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Gallic acid-l-leucine (GAL) conjugate enhances macrophage phagocytosis via inducing leukotriene B4 12-hydroxydehydrogenase (LTB4DH) expression

机译:没食子酸-1-亮氨酸(GAL)缀合物通过诱导白三烯B4 12-羟基脱氢酶(LTB4DH)表达来增强巨噬细胞吞噬作用

摘要

Timely clearance of apoptotic cells is an important step in the resolution of ongoing inflammation and the restoration of tissue integrity and function after acute myocardial infarction. Natural products gallic acid and l-leucine are well-documented for anti-inflammatory and anabolic effects. We synthesized gallic acid-. l-leucine (GAL) conjugate via direct coupling gallic acid and l-leucine. The aim of the present study was to investigate the effect of GAL conjugate on the phagocytotic activity of macrophages. By using murine macrophage cell line RAW264.7 as an in vitro model, we evaluated the effect of GAL conjugate on the phagocytic uptake of fluorescently labeled latex beads and apoptotic cardiomyocyte H9c2 cells. We found that GAL conjugate enhanced the phagocytic activity of macrophage RAW264.7 cells in a concentration-dependent manner. Further mechanistic studies revealed that the effect of GAL conjugate on macrophage phagocytosis was positively correlated with the up-regulation of leukotriene B4 12-hydroxydehydrogenase (LTB4DH) expression at both mRNA and protein levels. By ESI-MS based lipidomics profiling, GAL conjugate increased the enzymatic activities of LTB4DH, leading to the formation of lipid metabolites including 12-oxo-LTB4, 13,14-dh-oxo-PGE2 and 13,14-dh-oxo-PGF2α. Interestingly, GAL conjugate failed to increase macrophage phagocytosis upon silencing of LTB4DH by specific siRNA. Moreover, it appeared that GAL conjugate induced LTB4DH expression via activating the Nrf2/HO-1 pathway. After Nrf-2 was silenced by specific siRNA, GAL conjugate no longer induced LTB4DH expression in the Nrf2-siRNA transfected cells. Taken together, our results suggest that GAL enhances macrophage phagocytosis via sequentially activating Nrf2 and up-regulating LTB4DH expression. Thus, GAL conjugate may serve as a lead compound for the development of new anti-inflammatory drugs.
机译:在急性心肌梗死后,及时清除凋亡细胞是解决正在进行的炎症以及恢复组织完整性和功能的重要步骤。天然产物没食子酸和L-亮氨酸已被证明具有抗炎和合成代谢作用。我们合成了没食子酸。 l-亮氨酸(GAL)偶联物通过直接偶联没食子酸和l-亮氨酸而形成。本研究的目的是研究GAL共轭物对巨噬细胞吞噬活性的影响。通过使用小鼠巨噬细胞系RAW264.7作为体外模型,我们评估了GAL共轭物对荧光标记的乳胶珠和凋亡性心肌H9c2细胞吞噬吞噬的影响。我们发现GAL缀合物以浓度依赖的方式增强了巨噬细胞RAW264.7细胞的吞噬活性。进一步的机理研究表明,GAL缀合物对巨噬细胞吞噬作用的影响与白三烯B4 12-羟基脱氢酶(LTB4DH)在mRNA和蛋白质水平上的表达上调正相关。通过基于ESI-MS的脂质组学分析,GAL缀合物增加了LTB4DH的酶活性,导致脂质代谢物的形成,包括12-氧代-LTB4、13,14-dh-氧代-PGE2和13,14-dh-氧代-PGF2α 。有趣的是,当通过特异性siRNA沉默LTB4DH时,GAL缀合物不能增加巨噬细胞的吞噬作用。此外,似乎GAL缀合物通过激活Nrf2 / HO-1途径诱导了LTB4DH表达。 Nrf-2被特异性siRNA沉默后,GAL偶联物不再诱导Nrf2-siRNA转染的细胞中LTB4DH表达。两者合计,我们的结果表明,GAL通过依次激活Nrf2和上调LTB4DH表达来增强巨噬细胞的吞噬作用。因此,GAL缀合物可以用作开发新的抗炎药的先导化合物。

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