开心散通过减轻前额叶皮质铁死亡缓解小鼠的阿霉素化疗性抑郁

doi:10.12122/j.issn.1673-4254.2024.08.02

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (8): 1441-1449.doi: 10.12122/j.issn.1673-4254.2024.08.02

开心散通过减轻前额叶皮质铁死亡缓解小鼠的阿霉素化疗性抑郁

欧阳明子¹(), 崔佳琦¹, 王慧¹, 梁正¹, 皮大锦¹, 陈利国¹, 陈前军²^,³^,⁴(), 吴迎朝¹^,²^,³^,⁴^,⁵()

^1.暨南大学中医学院，广东广州 510632
^2.广州中医药大学第二附属医院中医证候全国重点实验室，广东广州 510120
^3.广东省中医院乳腺科，广东广州 510120
^4.广东省中医药科学院，广东广州 510120
^5.广州中医药大学第二临床医学院，广东广州 510405

收稿日期:2024-05-09 出版日期:2024-08-20 发布日期:2024-09-06
通讯作者: 陈前军,吴迎朝 E-mail:mingzioy@jnu.edu.cn;cqj55@163.com;yc1996@stu2020.jnu.edu.cn
作者简介:欧阳明子，博士，副教授、副主任医师，硕士生导师，E-mail: mingzioy@jnu.edu.cn
基金资助:
国家自然科学基金(81873155);广东省自然科学基金(2020A15110760);广州市科技计划(SL2023A03J01120);广东省中医院中医药科技专项科研项目(YN2022QN32);广东省中医证候临床研究重点实验室项目(YN2023ZH10);中医湿证国家重点实验室自主项目(QZ2023ZZ13);第七批全国老中医药专家学术经验继承工作

Kaixinsan alleviates adriamycin-induced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex

Mingzi OUYANG¹(), Jiaqi CUI¹, Hui WANG¹, Zheng LIANG¹, Dajin PI¹, Liguo CHEN¹, Qianjun CHEN²^,³^,⁴(), Yingchao WU¹^,²^,³^,⁴^,⁵()

^1.College of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China
^2.State Key Laboratory of Traditional Chinese Medicine Syndrome, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
^3.Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China
^4.Guangdong Academy of Traditional Chinese Medicine, Guangzhou 510120, China
^5.Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510405, China

Received:2024-05-09 Online:2024-08-20 Published:2024-09-06
Contact: Qianjun CHEN, Yingchao WU E-mail:mingzioy@jnu.edu.cn;cqj55@163.com;yc1996@stu2020.jnu.edu.cn
Supported by:
National Natural Science Foundation of China(81873155)

摘要/Abstract

摘要：

目的明确中药复方开心散缓解乳腺癌阿霉素化疗性抑郁的疗效，并分析其药理机制。方法将40只雌性BALB/c小鼠通过原位注射4T1细胞建立乳腺癌小鼠模型，将小鼠随机分为对照组、模型组、开心散低剂量组和开心散高剂量组，10只/组。通过旷场试验和高架十字迷宫实验行为学分析、抑郁相关因子血清学检测、转录组学分析、透射电镜病理分析和铁死亡相关因子检测分析阿霉素诱导的化疗性抑郁产生的病因以及开心散的作用机制。利用SH-SY5Y细胞系构建体外模型并使用铁死亡抑制剂Fer-1进行阳性对照，验证动物实验结果。结果开心散显著逆转阿霉素化疗所致的抑郁样行为（P<0.001）、逆转抑郁相关血清学的改变（P<0.05）；转录组学结果显示，开心散缓解化疗性抑郁与调控前额叶皮质组织氧化应激、脂质代谢和铁离子结合等过程有关；病理学分析、铁死亡相关因子检测结果显示，开心散能减轻阿霉素化疗所致的前额叶皮质组织铁死亡（P<0.01）。体外实验结果也显示，开心散含药血清和铁死亡抑制剂均能逆转阿霉素诱导的神经细胞铁死亡（P<0.001）。结论开心散通过减轻乳腺癌阿霉素化疗所致的大脑前额叶皮质组织铁死亡，进而缓解化疗性抑郁。

关键词: 开心散, 乳腺癌, 化疗, 抑郁, 铁死亡

Abstract:

Objective To investigate the effect of Kaixinsan (KXS, a traditional Chinese medicine formula) for alleviating adriamycin-induced depression-like behaviors in mice bearing breast cancer xenografts and explore the pharmacological mechanism. Methods Forty female BALB/c mice were randomized equally into control group, model group, and low- and high-dose KXS treatment groups, and in the latter 3 groups, mouse models bearing orthotopic breast cancer 4T1 cell xenografts were established and treated with adriamycin along with saline or KXS via gavage. Depression-like behaviors of the mice were assessed using open field test and elevated plus-maze test, and the changes in serum levels of depression-related factors were examined. RNA-seq analysis and transmission electron microscopy were used and ferroptosis-related factors were detected to explore the mechanisms of adriamycin-induced depression and the therapeutic mechanism of KXS. The results were verified in SH-SY5Y cells using ferroptosis inhibitor Fer-1 as the positive control. Results KXS significantly alleviated depression-like behaviors and depression-related serological changes induced by adriamycin in the mouse models. RNA-seq results suggested that KXS alleviated chemotherapy-induced depression by regulating oxidative stress, lipid metabolism and iron ion binding in the prefrontal cortex. Pathological analysis and detection of ferroptosis-related factors showed that KXS significantly reduced ferroptosis in the prefrontal cortex of adriamycin-treated mice. In SH-SY5Y cells, both KXS-medicated serum and the ferroptosis inhibitor were capable of attenuating adriamycin-induced cell ferroptosis. Conclusion KXS alleviates adriamycin-induced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex of breast cancer-bearing mice.

