Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Sci Rep. 2024 Jan 2;14(1):287. doi: 10.1038/s41598-023-50712-1.
The fusion of mononuclear trophoblasts into multinucleate syncytiotrophoblasts is the critical event in the process of syncytialization, and its dysregulation can lead to pregnancy complications, notably hypertensive disorders of pregnancy (HDP). Oxidative stress may disrupt trophoblast syncytialization in HDP. Specifically, placentas with HDP exhibit impaired mitochondria, giving rise to the generation of reactive oxygen species (ROS) and subsequent oxidative stress. Quercetin, a bioflavonoid known for its antioxidant and anti-aging properties, has the potential to mitigate oxidative stress during trophoblast syncytialization. However, the precise mechanism underlying the action of quercetin in these processes remains to be elucidated. To explore the impact of quercetin on syncytialization, mitochondrial function, and ROS generation, cyclic AMP-stimulated BeWo cells were treated with quercetin. The expression of markers associated with cell fusion, mitochondrial function, and oxidative stress was determined using qPCR and western blotting. Additionally, morphological syncytialization and mitophagy (mitochondrial degradation) were assessed by immunofluorescence analysis. Our results revealed that quercetin increased the expression of syncytialization markers and promoted cell fusion. Furthermore, this compound also upregulated markers associated with mitophagy and mitochondrial fusion, which are corroborated by visual evidence of mitophagy through the fluorescence microscope. Cell fusion naturally stimulated ROS generation, which was attenuated by quercetin. Quercetin downregulated the expression of NRF2 and HO-1 during syncytialization, while increasing the expression of sirtuin1/3/6, which are known to play essential roles in antioxidant responses. In conclusion, quercetin effectively regulates mitochondrial function through its antioxidant properties and the suppression of ROS generation, ultimately promoting trophoblast fusion, suggesting that the flavonoid has the potential to ameliorate pregnancy-related disorder stemming from placental dysplasia.
单核滋养细胞融合为多核合体滋养细胞是合胞体化过程中的关键事件，其失调可导致妊娠并发症，特别是妊娠高血压疾病（HDP）。氧化应激可能会破坏 HDP 中的滋养细胞合胞体化。具体来说，HDP 胎盘表现出受损的线粒体，导致活性氧物种（ROS）的产生和随后的氧化应激。槲皮素是一种具有抗氧化和抗衰老特性的生物类黄酮，具有减轻滋养细胞合胞体化过程中氧化应激的潜力。然而，槲皮素在这些过程中的作用的精确机制仍有待阐明。为了探讨槲皮素对合胞体化、线粒体功能和 ROS 生成的影响，用槲皮素处理环 AMP 刺激的 BeWo 细胞。使用 qPCR 和 Western blot 测定与细胞融合、线粒体功能和氧化应激相关的标志物的表达。此外，通过免疫荧光分析评估形态合胞体化和线粒体自噬（线粒体降解）。我们的结果表明，槲皮素增加了合胞体化标志物的表达并促进了细胞融合。此外，该化合物还上调了与线粒体自噬和线粒体融合相关的标志物，通过荧光显微镜观察到线粒体自噬的视觉证据进一步证实了这一点。细胞融合自然会刺激 ROS 的产生，而槲皮素可以减弱这种产生。在合胞体化过程中，槲皮素下调了 NRF2 和 HO-1 的表达，同时增加了 Sirtuin1/3/6 的表达，Sirtuin1/3/6 已知在抗氧化反应中发挥重要作用。总之，槲皮素通过其抗氧化特性和抑制 ROS 生成有效调节线粒体功能，最终促进滋养细胞融合，这表明该类黄酮有可能改善由胎盘发育不良引起的妊娠相关疾病。
