Abstract：
Acute lung injury (ALI) is a highly heterogeneous clinical syndrome and an important cause of mortality in critically ill patients, with limited treatment options currently available. Chalcone, an essential secondary metabolite found in edible or medicinal plants, exhibits good antioxidant activity and simple structure for easy synthesis. In our study, we synthesized a novel chalcone derivative, compound 27 (C27). We hypothesized that C27 could be a potential treatment for acute respiratory distress syndrome (ARDS). Therefore, the protective effects of C27 on lung epithelial cells during ALI and the underlying molecular mechanisms were investigated. In vivo, Intratracheal instillation of LPS (10 mg/kg) was used to induce acute lung injury in mice. In vitro, the bronchial epithelial cell line (Beas-2b) was treated with 30 μM tert-butyl hydroperoxide (t-BHP) to simulate oxidative stress. Our findings demonstrate that pretreatment with C27 reduces LPS-induced oxidative destruction and cellular apoptosis in lung tissues of mice. Furthermore, it significantly attenuates t-BHP-induced cellular reactive oxygen species (ROS) generation, mitochondrial damage, and apoptosis in vitro. Mechanistically, the signaling pathway involving Nrf2-Keap1 and the downstream antioxidative proteins were activated by C27 in vivo. Additionally, PI3K inhibitor LY294002 and Nrf2 inhibitor ML385 abolished the effect of C27 in vitro, indicating that the protective effect of C27 is mediated via the PI3K/AKT/Nrf2-Keap1 pathway. Our study provides evidence that C27 protects against LPS-induced ALI by mitigating oxidative stress via activation of the PI3K/AKT/Nrf2-Keap1 signaling pathway. Therefore, we hypothesize that C27 represents a viable alternative for ALI therapy.
摘要：
急性肺损伤(ALI)是一种高度异质性的临床综合征,是导致危重患者死亡的重要原因,目前可用的治疗选择有限。Chalcone,在可食用或药用植物中发现的必需次生代谢产物，具有良好的抗氧化活性，结构简单，易于合成。在我们的研究中,我们合成了一种新的查尔酮衍生物,化合物27(C27)。我们假设C27可能是急性呼吸窘迫综合征（ARDS）的潜在治疗方法。因此,研究了C27在ALI期间对肺上皮细胞的保护作用及其潜在的分子机制。在体内,气管内滴注LPS（10mg/kg）诱导小鼠急性肺损伤。体外，用30μM叔丁基过氧化氢（t-BHP）处理支气管上皮细胞系（Beas-2b）以模拟氧化应激。我们的发现表明，用C27预处理可以减少LPS诱导的小鼠肺组织的氧化破坏和细胞凋亡。此外，它显著减弱t-BHP诱导的细胞活性氧（ROS）的产生，线粒体损伤，和体外凋亡。机械上,涉及Nrf2-Keap1和下游抗氧化蛋白的信号通路在体内被C27激活。此外,PI3K抑制剂LY294002和Nrf2抑制剂ML385在体外消除了C27的作用，表明C27的保护作用是通过PI3K/AKT/Nrf2-Keap1途径介导的。我们的研究提供了证据，表明C27通过激活PI3K/AKT/Nrf2-Keap1信号通路减轻氧化应激来保护LPS诱导的ALI。因此,我们假设C27代表ALI治疗的可行替代方案.
