Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (6): 1238-1253.DOI: 10.19852/j.cnki.jtcm.20250929.002
• Original Articles • Previous Articles Next Articles
Four-dimensional data independent acquisition proteomics and metabolomics reveal mechanisms of hydrogen-rich water at Zusanli (ST36) point against triple-negative breast cancer in mice
LIU Jingxuan1, MO Qian1, LEI Guowu1, JIA Yejuan1, LI Aiying2, JIA Chunsheng1(
), PAN Lijia1()
- 1 College of Acupuncture and moxibustion and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
2 College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
-
Received:2025-06-03Accepted:2025-09-09Online:2025-12-15Published:2025-09-29 -
Contact:Prof. PAN Lijia, College of Acupuncture and moxibustion and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China. panlijia369@126.com, Telephone: +86-13373013018; +86-18032003570;
Prof. JIA Chunsheng, College of Acupuncture and moxibustion and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China. jia7158@163.com -
Supported by:Exploring the Advantages of Micro-needle System Therapy for Specific Diseases and the Patterns of Acupoint Selection through Data Mining Techniques(81473773);Exploring the Molecular Mechanism behind How Hydrogen Mitigates the Aging of Vascular Endothelial Cells Induced by Chronic Intermittent Hypoxia, Utilizing the Keap1-Nuclear factor erythroid 2-related factor 2 Signaling Pathway(ZD2020142);Inhibitory Effect and Mechanism of Hydrogen-rich Water Acupoint Injection on Tumors in Mice with Triple-negative Breast Cancer(CXZZBS2024154)
Cite this article
LIU Jingxuan, MO Qian, LEI Guowu, JIA Yejuan, LI Aiying, JIA Chunsheng, PAN Lijia. Four-dimensional data independent acquisition proteomics and metabolomics reveal mechanisms of hydrogen-rich water at Zusanli (ST36) point against triple-negative breast cancer in mice[J]. Journal of Traditional Chinese Medicine, 2025, 45(6): 1238-1253.
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Figure 1 Impact of injecting hydrogen-rich water into the Zusanli (ST36) acupoint on the growth of triple-negative breast cancer in mice A: variations in body mass, n = 8; B: tumor volumes of mice on day 1 of intervention, n = 8; C: tumor volume of mice on day 21 of intervention, n = 8. D: tumor weights of mice on day 21 of intervention, n = 8. E: tumor HE staining: Black stars, necrotic areas; black arrows, inflammatory cells; red arrows, mitotic figures; E1: Model group; E2: H2ST36 group; E3: AcST36 group; E4: NaST36 group; 200 ×; n = 3; F: statistical graph of TUNEL (TdT-mediated dUTP nick end labeling) fluorescence intensity, n = 3; G: TUNEL fluorescence intensity (scale bar =75 μm; 200 ×); G1: Model group-DAPI; G2: Model group-TUNEL; G3:Model group-Merge; G4: H2ST36 group-DAPI; G5: H2ST36 group-TUNEL; G6: H2ST36 group-Merge; G7: AcST36 group-DAPI; G8: AcST36 group-TUNEL; G9: AcST36 group-Merge; G10: NaST36 group-DAPI; G11: NaST36 group-TUNEL; G12: NaST36 group-Merge. Control and Model groups: no treatment + 21 d; H2ST36 group: hydrogen-rich water + 0.05 mL into each acupoint every other day + 21 d; AcST36 group: acupuncture + 15 min every other day + 21 d; NaST36 group: saline solution + 0.05 mL into each acupoint every other day + 21 d. HE: hematoxylin and eosin; H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; AcST36: acupuncture; NaST36: sodium chloride injection Zusanli (ST36); TUNEL: TdT-mediated dUTP nick end labeling; DAPI: ?4',6-diamidino-2-phenylindole. One-way analysis of variance was used to compare more than two groups, followed by the least significant difference test to detect differences between groups. The data are presented as the mean ± standard deviation. Comparison with the Model group, aP < 0.05; comparison with the H2ST36 group, bP < 0.05; comparison with the AcST36 group; cP < 0.05, comparison with the NaST36 group; dP < 0.05, comparison with the Control group, eP < 0.05.
