Zhu Qing, Tao Ye, Han Yuanshan, He Ying, Fu Yilan, Yang Hui, Chen Yun, Shi Yingrui
Department of Pharmacy, Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Central South University, Xiangya School of Medicine, Changsha, Hunan, China.
Phytother Res. 2025 May 2. doi: 10.1002/ptr.8513.
Breast cancer is associated with a higher incidence of depression and decreased quality of life. Previous studies have indicated that quercetin can mitigate the advancement of breast cancer-related depression (BCRD); however, the specific mechanism by which quercetin affects BCRD is yet to be determined. In this study, we aimed to examine the effect of quercetin on BCRD and explore the underlying mechanisms. We established a mouse model of BCRD and administered quercetin. LC-MS was used to analyze and determine distinct alterations in metabolites in mouse tumor samples. Polymorphonuclear neutrophils (PMNs) were extracted from mouse femurs and treated with PMA and quercetin/Sphingosine 1-phosphate (S1P). Mouse breast cancer cells 4 T1 were treated with lipopolysaccharides (LPS), neutrophil extracellular traps (NETs) and S1P. Neuronal cells were treated with LPS, NETs, S1P, and Corticosterone. Pearson's correlation coefficient was used to evaluate the relationship between differential metabolites and NETs. Quercetin inhibited NET formation in BCRD mice. In vitro, quercetin reversed NET-induced 4 T1 cell proliferation, migration, and ROS production. Quercetin also reversed the effects of NET-induced 4 T1 cells on neuronal cells. LC-MS analysis demonstrated that quercetin ameliorated the metabolic abnormalities in the tumors of BCRD mice. Pearson's correlation analysis showed that S1P, Oleoyl glycine, N-Arachidonoylglycine, 2, 3-butanediol apiosylglucoside, and tetracosatetraenoyl carnitine levels positively correlated with MPO DNA levels. Furthermore, in vitro, S1P enhanced NET-induced 4 T1 cell proliferation, migration, and ROS production, as well as enhanced NET-induced 4 T1 cell damage to neuronal cells. Quercetin alleviated BCRD by inhibiting NETs via inhibition of the S1P/S1PR axis.
乳腺癌与抑郁症发病率较高及生活质量下降相关。先前的研究表明，槲皮素可减轻乳腺癌相关抑郁症（BCRD）的进展；然而，槲皮素影响BCRD的具体机制尚待确定。在本研究中，我们旨在研究槲皮素对BCRD的影响并探索其潜在机制。我们建立了BCRD小鼠模型并给予槲皮素。采用液相色谱-质谱联用（LC-MS）分析并确定小鼠肿瘤样本中代谢物的明显变化。从小鼠股骨中提取多形核中性粒细胞（PMN），并用佛波酯（PMA）和槲皮素/鞘氨醇-1-磷酸（S1P）进行处理。用脂多糖（LPS）、中性粒细胞胞外陷阱（NETs）和S1P处理小鼠乳腺癌细胞4T1。用LPS、NETs、S1P和皮质酮处理神经元细胞。采用Pearson相关系数评估差异代谢物与NETs之间的关系。槲皮素抑制BCRD小鼠的NET形成。在体外，槲皮素可逆转NET诱导的4T1细胞增殖、迁移和活性氧（ROS）生成。槲皮素还可逆转NET诱导的4T1细胞对神经元细胞的影响。LC-MS分析表明，槲皮素改善了BCRD小鼠肿瘤中的代谢异常。Pearson相关分析表明，S1P、油酰甘氨酸、N-花生四烯酰甘氨酸、2,3-丁二醇芹菜糖基葡萄糖苷和二十四碳四烯酰肉碱水平与髓过氧化物酶（MPO）DNA水平呈正相关。此外，在体外，S1P增强了NET诱导的4T1细胞增殖、迁移和ROS生成，以及增强了NET诱导的4T1细胞对神经元细胞的损伤。槲皮素通过抑制S1P/S1PR轴来抑制NETs，从而减轻BCRD。
