Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (5): 1087-1097.DOI: 10.19852/j.cnki.jtcm.2025.05.015
• Original Articles • Previous Articles Next Articles
QI Yafeng1, LIU Yu1, LIU Yeyuan1, LI Yangyang1, ZHANG Shangzu1, CHEN Yaping1, XU Qian1, HAO Guoxiong1, LIU Yongqi3, ZHANG Liying2(
), ZHANG Zhiming4(
)
Received:2024-08-22
Accepted:2024-12-25
Online:2025-10-15
Published:2025-09-15
Contact:
Prof. ZHANG Liying, School of Integrative Chinese and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China. zhangliying201212@163.com;Supported by:QI Yafeng, LIU Yu, LIU Yeyuan, LI Yangyang, ZHANG Shangzu, CHEN Yaping, XU Qian, HAO Guoxiong, LIU Yongqi, ZHANG Liying, ZHANG Zhiming. Therapeutic potential of Traditional Chinese Medicine Yisui Shengxue pills (益髓生血丸) to inhibit hypoxia-inducible factor-1alpha and general control nonderepressible 2 to regulate the post-chemotherapy immune response: integrating network pharmacology and experimental validation[J]. Journal of Traditional Chinese Medicine, 2025, 45(5): 1087-1097.
Figure 1 The target pathways of YSSX for the treatment of post-chemotherapy immunosuppression were predicted by network pharmacology A: the targets of YSSX, targets of post-chemotherapy immunosuppression, and the intersection of active ingredient targets between different drugs; B: Interaction network map of PPI proteins of core targets in the first 60 core targets after immunosuppression following YSSX treatment with chemotherapy, and Cytohubba plugin screening and mapping of the core target network. B1: Interaction network map of PPI proteins of core targets in the first 60 core targets after immunosuppression following YSSX treatment with chemotherapy; B2: Cytohubba plugin screening and mapping of the core target network. C: depict GO functional enrichment analysis; D: depict KEGG pathway enrichment analysis. YSSX: Yishui Shengxue pills; PPI: protein-protein interaction; GO: gene ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes.
Figure 2 Effects of YSSX on the overall health and immunity of mice that were immunosuppressed by different chemotherapy drugs A: changes in the weight of mice in each group; B: spleen thymus indices; B1: spleen indices; B2: thymus indices; C: changes in the peripheral white blood cells, lymphocytes, and neutrophils content of experimental mice; C1: white blood cells; C2: lymphocytes; C3: neutrophils; D: pathological changes in the thymus after HE staining (size: 20 μm); E: pathological changes in the spleen after HE staining (size: 20 μm); F: Pathological changes in the bone marrow after HE staining (size: 20 μm); D1, E1, F1: Ctrl group; D2, E2, F2: CBP group; D3, E3, F3: CBP+YSSX group; D4, E4, F4: 5-Fu group; D5, E5, F5: 5-Fu + YSSX group; D6, E6, F6: PTX group; D7, E7, F7: PTX + YSSX group. Ctrl group: received a normal diet and drinking water without any intervention; CBP group: received CBP intraperitoneally at a dose of 82.3 mg/kg for five consecutive days, followed by 0.2 mL/animal per day of normal saline for seven consecutive days after modelling; CBP + YSSX group: received CBP intraperitoneally at a dose of 82.3 mg/kg for five consecutive days, followed by the intragastric administration of YSSX at a dose of 1.05 g/kg for 7 d after modelling; PTX group: the mice received PTX at a dose of 41.6 mg/kg once every three days for a total of 14 d, and then received the intragastric administration of 0.2 mL/animal per day with normal saline for seven consecutive days; PTX + YSSX group: the mice were treated with PTX at a dose of 41.6 mg/kg once every three days for a total of 14 d, followed by the intragastric administration of YSSX at a dose of 1.05 g/kg for 7 d after modelling; 5-Fu group: the mice received 5-Fu at a dose of 182 mg/kg three times per week for 7 d, and then normal saline was administered by oral gavage at a dose of 0.2 mL/animal per day for 7 d after modelling; 5-Fu + YSSX group: the mice were treated with 5-Fu at a dose of 182 mg/kg three times per week for 7 d, followed by the intragastric administration of YSSX at a dose of 1.05 g/kg for 7 d after modeling. Ctrl: blank group; CBP: carboplatin group; 5-Fu: fluorouracil group; PTX: paclitaxel; YSSX: Yishui Shengxue pills; WBC: white blood cell; HE: hematoxylin-eosin. Statistical significance was assessed using one-way analysis of variance. All data were expressed as the mean ± standard deviation (n = 3). Compared with the blank group, aP < 0.05; compared with the CBP, bP < 0.05; compared with the 5-Fu group, cP < 0.05; compared with the PTX group dP < 0.05.