Figure 1 Impact of injecting hydrogen-rich water into the Zusanli (ST36) acupoint on the growth of triple-negative breast cancer in mice A: variations in body mass, n = 8; B: tumor volumes of mice on day 1 of intervention, n = 8; C: tumor volume of mice on day 21 of intervention, n = 8. D: tumor weights of mice on day 21 of intervention, n = 8. E: tumor HE staining: Black stars, necrotic areas; black arrows, inflammatory cells; red arrows, mitotic figures; E1: Model group; E2: H2ST36 group; E3: AcST36 group; E4: NaST36 group; 200 ×; n = 3; F: statistical graph of TUNEL (TdT-mediated dUTP nick end labeling) fluorescence intensity, n = 3; G: TUNEL fluorescence intensity (scale bar =75 μm; 200 ×); G1: Model group-DAPI; G2: Model group-TUNEL; G3:Model group-Merge; G4: H2ST36 group-DAPI; G5: H2ST36 group-TUNEL; G6: H2ST36 group-Merge; G7: AcST36 group-DAPI; G8: AcST36 group-TUNEL; G9: AcST36 group-Merge; G10: NaST36 group-DAPI; G11: NaST36 group-TUNEL; G12: NaST36 group-Merge. Control and Model groups: no treatment + 21 d; H2ST36 group: hydrogen-rich water + 0.05 mL into each acupoint every other day + 21 d; AcST36 group: acupuncture + 15 min every other day + 21 d; NaST36 group: saline solution + 0.05 mL into each acupoint every other day + 21 d. HE: hematoxylin and eosin; H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; AcST36: acupuncture; NaST36: sodium chloride injection Zusanli (ST36); TUNEL: TdT-mediated dUTP nick end labeling; DAPI: ?4',6-diamidino-2-phenylindole. One-way analysis of variance was used to compare more than two groups, followed by the least significant difference test to detect differences between groups. The data are presented as the mean ± standard deviation. Comparison with the Model group, aP < 0.05; comparison with the H2ST36 group, bP < 0.05; comparison with the AcST36 group; cP < 0.05, comparison with the NaST36 group; dP < 0.05, comparison with the Control group, eP < 0.05.
Figure 2 OPLS-DA models and volcano plots of differential metabolites for different comparison groups (n = 5) A: OPLS-DA score plot of Model group vs H2ST36 group; B: OPLS-DA score plot of Control group vs H2ST36 group; C: OPLS-DA score plot of Control group vs Model group; D: OPLS-DA permutation plot of Model group vs H2ST36 group; E: OPLS-DA permutation plot of Control group vs H2ST36 group; F: OPLS-DA permutation plot of Control group vs Model group; G: volcano plot of Model group vs H2ST36 group; H: volcano plot of Control group vs H2ST36 group; I: volcano plot of Control group vs Model group. Control group: no treatment was administered to the mice following the sham surgery procedure; Model group: the mice received no post-modeling treatment, 21 d; H2ST36 group: inject hydrogen-rich water into the Zusanli (ST36) acupoint, inject 0.05 mL into each acupoint every other day, for a total of 21 d. H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; VIP: variable importance in projection; OPLS-DA: Orthogonal partial least squares discriminant analysis.
Figure 2 OPLS-DA models and volcano plots of differential metabolites for different comparison groups (n = 5) A: OPLS-DA score plot of Model group vs H2ST36 group; B: OPLS-DA score plot of Control group vs H2ST36 group; C: OPLS-DA score plot of Control group vs Model group; D: OPLS-DA permutation plot of Model group vs H2ST36 group; E: OPLS-DA permutation plot of Control group vs H2ST36 group; F: OPLS-DA permutation plot of Control group vs Model group; G: volcano plot of Model group vs H2ST36 group; H: volcano plot of Control group vs H2ST36 group; I: volcano plot of Control group vs Model group. Control group: no treatment was administered to the mice following the sham surgery procedure; Model group: the mice received no post-modeling treatment, 21 d; H2ST36 group: inject hydrogen-rich water into the Zusanli (ST36) acupoint, inject 0.05 mL into each acupoint every other day, for a total of 21 d. H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; VIP: variable importance in projection; OPLS-DA: Orthogonal partial least squares discriminant analysis.
