酮增强了 12/15-LOX 产物的形成，这排除了仅增加底物供应作为唯一的潜在机制。相反，MF-14 和 MF-15 通过用转染了 5-LOX、15-LOX-1 或 15-LOX-2 的 HEK293 细胞进行的实验支持，刺激 15-LOX-1 的活性。总之，天然查尔酮 MF-14 和二氢查尔酮 MF-15 通过抑制促炎白三烯而有利于调节人类巨噬细胞中的 LM 生物合成，但通过差异干扰 5-LOX 和 15-LOX-1 来刺激 SPM 的形成。