Figure 3 The expression of key targets and blood immunity indicators were detected by WB and qRT-PCR A: protein and gene transcription of HIF-1α, iNOS, GCN2, eIF2α, and ATF4 protein in MDSCs from the thymus, spleen, and bone marrow; B: mRNA expression of HIF-1α, GCN2 and eIF2α in MDSCs in the thymus; C: mRNA expression of HIF-1α, GCN2 and eIF2α in MDSCs in the spleen; D: mRNA expression of HIF-1α, GCN2 and eIF2α in MDSCs in the bone marrow; B1, C1, D1: HIF-1α; B2, C2, D2: GCN2; B3, C3, D3: eIF2α. Ctrl group: received a normal diet and drinking water without any intervention; CBP group: received CBP intraperitoneally at a dose of 82.3 mg/kg for five consecutive days, followed by 0.2 mL/animal per day of normal saline for seven consecutive days after modelling; CBP + YSSX group: received CBP intraperitoneally at a dose of 82.3 mg/kg for five consecutive days, followed by the intragastric administration of YSSX at a dose of 1.05 g/kg for 7 d after modelling; PTX group: the mice received PTX at a dose of 41.6 mg/kg once every three days for a total of 14 d, and then received the intragastric administration of 0.2 mL/animal per day with normal saline for seven consecutive days; PTX + YSSX group: the mice were treated with PTX at a dose of 41.6 mg/kg once every three days for a total of 14 d, followed by the intragastric administration of YSSX at a dose of 1.05 g/kg for 7 d after modelling; 5-Fu group: the mice received 5-Fu at a dose of 182 mg/kg three times per week for 7 d, and then normal saline was administered by oral gavage at a dose of 0.2 mL/animal per day for 7 d after modelling; 5-Fu + YSSX group: the mice were treated with 5-Fu at a dose of 182 mg/kg three times per week for 7 d, followed by the intragastric administration of YSSX at a dose of 1.05 g/kg for 7 d after modeling. Ctrl: blank group; CBP: carboplatin group; 5-Fu: fluorouracil group; PTX: paclitaxel; YSSX: Yishui Shengxue pills; HIF-1α: hypoxia-inducible factor 1-alpha; iNOS: inducible nitric oxide synthase; eIF2α: eukaryotic initiation factor 2 alpha; GCN2: general control nonderepressible 2; ATF4: activating transcription factor 4; WB: Western blotting; qRT-PCR: real-time quantitative reverse transcription-polymerase chain reaction; MDSCs: myeloid-derived suppressor cells. Statistical significance was assessed using one-way analysis of variance. All data were expressed as the mean ± standard deviation (n = 3). Compared with the blank group, aP < 0.05; compared with the CBP group, bP < 0.05; compared with the 5-Fu group, cP < 0.05; compared with the PTX group, dP < 0.05.
Figure 4 YSSX improves the modulation of MDSCs-mediated immunosuppression after chemotherapy Chemotherapeutic agents triggered ROS accumulation, recruiting and activating MDSCs, whose high expression of HIF-1α promoted L-arginine depletion, followed by the release of iNOS, affecting T cell proliferation. Meanwhile, GCN2 senses L-arginine depletion activation and promotes eIF2α phosphorylation, which in turn inhibits T cell immune response, and in turn promotes increased translation of CREB2/ATF4, enhancing MDSCs activity (left). After YSSX intervention, HIF-1α transcription was blocked, and then L-arginine depletion was reduced, iNOS production was decreased, and T-cell proliferation was enhanced. reduced L-arginine depletion, GCN2 activity was reduced, and eIF2α phosphorylation was inhibited, which promoted T-cells to perform their normal immune functions; at the same time, due to the reduction in GCN2 expression mediating the reduction of CREB2/ATF4 translation, the activity of MDSCs was also inhibited (right). YSSX: Yishui Shengxue pills; ATF4: activating transcription factor 4; eIF2α: eukaryotic translation initiation factor 2α; iNOS: inducible nitric oxide synthase; HIF-1α: hypoxia-inducible factor-1α; GCN2: general control nonderepressible 2; GCN2: general control nonderepressible 2; CREB2: cAMP response element-binding protein 2; ATF4: activating transcription factor 4. This image was created by Adobe Illustr (San Jose, CA, USA).
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