Archive > Volume 18 Issue 1 > 2026,18(1):178-187. DOI:https://doi.org/10.1016/j.chmed.2025.03.007 Prev Next

黄芪多糖通过抑制Jnk/p38信号通路抑制三氧化二砷诱导的BMSCs损伤

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Astragalus polysaccharides inhibit arsenic trioxide-induced BMSCs damage through inhibition of Jnk and p38 signaling pathways

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摘要:

目的：?三氧化二砷（ATO）是临床治疗白血病的有效抗癌药物。然而，在癌症治疗期间，其可对体内多种非肿瘤细胞如骨髓间充质干细胞（BMSCs）等产生不利影响。因此，减少或消除ATO的副作用对其临床应用至关重要。黄芪多糖（APS）是从中药黄芪中分离出来的主要生物活性成分。然而，目前尚不清楚APS能否保护BMSCs免受ATO毒性损伤。因此，本研究旨在将BMSCs暴露于ATO中以阐明APS抑制ATO诱导的BMSCs细胞凋亡的潜在作用及机制。方法：应用MTT活力检测、EdU染色、transwell迁移和伤口愈合实验检测不同浓度APS在ATO诱导的BMSCs中的保护作用。应用TUNEL、Hoechst 33258染色、流式细胞术、DCFH-DA染色和JC-1染色检测APS对ATO作用下的BMSCs 凋亡细胞百分比和凋亡形态变化的影响。最后，通过western blot检测凋亡相关蛋白的表达。结果：?我们发现ATO暴露可抑制BMSCs的增殖和迁移，并诱导细胞凋亡。APS显著减轻了ATO诱导的BMSCs细胞凋亡，促进了细胞的增殖和迁移。在机制上，APS缓解了ATO诱导的ROS生成，降低了Bax和cleaved?Caspase-3的表达，并增加了Bcl-2的表达。此外，APS抑制了ATO诱导的BMSCs中Jnk和p38的激活。同时，APS抑制了ATO诱导的p16和p53的上调，并增加了ATO诱导的p-Akt和p-Erk的下调。结论：?我们的研究表明，APS可通过抑制Jnk和p38 MAPK信号通路逆转ATO诱导的BMSCs增殖和迁移减少以及细胞凋亡增加。我们的研究结果可能为预防和治疗ATO的副作用提供新思路。

Abstract:

Objective: Arsenic trioxide (ATO) is a clinically effective anticancer agent used in the treatment of leukemia. However, it exerts adverse effects on non-tumor cells, including bone marrow mesenchymal stem cells (BMSCs). This study aims to investigate the protective role and molecular mechanism of traditional Chinese medicine Astragalus polysaccharides (APS) in mitigating ATO-induced apoptosis in BMSCs. Methods: BMSCs exposed to ATO (0.5 lmol/L) were treated with APS (20, 40, 100, and 200 lg/mL). Cell viability, proliferation, and migration were assessed by using MTT, EdU staining, Transwell, and scratch wound healing assays. Apoptosis was evaluated via TUNEL assay, Hoechst 33258 staining, and flow cytometry. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by using DCFH-DA and JC-1 staining. Apoptotic protein expression was analyzed by Western blotting. Results: ATO exposure significantly inhibited the proliferation and migration of BMSCs and induced apoptosis, while APS markedly attenuated the apoptosis of BMSCs induced by ATO, and significantly improved cell proliferation and migration (P < 0.01). Mechanistically, APS effectively reduced ATOinduced ROS (P < 0.01), while the protein expression of Bcl-2-associated X protein (Bax) and cleaved Caspase-3 was significantly decreased (P < 0.05), and the protein expression of Bcl-2 was significantly increased (P < 0.01). In addition, APS markedly decreased the protein expression of c-Jun N-terminal kinase (Jnk) and p38 in ATO-activated BMSCs (P < 0.05), and significantly decreased the protein expression of p16 and p53 (P < 0.01), and increased the protein expression of phosphorylated protein kinase B (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-Erk) (P < 0.01, 0.05). Conclusion: Our study reveals that APS exert significant protective effects against ATO-induced apoptosis in BMSCs. The mechanisms involve suppressing ROS generation, maintaining mitochondrial membrane stability, enhancing cell viability, migration, and proliferation, as well as inhibiting Jnk and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways. The findings highlight potential molecular targets and novel strategies for the clinical prevention and treatment of ATO-related toxicity

关键词:

黄芪多糖;三氧化二砷;凋亡;骨髓间充质干细胞;Jnk;MAPK

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Project Supported:

This work was supported by the National Natural Science Foundation of China (No. 82473925, 81800784, 81972117, 82472477), the Young Elite Scientists Sponsorship Program by CAST (No. 2019QNRC001), the Postdoctoral Science Foundation of China (No. 2018M630370), the Key Research and Development Program of Heilongjiang Province (No. GA21C006), the Heilongjiang Postdoctoral Fund for Young Talent Program (No. LBH-TZ1020), the Natural Science Foundation of Heilongjiang Province (No.YQ2020H003), the Research Institution’s Scientific Research Expenses Project of Heilongjiang Province (No. CZKYF2022-1-C006), the Excellent Young Talents Funding (No. 2019-QD-11),the CAMS Innovation Fund for Medical Sciences (No. CIFMS 2020-I2M-5-003), the Natural Science Foundation of Jiangsu Province (No. BK20210110), and the Program of Science and Technology of Suzhou (No. SYG202119).

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