Fangxia Dihuang Formula regulates PERK/eIF2α axis-mediated microglial polarization in treatment of breast cancer complicated by depression.
10.19540/j.cnki.cjcmm.20250325.501
- Author:
Hong-Qiao FAN
1
;
Ying-Yi FAN
2
;
Xiao-Hua PEI
2
Author Information
1. Department of Surgery of Traditional Chinese Medicine, the First Hospital of Hunan University of Chinese Medicine Changsha 410007, China Department of Breast, Xiamen Hospital, Beijing University of Chinese Medicine Xiamen 361000, China.
2. Department of Breast, Beijing University of Chinese Medicine Third Affiliated Hospital Beijing 100029, China.
- Publication Type:Journal Article
- Keywords:
Fangxia Dihuang Formula;
PERK/eIF2α axis;
breast cancer complicated by depression;
microglial polarization
- MeSH:
Animals;
Drugs, Chinese Herbal/administration & dosage*;
Female;
Microglia/cytology*;
Mice;
Depression/complications*;
eIF-2 Kinase/genetics*;
Humans;
Breast Neoplasms/psychology*;
Eukaryotic Initiation Factor-2/genetics*;
Mice, Inbred BALB C;
Signal Transduction/drug effects*;
Cell Line, Tumor
- From:
China Journal of Chinese Materia Medica
2025;50(14):4015-4025
- CountryChina
- Language:Chinese
-
Abstract:
Study on the mechanism of Fangxia Dihuang Formula(FXDH) in treating breast cancer complicated with depression through the regulation of M1/M2 microglial polarization via the PERK/eIF2α axis. In addition to control group and 4T1 group, a mouse model of breast cancer complicated with depression was established using 4T1 cells combined with corticosterone. The mice were divided into model group, PERK/eIF2α signaling axis agonist(CCT020312, 2 mg·kg~(-1)·d~(-1)) group, CCT020312(2 mg·kg~(-1)·d~(-1)) + FXDH(13.65 g·kg~(-1)·d~(-1)) group, FXDH(13.65 g·kg~(-1)·d~(-1)) group, FXDH(13.65 g·kg~(-1)·d~(-1)) + Capecitabine Tablets(CAP, 390 mg·kg~(-1)·d~(-1)) group, and Fluoxetine Hydrochloride Capsules(FXT, 2.6 mg·kg~(-1)·d~(-1)) + CAP(390 mg·kg~(-1)·d~(-1)) group, with continuous intervention for 21 d. Depression-like behaviors in mice were assessed through sugar preference test and open field test. Hematoxylin-eosin(HE) staining was used to evaluate the morphology of tumor and hippocampal DG region neurons. Nissl staining was employed to detect changes in Nissl bodies in the hippocampal CA3 region. Immunofluorescence was used to observe cluster of differentiation 86(CD86)/ionized calcium-binding adapter molecule 1(Iba-1) and cluster of differentiation 206(CD206)/Iba-1 in hippocampal tissue. Real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) was used to detect the mRNA expression of M1-type microglia [interleukin-6(IL-6), tumor necrosis factor-α(TNF-α)] and M2-type [arginase-1(Arg-1), IL-10] in hippocampal tissue. Western blot was used to detect the protein expression of key factors in the PERK/eIF2α axis, including PERK, eIF2α, activating transcription factor 4(ATF4), and C/EBP homologous protein(CHOP) in hippocampal tissue. The results showed that compared to model group/CCT020312 + FXDH group, FXDH group increased sugar preference index, total movement distance, central zone distance, and central zone entries; reduced tumor mass and volume; tumor cells were sparsely arranged, with a smaller nuclear-to-cytoplasmic ratio and reduced nuclear division figures, increased Nissl body count, and alleviated neuronal nuclear pyknosis; increased CD206-positive M2-type microglia expression, decreased CD86/Iba-1-positive M1-type microglia expression; reduced IL-6 and TNF-α mRNA expression, and increased Arg-1 and IL-10 mRNA expression; downregulated PERK, eIF2α, ATF4, and CHOP protein expression levels. The results indicate that the mechanism of FXDH in treating breast cancer complicated with depression may be related to inhibiting the activity of the PERK/eIF2α axis, reducing the proportion of M1-type microglia, increasing the proportion of M2-type microglia, thereby suppressing neuronal immune inflammation, improving depressive symptoms, and subsequently delaying the progression of breast cancer.
