Fraxetin attenuates DNA damage and inflammation in cisplatin-induced nephrotoxicity via FoxO1 activation

IF 4.8 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2024.114010

Ziwei Yuan , Shenlei Yu , Dongyan Su , Yuanyuan Gao , Fan Zheng , Penghua Yan , Xuejia Yang , Zujian Hu , Chaosheng Chen , Hong Lu , Yongheng Bai , Shuibing Cheng

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Abstract

Background

Cisplatin-induced acute kidney injury (CKI) represents a severe renal dysfunction characterized by DNA damage and tubular injury. Fraxetin, derived from the Chinese herb Qinpi (Fraxinus bungeana A.DOC), is recognized for its neuroprotective effects and has been used for the prevention of various diseases.

Methods

This study investigated the renoprotective effects and molecular mechanisms of fraxetin in CKI. A mouse CKI model and a cisplatin-induced tubule epithelial cell (TEC) injury model were established to evaluate fraxetin’s effects by measuring diverse parameters associated with kidney injury, focusing on DNA damage and inflammation. Additionally, network pharmacology and cellular sequencing analysis were employed to identify altered pathways or targets after fraxetin treatment. Subsequent experiments involved siRNA and pharmacological regulation to identify fraxetin targets, alongside molecular docking to unravel binding mechanisms.

Results

Fraxetin pretreatment significantly ameliorated CKI, with a 45% reduction in in tubular damage compared to the cisplatin-only group. Additionally, fraxetin notably enhanced DNA repair. Fraxetin pretreatment reduced cisplatin-induced DNA damage in HK-2 cells by 42.8% in comet assays. Fraxetin also mitigated inflammation, with pro-inflammatory cytokine levels decreasing by approximately 20–30% in both mouse and cell models. Notable changes were observed in the FoxO pathway. Specifically, manipulating Forkhead box O1 (FoxO1), a transcription factor involved in stress responses and longevity, influenced fraxetin’s protective effect. Molecular docking revealed that fraxetin binds to the Forkhead (FH) domain of FoxO1, promoting its nuclear localization.

Conclusions

Fraxetin protects against CKI by activating FoxO1, providing a foundation for novel therapeutic strategies and underscoring fraxetin’s potential in treating kidney injury.

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背景：顺铂诱导的急性肾损伤（CKI）是一种以 DNA 损伤和肾小管损伤为特征的严重肾功能障碍。从中草药秦皮（Fraxinus bungeana A.DOC）中提取的梣皮素具有神经保护作用，已被用于多种疾病的预防：本研究探讨了梣皮素对 CKI 的肾脏保护作用及其分子机制。建立了小鼠 CKI 模型和顺铂诱导的肾小管上皮细胞（TEC）损伤模型，通过测量与肾损伤相关的各种参数来评估 fraxetin 的作用，重点是 DNA 损伤和炎症。此外，还采用了网络药理学和细胞测序分析，以确定经氟塞汀治疗后发生改变的通路或靶点。随后的实验包括 siRNA 和药理学调控，以确定 fraxetin 的靶点，同时进行分子对接以揭示结合机制：结果：与纯顺铂组相比，氟西汀预处理明显改善了CKI，使肾小管损伤减少了45%。此外，氟西汀还能显著增强 DNA 修复能力。在彗星试验中，Fraxetin 预处理可使 HK-2 细胞中顺铂诱导的 DNA 损伤减少 42.8%。Fraxetin 还能减轻炎症反应，在小鼠和细胞模型中，促炎细胞因子水平都下降了约 20-30%。在 FoxO 通路中观察到了显著的变化。具体来说，Forkhead box O1（FoxO1）是一种参与应激反应和长寿的转录因子，它的操作影响了fraxetin的保护作用。分子对接显示，梣酮能与 FoxO1 的叉头 (FH) 结构域结合，促进其核定位：结论：梣酮素通过激活 FoxO1 防止 CKI，为新的治疗策略提供了基础，并强调了梣酮素治疗肾损伤的潜力。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.