Synergistic effects of heterophyllin B with nintedanib against experimental pulmonary fibrosis in mice

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-28 DOI:10.1016/j.phymed.2025.156922

Ce Chen , Zeyu Han , Jiawen Luo , Jialin Wang , Tingting Liu , Jie Zhang , Chaofeng Zhang

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引用次数: 0

Abstract

Background

Pulmonary fibrosis (PF) is a chronic, lethal lung disease marked by permanent alterations to the lung tissue architecture. Although nintedanib (NDN) has been approved for clinical use, its therapeutic potential is substantially hampered by severe gastrointestinal side effects, notably diarrhea, which compromise patient adherence and quality of life.

Purpose

This study aimed to investigate whether heterophyllin B (HB) could augment the antifibrotic efficacy of NDN while mitigating its gastrointestinal toxicity.

Methods

The therapeutic potential of HB was evaluated in a bleomycin (BLM)-induced murine model of PF. Alterations in gut microbiota and serum metabolic profiles were determined via 16S rRNA gene sequencing and untargeted metabolomics, respectively. Mechanistic insights were performed in NCM460 colonic epithelial cells through IDO1 silencing, ferroptosis inhibition, CETSA and molecular dynamics experiments. Furthermore, the synergistic and protective effects of HB on NDN were investigated in BLM-induced mice, along with analysis of intestinal microbiota composition. The active constituents of the EtOAc extract of Radix Pseudostellariae were identified using UPLC-Q-TOF-MS/MS, GNPS, and NMR spectroscopy.

Results

Administration of HB (40 mg/kg/day for approximately 14 days) significantly attenuated lung fibrosis progression and substantially alleviated diarrhea in BLM-induced PF mice. HB reshaped the intestinal microecology and reprogrammed serum metabolism, notably by reducing the abundance of Escherichia-Shigella, as revealed by 16S rRNA sequencing and untargeted metabolomics analyses. Furthermore, the co-treatment of HB and NDN demonstrated enhanced efficacy and reduced gastrointestinal toxicity both in vivo and in vitro. Mechanistic investigations indicated that HB-enriched 3-hydroxybutyric acid (3-HA) restored intestinal mucosal barrier integrity by inhibiting IDO1-mediated ferroptosis. Additionally, extracts of Radix Pseudostellariae containing HB-like cyclopeptides significantly improved PF symptoms and intestinal epithelial injury in BLM-induced mice. Nine cyclopeptide compounds (Herterophyllin A-B, D and Psedostellarin A-E, G) were identified in the extract via UPLC-Q-TOF-MS/MS analysis.

Conclusion

HB offers dual protection against pulmonary fibrosis and intestinal damage through its regulatory impact on the gut–lung axis and suppression of ferroptosis mechanisms. Collectively, HB offers a promising adjuvant to optimize NDN-based antifibrotic therapy, offering a novel strategy for integrated pulmonary and gastrointestinal protection in PF management.

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异茶碱B与尼达尼布对小鼠实验性肺纤维化的协同作用

肺纤维化（PF）是一种慢性、致死性肺部疾病，其特征是肺组织结构的永久性改变。尽管尼达尼布（nintedanib， NDN）已被批准用于临床，但其治疗潜力受到严重胃肠道副作用（尤其是腹泻）的严重阻碍，这些副作用会损害患者的依从性和生活质量。目的探讨异茶碱B （heteroophyllin B， HB）是否能增强NDN的抗纤维化作用，同时减轻其胃肠道毒性。方法采用博来霉素（BLM）诱导的PF小鼠模型，评估HB的治疗潜力，并分别通过16S rRNA基因测序和非靶向代谢组学检测肠道微生物群和血清代谢谱的变化。通过IDO1沉默、铁凋亡抑制、CETSA和分子动力学实验，对NCM460结肠上皮细胞的机制进行了深入研究。此外，研究了HB对blm诱导小鼠NDN的协同作用和保护作用，并分析了肠道菌群组成。采用UPLC-Q-TOF-MS/MS、GNPS、NMR等方法对太子参乙酸乙酯提取物的有效成分进行鉴定。结果给药HB （40 mg/kg/天，持续约14天）可显著减轻blm诱导的PF小鼠肺纤维化进展，并显著减轻腹泻。16S rRNA测序和非靶向代谢组学分析显示，HB重塑了肠道微生态，并重新编程了血清代谢，特别是通过降低埃希氏-志贺氏菌的丰度。此外，HB和NDN共同治疗在体内和体外均显示出增强的疗效和降低的胃肠道毒性。机制研究表明，富含hb的3-羟基丁酸（3-HA）通过抑制ido1介导的铁上吊而恢复肠黏膜屏障的完整性。此外，含hb样环肽的太子参提取物可显著改善blm诱导小鼠的PF症状和肠上皮损伤。通过UPLC-Q-TOF-MS/MS分析，从提取物中鉴定出9个环肽化合物（Herterophyllin A-B、D和pseudostellarin A-E、G）。结论hb通过调节肠-肺轴和抑制铁上吊机制，对肺纤维化和肠道损伤具有双重保护作用。总的来说，HB为优化基于ndn的抗纤维化治疗提供了一种有希望的辅助剂，为PF治疗提供了一种综合肺和胃肠道保护的新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.