山核桃多酚通过调节DAF-16/DAF-2胰岛素/IGF-1信号通路，增强秀丽隐杆线虫的氧化应激恢复能力，延长其寿命

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-27 DOI:10.1016/j.phymed.2025.156918

Song Wang , Chenyu Jiang , Shitong Yu , Qianru Fan , Kai Yang , Jianqin Huang , Yan Li

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引用次数: 0

摘要

山核桃（Carya cathayensis）坚果以其健康益处和令人愉悦的味道而闻名，含有丰富的生物活性化合物，特别是多酚。然而，其抗氧化性能和抗衰老作用的具体机制尚不清楚。目的研究山核桃多酚（HNP）对氧化应激和衰老的调节作用。方法采用中压液相色谱法（MPLC）和体外生物活性筛选相结合的创新方法，优选HNP部位（HNP3-2）。通过寿命分析、脂褐素积累量化和运动评估来确定HNP3-2对秀丽隐杆线虫（C. elegans）的抗衰老作用。通过检测活性氧（ROS）含量、脂质过氧化和抗氧化酶活性进一步评价其抗氧化能力。利用转录组学、qRT-PCR、GFP报告菌株和基因敲除突变体的综合方法来探索潜在的调控机制。采用非靶向代谢组学对HNP及其生物活性组分进行综合分析。结果shnp3 - 2显著降低ROS生成、脂褐素积累和脂质过氧化，提高超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）活性。它还具有抗H2O2和核桃酮诱导的氧化应激的强大保护作用。HNP3-2主要通过DAF-16/-2胰岛素/IGF-1信号（IIS）调节寿命延长，这一点通过功能缺失和功能获得突变体（包括age-1、akt-1/2、daf-2和DAF-16）以及过表达SOD-3、GST-4和DAF-16进一步得到验证。代谢组学分析鉴定出31种多酚类化合物，其丰度模式与体外总体抗氧化能力一致。结论本研究首次揭示了HNP作为抗氧化和抗衰老干预手段的应用前景。值得注意的是，筛选的生物活性组分HNP3-2主要通过调节DAF-16/DAF-2胰岛素/IGF-1信号级联起作用，其作用机制独立于饮食限制。总的来说，这些发现将HNP定位为下一代老年治疗药物的突破性候选药物，具有推进人类衰老研究的转化潜力。

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Hickory nut polyphenols enhance oxidative stress resilience and improve the longevity of Caenorhabditis elegans through modulating DAF-16/DAF-2 insulin/IGF-1 signaling

Background

Hickory (Carya cathayensis) nuts, renowned for their health benefits and delightful taste, contain abundant bioactive compounds, particularly polyphenols. However, the specific mechanisms underlying their antioxidant properties and anti-aging effects remain elusive.

Purpose

This study aims to investigate the effects of hickory nut polyphenols (HNP) on oxidative stress mitigation and aging modulation.

Methods

The innovative integration of medium-pressure liquid chromatography (MPLC) with in vitro bioactive screening was employed to discover an optimized HNP fraction (HNP3–2). Anti-aging effects of HNP3–2 on Caenorhabditis elegans (C. elegans) were determined through lifespan analysis, lipofuscin accumulation quantification, and motility assessments. Oxidative stress resistance was further evaluated by detecting the reactive oxygen species (ROS) contents, lipid peroxidation, and antioxidase activities. Integrative approaches combining transcriptomic, qRT-PCR, GFP reporter strains, and gene knockout mutants were utilized to explore the potential regulatory mechanisms. Non-targeted metabolomics was employed to conduct a comprehensive profiling analysis of HNP and their bioactive fractions.

Results

HNP3–2 significantly decreased ROS production, lipofuscin accumulation, and lipid peroxidation, while enhanced the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). It also conferred robust protection against oxidative stress induced by H₂O₂ and juglone. HNP3–2 regulated lifespan extension mainly via the DAF-16/-2 insulin/IGF-1 signaling (IIS), which was further validated using loss- and gain-of-function mutants including age-1, akt-1/2, daf-2, and daf-16, as well as worms overexpressing SOD-3, GST-4, and DAF-16. Metabolomic analysis identified 31 kinds of polyphenol compounds displaying abundance patterns congruent with the overall antioxidant potency in vitro.

Conclusion

This study first reveals the efficacy of HNP as a promising antioxidant and anti-aging intervention. Notably, the screened bioactive fraction HNP3–2 acts primarily by modulating the DAF-16/DAF-2 insulin/IGF-1 signaling cascade, operating through a mechanism independent of dietary restriction. Collectively, these findings position HNP as a breakthrough candidate for next-generation gerotherapeutics, with translational potential for advancing human aging research.

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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.