阿尔品乌司柚酮通过激活SIRT1改善H2O2诱导的细胞内损伤在先兆子痫细胞模型中的作用

Alpinumisoflavone ameliorates H2O2-induced intracellular damages through SIRT1 activation in pre-eclampsia cell models

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BIOORGANIC CHEMISTRY

影响因子:4.7

分区:医学2区 / 有机化学1区生化与分子生物学2区

发表日期:2024 Nov

作者: Woonghee Lee, Gwonhwa Song, Hyocheol Bae

DOI: 10.1016/j.bioorg.2024.107720

摘要

先兆子痫（PE）是一种孕期特异性高血压疾病，导致严重的胎儿和母体发病率与死亡率，影响发达及发展中国家大约3~8%的孕妇。然而，PE的确切发病机制尚未阐明，亟需开发创新的药物治疗。最新研究指出，胎盘氧化应激是PE发病的重要因素之一。因此，治疗PE的一种潜在策略是缓解胎盘的氧化应激。阿尔品乌司柚酮（AIF）是一种源自柚子果的 prenylated异黄酮，具有抗纤维化、抗炎、抗肿瘤和抗氧化等多种药理作用。然而，AIF在胎盘氧化应激条件下对外绒毛滋养层细胞（EVT）的保护作用尚未阐明。本研究评估了AIF对代表性EVT细胞系HTR-8/SVneo的存活、侵袭、迁移和线粒体功能的促进作用，并验证了AIF在减少凋亡、ROS生成和线粒体膜去极化方面的保护作用。通过分子对接分析确认了AIF与sirtuin1（SIRT1）的直接相互作用，并揭示了AIF通过SIRT1介导的信号通路发挥抗氧化保护作用的机制。最后，在绒毛滋养层细胞系BeWo中也证实了AIF对氧化应激的保护效果。这些结果提示，AIF可能通过激活SIRT1，减轻H2O2引起的人类滋养层细胞的细胞内损伤。

Abstract

Pre-eclampsia (PE) is classified as pregnancy-specific hypertensive disease and responsible for severe fetal and maternal morbidity and mortality, which influenced an approximate 3 ∼ 8 % of all pregnancies in both developed and developing countries. However, the exact pathological mechanism underlying PE has not been elucidated and it is urgent to find innovate pharmacotherapeutic agents for PE. Recent studies have reported that a crucial part of the etiology of PE is played by placental oxidative stress. Therefore, to treat PE, a possible treatment approach is to mitigate the placental oxidative stress. Alpinumisoflavone (AIF) is a prenylated isoflavonoid originated in mandarin melon berry called Cudrania tricuspidate, and is well known for its versatile pharmacotherapeutic properties, including anti-fibrotic, anti-inflammatory, anti-tumor, and antioxidant activity. However, protective property of AIF on extravillous trophoblast (EVT) under placental oxidative stress has not been elucidated yet. Therefore, we assessed stimulatory effects of AIF on the viability, invasion, migration, mitochondria function in the representative EVT cell line, HTR-8/SVneo cell. Moreover, protective activities of AIF from H2O2 were confirmed, in terms of reduction in apoptosis, ROS production, and depolarization of mitochondrial membrane. Furthermore, we confirmed the direct interaction of AIF with sirtuin1 (SIRT1) using molecular docking analysis and SIRT1-mediated signaling pathways associated with the protective effects of AIF on HTR-8/SVneo cells under oxidative stress. Finally, beneficial efficacy of AIF against oxidative stress was further confirmed using BeWo cells, syncytiotrophoblast cell lines. These results suggest that AIF may ameliorate H2O2-induced intracellular damages through SIRT1 activation in human trophoblast cells.