Key words: Kaixinsan, breast cancer, chemotherapy, depression, ferroptosis

欧阳明子, 崔佳琦, 王慧, 梁正, 皮大锦, 陈利国, 陈前军, 吴迎朝. 开心散通过减轻前额叶皮质铁死亡缓解小鼠的阿霉素化疗性抑郁[J]. 南方医科大学学报, 2024, 44(8): 1441-1449.

Mingzi OUYANG, Jiaqi CUI, Hui WANG, Zheng LIANG, Dajin PI, Liguo CHEN, Qianjun CHEN, Yingchao WU. Kaixinsan alleviates adriamycin-induced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex[J]. Journal of Southern Medical University, 2024, 44(8): 1441-1449.

图/表 6

图1 开心散缓解阿霉素诱导行为学改变

Fig.1 KXS alleviates depression-like behaviors in breast cancer-bearing mice receiving adriamycin treatment. A: Path trace and path heat map in open field test. B: Total distance in open field test. *P<0.05, ***P<0.001 vs control group; ###P<0.001 vs model group; &&P<0.01, &&&P<0.001 vs KXS-L group (n=10).

图2 开心散对阿霉素引起的抑郁相关血清学改变的影响

Fig.2 Effect of KXS on depression-related serological changes induced by adriamycin in breast cancer-bearing mice. The diagrams show comparisons of serum CRH (A), ACTH (B), GC (C), CORT (D), 5-HT (E), NPY (F), NE (G) and BDNF (H) contents among the 4 groups. *P<0.05, **P<0.01, ***P<0.001 vs control group; #P<0.05, ##P<0.01, ###P<0.001 vs model group; &P<0.05, &&P<0.01, &&&P<0.001 vs KXS-L group (n=3).

图3 开心散缓解阿霉素诱导的抑郁作用靶点分析

Fig.3 Target analysis of KXS in alleviating adriamycin-induced depression. A: PCA plot of RNA-seq gene expression. B, C: Volcano plot of differentially expressed genes (DEGs) identified by RNA-seq. D: Venn diagram of the DGEs. E: Cluster heatmap of the common DGEs. F: PPI network of the common DGEs. G: Common DGEs interaction network degree value plot. The top 10 common DGEs are shown on the left.

图4 开心散缓解阿霉素诱导的抑郁靶点富集分析

Fig.4 Target enrichment analysis of KXS in alleviating adriamycin-induced depression. A: GO enrichment analysis of the common DGEs. From top to bottom: molecular function (MF), cellular component (CC), and biological process (BP). B: KEGG pathway enrichment analysis of the common DGEs. C: Reactome pathway enrichment analysis of the common DGEs.

图5 开心散抑制阿霉素引起的前额叶皮质组织铁死亡

Fig.5 KXS inhibits adriamycin-induced ferroptosis in the prefrontal cortex of the tumor-bearing mice. A: Transmission electron microscopy of the prefrontal cortex tissue of the mice. B: ROS content in the prefrontal cortex tissue. C: Iron content in the prefrontal cortex tissue. D: GSH content in the prefrontal cortex tissue. E: MDA content in the prefrontal cortex tissue. *P<0.05, **P<0.01, ***P<0.001 vs control group; #P<0.05, ##P<0.01, ###P<0.001 vs model group; &&P<0.01 vs KXS-L group (n=3).

图6 开心散含药血清对阿霉素处理的SH-SY5Y细胞的影响

Fig.6 Effect of KXS-medicated serum on adriamycin-treated SH-SY5Y cells. A:Growth of SH-SY5Y cells treated with medicated sera for 48 h (Blank: Serum derived from the control group; Adriamycin: Serum from model group containing 10 nmol/L Adriamycin; KXS-L: Serum from low-dose KXS treatment group containing 10 nmol/L Adriamycin; KXS-H: Serum from high-dose KXS treatment group containing 10 nmol/L Adriamycin; Fer-1: Serum from model group containing 10 nmol/L adriamycin and 2 μmol/L Fer-1). B: Cell viability measured by MTT colorimetric assay. C: Lipid ROS content in cell cultures. D: Iron content in the cell cultures. E: GSH content in the cell cultures. F: MDA content in the cell cultures. *P<0.05, **P<0.01, ***P<0.001 vs blank group; ##P<0.01, ###P<0.001 vs adriamycin group; &&P<0.01, &&&P<0.001 vs KXS-L group (n=3).

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开心散通过减轻前额叶皮质铁死亡缓解小鼠的阿霉素化疗性抑郁

Kaixinsan alleviates adriamycin-induced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex

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