Department of Pharmacy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, PR China.
Research Office of the First Hospital of Hunan University of Chinese Medicine, Changsha 410007, PR China.
Phytomedicine. 2024 Jul 25;130:155560. doi: 10.1016/j.phymed.2024.155560. Epub 2024 Apr 4.
Quercetin, the key ingredient in Xiaoyao Kangai Jieyu Formula, has been previously found to relieve breast cancer-related depression (BCRD).
We want to explore the potential mechanisms and therapeutic targets of quercetin alleviating BCRD.
BALB/c mice were injected subcutaneously with 4T1 cells and corticosterone (CORT) to create a BCRD mice model. The primary hippocampal neurons were co-induced with 10 μg/ml lipopolysaccharide (LPS) and 200 μM CORT for 6 h to establish an in vitro model of BCRD. Quercetin was applied to explore its effect on disease symptoms, gut microbiota, and lipid metabolism of BCRD mice. Lipid metabolism-related genes were screened based on network pharmacology. Molecular docking was employed to prove whether quercetin bound to prostaglandin-endoperoxide synthase 2 (PTGS2). PTGS2 overexpression was carried out to explore the underlying mechanism of quercetin treatment on BCRD.
Quercetin treatment not only altered the composition and abundance of gut microbiota but also alleviated abnormal lipid metabolism in BCRD mice. In particular, quercetin down-regulated BCRD and lipid metabolism-related genes screened by network pharmacology, especially PTGS2. Further, molecular docking verified the stable binding between quercetin and PTGS2. In hippocampal neurons, quercetin promoted proliferation but reduced ferroptosis-related markers (total Fe, Fe2+, MDA, and ROS) levels by targeting PTGS2. In BCRD mice, quercetin reduced the high immobility time and increased the sucrose preference rate and serotonin (5-HT), dopamine (DA), and noradrenaline (NE) levels. Meanwhile, quercetin increased CD4+/CD8+ T cells ratio and IL-2 and IFN-γ levels but reduced CA153 and IL-10 levels to alleviate BCRD development. However, PTGS2 overexpression reversed these effects of quercetin on BCRD.
Quercetin inhibited neuronal ferroptosis and promoted immune responses in BCRD mice by targeting the lipid metabolism-related gene PTGS2. This provided a reference for quercetin in the treatment of BCRD.
槲皮素是逍遥抗癌解郁方的主要成分，先前已被发现可缓解乳腺癌相关抑郁（BCRD）。
我们旨在探索槲皮素缓解 BCRD 的潜在机制和治疗靶点。
BALB/c 小鼠皮下注射 4T1 细胞和皮质酮（CORT），建立 BCRD 小鼠模型。原代海马神经元与 10μg/ml 脂多糖（LPS）和 200μM CORT 共同诱导 6 小时，建立 BCRD 体外模型。用槲皮素处理以探讨其对疾病症状、肠道微生物群和 BCRD 小鼠脂质代谢的影响。基于网络药理学筛选脂质代谢相关基因。采用分子对接验证槲皮素是否与前列腺素内过氧化物合酶 2（PTGS2）结合。进行 PTGS2 过表达以探索槲皮素治疗 BCRD 的潜在机制。
槲皮素治疗不仅改变了肠道微生物群的组成和丰度，还缓解了 BCRD 小鼠的异常脂质代谢。特别是，网络药理学筛选的 BCRD 和脂质代谢相关基因被槲皮素下调，尤其是 PTGS2。进一步的分子对接验证了槲皮素与 PTGS2 的稳定结合。在海马神经元中，槲皮素通过靶向 PTGS2 促进增殖，但降低铁死亡相关标志物（总铁、Fe2+、MDA 和 ROS）水平。在 BCRD 小鼠中，槲皮素降低了高不动时间，增加了蔗糖偏好率和血清素（5-HT）、多巴胺（DA）和去甲肾上腺素（NE）水平。同时，槲皮素增加了 CD4+/CD8+T 细胞比例以及 IL-2 和 IFN-γ 水平，但降低了 CA153 和 IL-10 水平，从而缓解 BCRD 进展。然而，PTGS2 过表达逆转了槲皮素对 BCRD 的这些作用。
槲皮素通过靶向脂质代谢相关基因 PTGS2 抑制 BCRD 小鼠神经元铁死亡并促进免疫反应。这为槲皮素治疗 BCRD 提供了参考。