Figure 3 Immunofluorescence assay for differentially expressed proteins A: analysis results of differential immunofluorescence staining for IL6ST; B: analysis results of differential immunofluorescence staining for NFATC4; C: analysis results of differential immunofluorescence staining for Lat; D: analysis results of differential immunofluorescence staining for STAT1; E: analysis results of differential immunofluorescence staining for MAPK10; F: analysis results of differential immunofluorescence staining for MAPK11; G: analysis results of differential immunofluorescence staining for PRKCQ. Model group: no post-modeling treatment + 21 d; H2ST36 group: inject hydrogen-rich water + 0.05 mL into each acupoint every other day + 21 d; AcST36 group: acupuncture stimulation + 15 min every other day + 21 d; NaST36 group: saline solution injection + 0.05 mL into each acupoint every other day + 21 d. H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; AcST36: acupuncture; NaST36: sodium chloride injection Zusanli (ST36); IL6ST: interleukin 6 signal transducer; NFATC4: nuclear factor of activated T cells 4; Lat: linker for activation of T cells; PRKCQ: protein kinase C, theta; MAPK10: recombinant mitogen activated protein kinase 10; MAPK11: recombinant mitogen activated protein kinase 11; STAT1: signal transducer and activator of transcription 1. One-way analysis of variance was used to compare more than two groups, followed by the least significant difference test to detect differences between groups. The data are presented as the mean ± standard deviation (n = 3). Comparison with the Model group, aP < 0.05.
Figure 3 Immunofluorescence assay for differentially expressed proteins A: analysis results of differential immunofluorescence staining for IL6ST; B: analysis results of differential immunofluorescence staining for NFATC4; C: analysis results of differential immunofluorescence staining for Lat; D: analysis results of differential immunofluorescence staining for STAT1; E: analysis results of differential immunofluorescence staining for MAPK10; F: analysis results of differential immunofluorescence staining for MAPK11; G: analysis results of differential immunofluorescence staining for PRKCQ. Model group: no post-modeling treatment + 21 d; H2ST36 group: inject hydrogen-rich water + 0.05 mL into each acupoint every other day + 21 d; AcST36 group: acupuncture stimulation + 15 min every other day + 21 d; NaST36 group: saline solution injection + 0.05 mL into each acupoint every other day + 21 d. H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; AcST36: acupuncture; NaST36: sodium chloride injection Zusanli (ST36); IL6ST: interleukin 6 signal transducer; NFATC4: nuclear factor of activated T cells 4; Lat: linker for activation of T cells; PRKCQ: protein kinase C, theta; MAPK10: recombinant mitogen activated protein kinase 10; MAPK11: recombinant mitogen activated protein kinase 11; STAT1: signal transducer and activator of transcription 1. One-way analysis of variance was used to compare more than two groups, followed by the least significant difference test to detect differences between groups. The data are presented as the mean ± standard deviation (n = 3). Comparison with the Model group, aP < 0.05.
