Delenko Julia, Hyman Nathaniel, Chatterjee Prodyot K, Safaric Tepes Polona, Shih Andrew J, Xue Xiangying, Gurney Jane, Baker Andrew G, Wei Cheng, Munoz Espin Daniel, Fruk Ljiljana, Gregersen Peter K, Metz Christine N
Northwell, 2000 Marcus Ave, Suite 300, New Hyde Park, NY 11042, USA.
The Feinstein Institutes for Medical Research/Northwell, 350 Community Drive, Manhasset, NY 11030, USA.
Biomolecules. 2025 Jun 16;15(6):873. doi: 10.3390/biom15060873.
Cellular senescence leads to stable cell cycle arrest and an inflammatory senescence-associated secretory phenotype that varies with stressor and cell type. To mitigate these effects and improve health, senotherapeutics (e.g., senolytics and senomorphics) have been developed. Senescent-like endometrial stromal cells (eSCs) lining the uterus of patients with endometriosis and infertility are proposed to impair decidualization, a differentiation process required for uterine receptivity in humans. Quercetin, a natural flavonoid senolytic, dramatically improves decidualization and reduces endometriosis in rodent models. However, little is known about the comparative effects of various senotherapeutics on eSCs. Using menstrual effluent-derived eSCs, we evaluated the effects of flavonoid and non-flavonoid compounds on eSC functions associated with endometriosis, aiming to identify optimal senotherapeutics for future clinical trials. Among flavonoids tested, all senolytics (quercetin, fisetin, and luteolin) and kaempferol, a senomorphic, significantly improved decidualization without cytotoxicity. Although non-flavonoids exhibited notable cytotoxicity, dasatinib, but neither ABT-737 nor navitoclax, enhanced decidualization. Flavonoid senotherapeutics and dasatinib significantly inhibited eSC migration. Mechanistic studies revealed that all flavonoids and dasatinib suppressed AKT phosphorylation and upregulated p53 expression. Notably, only quercetin and fisetin reduced ERK1/2 phosphorylation. Furthermore, flavonoid-senolytics and dasatinib consistently eliminated senescent eSCs. These findings support future studies to assess the therapeutic potential of in vivo supplementation with flavonoid senolytics on eSC function using menstrual effluent.
细胞衰老会导致稳定的细胞周期停滞以及一种与衰老相关的炎症性分泌表型，该表型会因应激源和细胞类型的不同而有所变化。为了减轻这些影响并改善健康状况，人们开发了衰老治疗药物（如衰老溶解剂和衰老形态调节剂）。据推测，子宫内膜异位症和不孕症患者子宫内的衰老样子宫内膜基质细胞（eSCs）会损害蜕膜化，而蜕膜化是人类子宫接受性所需的分化过程。槲皮素是一种天然的类黄酮衰老溶解剂，在啮齿动物模型中能显著改善蜕膜化并减轻子宫内膜异位症。然而，关于各种衰老治疗药物对eSCs的比较作用，人们知之甚少。我们使用月经流出物来源的eSCs，评估了类黄酮和非类黄酮化合物对与子宫内膜异位症相关的eSC功能的影响，旨在确定未来临床试验的最佳衰老治疗药物。在所测试的类黄酮中，所有的衰老溶解剂（槲皮素、非瑟酮和木犀草素）以及一种衰老形态调节剂山奈酚，均能显著改善蜕膜化且无细胞毒性。尽管非类黄酮表现出显著的细胞毒性，但达沙替尼能增强蜕膜化，而ABT - 737和navitoclax则不能。类黄酮衰老治疗药物和达沙替尼显著抑制eSC迁移。机制研究表明，所有类黄酮和达沙替尼均抑制AKT磷酸化并上调p53表达。值得注意的是，只有槲皮素和非瑟酮能降低ERK1/2磷酸化。此外，类黄酮衰老溶解剂和达沙替尼能持续清除衰老的eSCs。这些发现为未来的研究提供了支持，即使用月经流出物评估体内补充类黄酮衰老溶解剂对eSC功能的治疗潜力。
