阿司匹林丁香酚酯通过 ROS/p38-MAPK 介导的线粒体凋亡途径改善百草枯诱导的氧化损伤。
Aspirin eugenol ester ameliorates paraquat-induced oxidative damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway.
机构信息
Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, 730050, China.
出版信息
Toxicology. 2021 Apr 15;453:152721. doi: 10.1016/j.tox.2021.152721. Epub 2021 Feb 13.
Paraquat (PQ) is an effective and commercially important herbicide that is widely used worldwide. However, PQ is highly toxic and can cause various complications and acute organ damage. Aspirin eugenol ester (AEE) is a potential new compound with anti-inflammatory and antioxidant stress pharmacological activity. The present study was to reveal the therapeutic effects and the protective effect of AEE against PQ-induced acute lung injury (ALI) with the help of PQ-induced oxidative damage in A549 cells and PQ-induced lung injury in rats. AEE might have no significant therapeutic effect on PQ-induced lung injury in rats. However, AEE had a significant protective effect on PQ-induced lung injury in rats. AEE pretreatment significantly reduced the stimulatory effect of PQ on malondialdehyde (MDA), the inhibitory effect of PQ on catalase (CAT) activity, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, the ratio of GSH/GSSH, the activity of caspase-3 and the overexpression of p38 mitogen-activated protein kinase (MAPK) phosphorylation in vivo. In vitro, A549 cells were treated with 250 μM PQ for 24 h. Incubation of A549 cells with PQ led to apoptosis, and increased the level of superoxide anions, reactive oxygen species (ROS), malondialdehyde and the activity of caspase-3 and up-regulation of phosphorylated p38-MAPK, reduced mitochondrial membrane potential (ΔΨm) and the activity of SOD. However, after 24 h on AEE pretreatment of A549 cells, the above-mentioned adverse reactions caused by PQ were significantly alleviated. In addition, AEE pretreatment reduced p38-MAPK phosphorylation in PQ-treated A549 cells. SB203580, the specific p38-MAPK inhibitor, and p38-MAPK shRNA attenuated the activation of the p38-MAPK signaling pathway. N-acetylcysteine (NAC) reduced the level of phosphorylated p38-MAPK and the production of intracellular ROS and inhibited apoptosis. The results showed that AEE may inhibit PQ-induced cell damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway.
百草枯（PQ）是一种有效且重要的商业除草剂，在全球范围内广泛使用。然而，PQ 毒性很高，可导致各种并发症和急性器官损伤。阿司匹林丁香酚酯（AEE）是一种具有抗炎和抗氧化应激药理学活性的潜在新化合物。本研究旨在通过 PQ 诱导的 A549 细胞氧化损伤和 PQ 诱导的大鼠肺损伤来揭示 AEE 对 PQ 诱导的急性肺损伤（ALI）的治疗作用和保护作用。AEE 对 PQ 诱导的大鼠肺损伤可能没有显著的治疗作用。然而，AEE 对 PQ 诱导的大鼠肺损伤具有显著的保护作用。AEE 预处理可显著降低 PQ 对丙二醛（MDA）的刺激作用、对过氧化氢酶（CAT）活性、超氧化物歧化酶（SOD）活性、谷胱甘肽过氧化物酶（GPx）活性、GSH/GSSH 比值、半胱天冬酶-3 活性和 p38 丝裂原活化蛋白激酶（MAPK）磷酸化的抑制作用。在体外，用 250μM PQ 处理 A549 细胞 24 小时。用 PQ 孵育 A549 细胞可导致细胞凋亡，并增加超氧阴离子、活性氧（ROS）、丙二醛的水平和半胱天冬酶-3 的活性，上调磷酸化的 p38-MAPK，降低线粒体膜电位（ΔΨm）和 SOD 的活性。然而，在用 AEE 预处理 A549 细胞 24 小时后，PQ 引起的上述不良反应明显减轻。此外，AEE 预处理可降低 PQ 处理的 A549 细胞中 p38-MAPK 的磷酸化。p38-MAPK 的特异性抑制剂 SB203580 和 p38-MAPK shRNA 减弱了 p38-MAPK 信号通路的激活。N-乙酰半胱氨酸（NAC）降低了磷酸化 p38-MAPK 的水平、细胞内 ROS 的产生并抑制了细胞凋亡。结果表明，AEE 可能通过 ROS/p38-MAPK 介导的线粒体凋亡途径抑制 PQ 诱导的细胞损伤。
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