Table 1 Western blotting analysis results ( $\bar{x}$ ± s)
| Protein | Model (n = 6) | H2ST36 (n = 6) | AcST36 (n = 6) | NaST36 (n = 6) |
|---|---|---|---|---|
| IL6ST | 1.00±0.16 | 2.67±0.25a | 1.99±0.10a | 1.45±0.18b |
| Lat | 1.00±0.15 | 0.34±0.04a | 0.62±0.10a | 0.83±0.10c |
| MAPK10 | 1.00±0.29 | 2.98±0.46a | 2.38±0.47a | 1.64±0.35d |
| STAT1 | 1.01±0.06 | 0.29±0.11a | 0.49±0.13a | 0.79±0.07b |
| MAPK11 | 0.99±0.16 | 2.93±0.38a | 2.26±0.30a | 1.66±0.22b |
| NFATC4 | 1.01±0.36 | 2.79±0.29a | 2.15±0.27a | 1.74±0.36b |
| PRKCQ | 1.00±0.08 | 0.36±0.14a | 0.54±0.11a | 0.78±0.06b |
Table 1 Western blotting analysis results ( $\bar{x}$ ± s)
| Protein | Model (n = 6) | H2ST36 (n = 6) | AcST36 (n = 6) | NaST36 (n = 6) |
|---|---|---|---|---|
| IL6ST | 1.00±0.16 | 2.67±0.25a | 1.99±0.10a | 1.45±0.18b |
| Lat | 1.00±0.15 | 0.34±0.04a | 0.62±0.10a | 0.83±0.10c |
| MAPK10 | 1.00±0.29 | 2.98±0.46a | 2.38±0.47a | 1.64±0.35d |
| STAT1 | 1.01±0.06 | 0.29±0.11a | 0.49±0.13a | 0.79±0.07b |
| MAPK11 | 0.99±0.16 | 2.93±0.38a | 2.26±0.30a | 1.66±0.22b |
| NFATC4 | 1.01±0.36 | 2.79±0.29a | 2.15±0.27a | 1.74±0.36b |
| PRKCQ | 1.00±0.08 | 0.36±0.14a | 0.54±0.11a | 0.78±0.06b |
Figure 4 qRT-PCR results A: relative Lat mRNA expression level; B: relative NFATC4 mRNA expression level; C: relative PRKCQ mRNA expression level; D: relative MAPK10 mRNA expression level; E: relative IL6ST mRNA expression level; F: relative MAPK11 mRNA expression level; G: relative STAT1 mRNA expression level. Model group: no post-modeling treatment + 21 d; H2ST36 group: inject hydrogen-rich water + 0.05 mL into each acupoint every other day + 21 d; AcST36 group: acupuncture stimulation + 15 min every other day + 21 d; NaST36 group: saline solution injection + 0.05 mL into each acupoint every other day + 21 d. qRT-PCR: quantitative reverse transcription polymerase chain reaction; H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; AcST36: acupuncture; NaST36: sodium chloride injection Zusanli (ST36); IL6ST: interleukin 6 signal transducer; NFATC4: nuclear factor of activated T cells 4; Lat: Linker for activation of T cells; PRKCQ: protein kinase C, theta; MAPK10: recombinant mitogen activated protein kinase 10; MAPK11: recombinant mitogen activated protein kinase 11; STAT1: signal transducer and activator of transcription 1. One-way analysis of variance was used to compare more than two groups, followed by the least significant difference test to detect differences between groups. The data are presented as the mean ± standard deviation (n = 5). Comparison with the Model group, aP < 0.05.
Figure 4 qRT-PCR results A: relative Lat mRNA expression level; B: relative NFATC4 mRNA expression level; C: relative PRKCQ mRNA expression level; D: relative MAPK10 mRNA expression level; E: relative IL6ST mRNA expression level; F: relative MAPK11 mRNA expression level; G: relative STAT1 mRNA expression level. Model group: no post-modeling treatment + 21 d; H2ST36 group: inject hydrogen-rich water + 0.05 mL into each acupoint every other day + 21 d; AcST36 group: acupuncture stimulation + 15 min every other day + 21 d; NaST36 group: saline solution injection + 0.05 mL into each acupoint every other day + 21 d. qRT-PCR: quantitative reverse transcription polymerase chain reaction; H2ST36: hydrogen-rich water injection into the Zusanli (ST36) acupoint; AcST36: acupuncture; NaST36: sodium chloride injection Zusanli (ST36); IL6ST: interleukin 6 signal transducer; NFATC4: nuclear factor of activated T cells 4; Lat: Linker for activation of T cells; PRKCQ: protein kinase C, theta; MAPK10: recombinant mitogen activated protein kinase 10; MAPK11: recombinant mitogen activated protein kinase 11; STAT1: signal transducer and activator of transcription 1. One-way analysis of variance was used to compare more than two groups, followed by the least significant difference test to detect differences between groups. The data are presented as the mean ± standard deviation (n = 5). Comparison with the Model group, aP < 0.05.
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