PDF(Pubmed)
Abstract：
The combination of a polyphenol, quercetin, with dasatinib initiated clinical trials to evaluate the safety and efficacy of senolytics in idiopathic pulmonary fibrosis, a lung disease associated with the presence of senescent cells. Another approach to senotherapeutics consists of controlling inflammation related to cellular senescence or \"inflammaging\", which participates, among other processes, in establishing pulmonary fibrosis. We evaluate whether polyphenols such as caffeic acid, chlorogenic acid, epicatechin, gallic acid, quercetin, or resveratrol combined with different senotherapeutics such as metformin or rapamycin, and antifibrotic drugs such as nintedanib or pirfenidone, could present beneficial actions in an in vitro model of senescent MRC-5 lung fibroblasts. A senescent-associated secretory phenotype (SASP) was evaluated by the measurement of interleukin (IL)-6, IL-8, and IL-1β. The senescent-associated β-galactosidase (SA-β-gal) activity and cellular proliferation were assessed. Fibrosis was evaluated using a Picrosirius red assay and the gene expression of fibrosis-related genes. Epithelial-mesenchymal transition (EMT) was assayed in the A549 cell line exposed to Transforming Growth Factor (TGF)-β in vitro. The combination that demonstrated the best results was metformin and caffeic acid, by inhibiting IL-6 and IL-8 in senescent MRC-5 cells. Metformin and caffeic acid also restore cellular proliferation and reduce SA-β-gal activity during senescence induction. The collagen production by senescent MRC-5 cells was inhibited by epicatechin alone or combined with drugs. Epicatechin and nintedanib were able to control EMT in A549 cells. In conclusion, caffeic acid and epicatechin can potentially increase the effectiveness of senotherapeutic drugs in controlling lung diseases whose pathophysiological component is the presence of senescent cells and fibrosis.
摘要：
多酚的组合，槲皮素,达沙替尼启动了临床试验，以评估senolytics在特发性肺纤维化中的安全性和有效性，与衰老细胞的存在有关的肺部疾病。另一种治疗方法包括控制与细胞衰老或“炎症”相关的炎症，参与,在其他过程中，建立肺纤维化。我们评估咖啡酸等多酚，绿原酸,表儿茶素,没食子酸,槲皮素,或白藜芦醇与二甲双胍或雷帕霉素等不同的安乐药联合使用，和抗纤维化药物如尼达尼布或吡非尼酮，可以在衰老MRC-5肺成纤维细胞的体外模型中表现出有益的作用。通过测量白介素（IL）-6，IL-8和IL-1β来评估衰老相关的分泌表型（SASP）。评估了衰老相关的β-半乳糖苷酶（SA-β-gal）活性和细胞增殖。使用Picrosiriusred测定和纤维化相关基因的基因表达来评估纤维化。在体外暴露于转化生长因子（TGF）-β的A549细胞系中测定了上皮-间质转化（EMT）。显示最佳结果的组合是二甲双胍和咖啡酸，通过抑制衰老MRC-5细胞中的IL-6和IL-8。二甲双胍和咖啡酸还在衰老诱导期间恢复细胞增殖并降低SA-β-gal活性。表儿茶素单独或与药物联合抑制衰老MRC-5细胞产生胶原蛋白。表儿茶素和尼达尼布能够控制A549细胞中的EMT。总之,咖啡酸和表儿茶素可能会增加治疗药物在控制肺部疾病的有效性，其病理生理成分是衰老细胞和纤维化的存在。
