Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
Phytomedicine. 2024 Jun;128:155427. doi: 10.1016/j.phymed.2024.155427. Epub 2024 Feb 7.
Depression is a clinically common co-morbidity in breast cancer cases that brings negative outcomes on quality of life and potentially survival. Jiawei Xiaoyao Wan (JXW) is widely used in treating breast cancer and depressive disorder, but its potential pharmacological mechanisms remain elusive.
We aimed to explore the dual therapeutic effects and mechanisms of JXW acting on breast cancer complicated with depression (BCCD) by network pharmacology and in vivo experimental verification.
The chemical constituents of JXW were characterized using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-Q-TOF/MS). The targets related to constituents of JXW were predicted by the TCMSP and Swiss Target Prediction databases, and targets of breast cancer and depression were screened by the GeneCards and OMIM databases. Gene Ontology annotation and KEGG enrichment analysis were performed with the DAVID database. Ultimately, a BCCD mouse model induced by chronic restraint stress (CRS) was used to explore therapeutic effects and mechanisms of JXW against BCCD. The efficacy of JXW in the treatment of BCCD was evaluated based on behavioral tests, tumor volume and weight, and pathological examination. Additionally, the underlying mechanisms were explored by measuring the levels of neurotransmitter and inflammatory factors, as well as detecting the expression of genes or proteins associated with candidate targets and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway through RT-PCR, western blotting, and immunohistochemistry.
Totals of 108 components were identified in JXW using LC-Q-TOF/MS. By network pharmacology analysis, 714 compound targets of JXW, 2114 breast cancer targets, 1122 depression targets, and 98 overlapping proteins were obtained. PPI network and KEGG analysis implied that TP53, ESR1, VEGFA, AKT1, IL6, TNF, EGFR and the JAK/STAT pathway might be the potential targets of JXW in treating BCCD. In vivo experiments indicated that JXW significantly ameliorated depressive symptoms and tumor progression in BCCD mice. Further mechanistic studies showed that JXW could reduce the levels of inflammatory factors, increase 5-HT level, and regulate mRNA expression levels of TP53, VEGFA, AKT1, IL6, TNF, and EGFR targets. Moreover, the expression levels of proteins related to the JAK2/STAT3 signaling pathway in BCCD mice were effectively regulated by JXW.
JXW exerts dual therapeutic effects in a BCCD mouse via multiple targets. The underlying mechanisms might be associated with regulating the levels of neurotransmitter and inflammatory factors; more importantly, the JAK2/STAT3 pathway plays a significant role in this process.
抑郁症是乳腺癌病例中一种常见的临床合并症，会对生活质量和潜在生存产生负面影响。加味逍遥丸（JXW）广泛用于治疗乳腺癌和抑郁症，但它的潜在药理机制仍不清楚。
我们旨在通过网络药理学和体内实验验证来探索 JXW 对乳腺癌合并抑郁症（BCCD）的双重治疗作用和机制。
采用液相色谱-四级杆飞行时间串联质谱法（LC-Q-TOF/MS）对 JXW 的化学成分进行了表征。通过 TCMSP 和瑞士靶向预测数据库预测与 JXW 成分相关的靶点，并通过基因卡片和 OMIM 数据库筛选乳腺癌和抑郁症的靶点。使用 DAVID 数据库进行基因本体论注释和 KEGG 富集分析。最终，使用慢性束缚应激（CRS）诱导的 BCCD 小鼠模型探索 JXW 对 BCCD 的治疗作用和机制。基于行为测试、肿瘤体积和重量以及组织病理学检查，评估 JXW 治疗 BCCD 的疗效。此外，通过测量神经递质和炎症因子的水平，以及通过 RT-PCR、western blot 和免疫组织化学检测与候选靶点和 Janus 激酶/信号转导和转录激活因子（JAK/STAT）信号通路相关的基因或蛋白的表达，来探讨潜在机制。
通过 LC-Q-TOF/MS 鉴定出 JXW 中的 108 种成分。通过网络药理学分析，获得了 JXW 的 714 个化合物靶点、2114 个乳腺癌靶点、1122 个抑郁症靶点和 98 个重叠蛋白。PPI 网络和 KEGG 分析表明，TP53、ESR1、VEGFA、AKT1、IL6、TNF、EGFR 和 JAK/STAT 通路可能是 JXW 治疗 BCCD 的潜在靶点。体内实验表明，JXW 可显著改善 BCCD 小鼠的抑郁症状和肿瘤进展。进一步的机制研究表明，JXW 可降低炎症因子水平，增加 5-HT 水平，并调节 TP53、VEGFA、AKT1、IL6、TNF 和 EGFR 靶点的 mRNA 表达水平。此外，JXW 可有效调节 BCCD 小鼠中与 JAK2/STAT3 信号通路相关的蛋白表达水平。
JXW 通过多种靶点对 BCCD 小鼠发挥双重治疗作用。其潜在机制可能与调节神经递质和炎症因子水平有关；更重要的是，JAK2/STAT3 通路在这一过程中起着重要作用。
