糖参方通过调节足细胞BAX串扰减轻阿霉素所致肾毒性

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-20 DOI:10.1016/j.phymed.2025.156858

Yuxi Li , Ge Hong , Liang Peng , Bo Zhang , Shaopeng Wang , Mengqi Gao , Xi Dong , Yuzhou Wan , Jin Rong , Kexu Chen , Huimin Su , Ping Li , Yuxin Zhang , Tingting Zhao

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引用次数: 0

摘要

多柔比星（DOX）是一种广泛使用的抗癌药物，具有显著的肾毒性作用。中药汤参方（TSF）对糖尿病肾病患者具有保护肾脏的作用，并已被证明可以减轻啮齿动物的肾脏损害。目的探讨TSF减轻dox所致肾毒性的可能靶点和调控机制。方法采用蛋白因子芯片技术、生物信息学分析、MPC5细胞系检测。通过生物信息分析、体外实验、体内实验、分子对接等综合手段，揭示了TSF与DOX致肾毒性的病理关系，并鉴定出潜在的小分子抑制剂。结果stsf可明显减轻蛋白尿和组织病理病变。大鼠肾细胞因子阵列和氧化石墨烯分析显示，TSF的信号通路与细胞凋亡和焦亡密切相关。体内实验结果证实，TSF可抑制DOX诱导的肾毒性大鼠足细胞凋亡和焦亡。TSF增加了大鼠肾脏中足细胞标记物WT1和nephrin的水平，并降低了大鼠肾脏中焦亡标记蛋白GSDMD的水平。免疫荧光共定位证实，TSF可降低DOX所致肾毒性大鼠足细胞BAX水平，升高BCL2水平。在体外实验中，作为BAX激活剂的BTSA1可以减轻TSF的有益作用。此外，我们通过CDOCKER从血浆中TSF中鉴定出与BAX结合效率高的化合物，并选择前三种化合物进行western blot验证，人参皂苷对MPC焦解效果最好。结论本研究证实了TSF通过调节bax介导的足细胞焦亡和凋亡之间的串扰，具有减轻足细胞死亡的新作用。TSF是一种潜在的治疗AN的草药疗法，人参皂苷是最有效的BAX水平的抑制。人参皂苷Rb1 (PubChem CID: 9898279)；三七皂苷R1 (PubChem CID: 441934)；柚皮苷（PubChem CID: 442428）

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Tangshen formula alleviates doxorubicin induced nephrotoxicity by regulating BAX crosstalk in podocyte

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Tangshen formula alleviates doxorubicin induced nephrotoxicity by regulating BAX crosstalk in podocyte

Background

Doxorubicin (DOX) is a widely used anticancer drug with a marked nephrotoxic effect. The Chinese medicine Tangshen Formula (TSF) has a kidney-protective effect in diabetic kidney disease patients and has been shown to attenuate kidney damage in rodents.

Purpose

Our study explored the putative targets and regulatory mechanisms of TSF in attenuating DOX-induced nephrotoxicity.

Methods

Protein factor microarray, bioinformatics analysis, MPC5 cell line were used in this work. Through the comprehensive means of biological information analysis, in vitro experiments, in vivo experiments and molecular docking, the pathological relationship between TSF and DOX induced nephrotoxic was revealed, and the potential small-molecule inhibitor were identified.

Results

TSF administration significantly alleviated albuminuria and histopathologic lesions. Rat renal cytokine array and GO analysis revealed that signaling pathways of TSF were closely related to apoptosis and pyroptosis. In vivo results verified that TSF inhibited the apoptosis and pyroptosis of DOX induced nephrotoxic rat podocyte. TSF increased levels of WT1, and nephrin, which are podocyte markers, and reduced levels of GSDMD, which is a pyroptosis marker protein in the rat kidney. Furthermore, immunofluorescence co-localization confirmed that TSF could decrease the level of BAX and increase the level of BCL2 in podocytes of DOX induced nephrotoxic rat. In vitro, BTSA1, which is a BAX activator, could mitigate the beneficial effects of TSF. In addition, we identified the compounds with high binding efficiency to BAX from TSF in plasma by CDOCKER, and the top three were selected for verification by western blot, ginsenoside having the best effect to MPC pyroptosis.

Conclusion

This study demonstrated a novel action of TSF in attenuating podocyte death by regulating BAX-mediated crosstalk between pyroptosis and apoptosis. TSF is a potential therapeutic herbal therapy against AN, and ginsenoside is the most effective inhibition of BAX levels.

Chemical compounds

Ginsenoside Rb1 (PubChem CID: 9898279); Notoginsenoside R1 (PubChem CID: 441934); Naringin (PubChem CID: 442428)

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.