Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Acute Care Surgery and Traumatology, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan.
Bioorg Chem. 2020 Mar;96:103639. doi: 10.1016/j.bioorg.2020.103639. Epub 2020 Jan 30.
Ruthenium metal complex has been shown to exert several chemical and biological activities. A series of three novel ruthenium derivatives (TQ 1, 2 and 4) were synthesized to evaluate the anti-inflammatory and hepatoprotective activities in lipopolysaccharide (LPS)-stimulated macrophages and mice liver injury. The hydroxyl radical (OH°) scavenging activity of these derivatives has also been evaluated. The results revealed that among the tested compounds, TQ-4 effectively attenuated LPS-induced abnormal alteration in liver histoarchistructure via reducing alanine transaminase (ALT) and aspartate transaminase (AST). This compound exhibited significant inhibition of inflammatory cytokines (TNF-α and IL-1β), inflammatory enzyme (iNOS), the component of NF-κB signaling pathway (p65) and JNK phosphorylation in LPS-induced mice liver tissues. In vitro results showed that TQ-4 had the best inhibition of NO production and iNOS expression in LPS-induced RAW 264.7 cells. Mechanistic approach indicated that TQ-4 inhibited the LPS-induced JNK phosphorylation, IκBα degradation, NF-κB p65 phosphorylation and its nuclear translocation, and hydroxyl radical (OH°) productions in RAW 264.7 cells. However, the compounds TQ-1 and 2 had no effects in this study. TQ-4 also inhibited LPS-induced OH° production. This study reveals the protective effect of TQ-4 against LPS-induced acute liver injury, inflammation, and oxidative reaction by destructing JNK/NF-κB signaling pathways. The result of this study may infer that TQ-4 might be a promising ruthenium metal derivative and/or therapeutic agent for treating liver injury.
钌金属配合物已被证明具有多种化学和生物活性。为了评估其在脂多糖（LPS）刺激的巨噬细胞和小鼠肝损伤中的抗炎和保肝活性，我们合成了一系列三种新型钌衍生物（TQ1、2 和 4）。还评估了这些衍生物的羟基自由基（OH°）清除活性。结果表明，在所测试的化合物中，TQ-4 通过降低丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST），有效减轻了 LPS 诱导的肝组织形态异常改变。该化合物对炎症细胞因子（TNF-α和 IL-1β）、炎症酶（iNOS）、NF-κB 信号通路组成部分（p65）和 LPS 诱导的小鼠肝组织中 JNK 磷酸化有显著抑制作用。体外结果表明，TQ-4 对 LPS 诱导的 RAW264.7 细胞中 NO 产生和 iNOS 表达的抑制作用最强。机制研究表明，TQ-4 抑制了 LPS 诱导的 JNK 磷酸化、IκBα降解、NF-κB p65 磷酸化及其核转位，以及 RAW264.7 细胞中羟基自由基（OH°）的产生。然而，在本研究中，化合物 TQ-1 和 2 没有作用。TQ-4 还抑制了 LPS 诱导的 OH°产生。本研究揭示了 TQ-4 通过破坏 JNK/NF-κB 信号通路，对 LPS 诱导的急性肝损伤、炎症和氧化反应具有保护作用。该研究结果可能暗示 TQ-4 可能是一种有前途的钌金属衍生物和/或治疗肝损伤的药物。
