连翘温丹汤通过减轻氧化磷酸化功能障碍减轻胃癌发生

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-28 DOI:10.1016/j.phymed.2025.156924

Xiuping Chi , Yanru Song , Sisi Wei , Guangjun Wang , Yang Wen , Zhe Zhang , Cong Zhang , Hongtao Zhang , Zhongdong Hu , Haiyang Yu , Bingjie Huo , Baoen Shan , Lianmei Zhao

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引用次数: 0

摘要

温胆汤在临床上主要是作为“祛痰剂”使用。WDD与连翘（LQWDD）联合使用在化痰、调气、解毒等方面具有协同作用。在初步临床实践中，我们观察到LQWDD能有效缓解胃癌前病变的严重程度。然而，潜在的机制仍然难以捉摸。目的：探讨白芍抗胃癌的作用及可能的机制。方法回顾性分析胃癌前病变患者及n -甲基- n9 -硝基-n -亚硝基胍（MNNG）诱导的大鼠胃癌模型，评价清汤寡糖对胃癌的抑制作用。蛋白质组学分析用于研究LQWDD的潜在机制。此外，利用代谢组学对能量代谢物进行了量化。采用网络药理学和高效液相色谱-质谱联用技术对其潜在有效成分进行了分析。此外，通过海马分析和RNA测序，探讨复合槲皮素对氧化磷酸化的影响及其机制。结果slqwdd能有效抑制mnng诱导的大鼠胃癌模型和患者的胃癌发生。蛋白质组学分析显示，LQWDD在胃癌发生过程中保护了氧化磷酸化通路的完整性，这在人胃上皮内瘤变和mnng诱导的胃癌中被显著抑制。此外，LQWDD显著逆转了mnng诱导的线粒体复合体i相关蛋白（ALDH3A1和NDUFS4）表达的降低，以及ATP、NAD+和代谢物水平的降低，表明其通过调节线粒体复合体i相关蛋白对氧化磷酸化功能障碍具有保护作用。此外，槲皮素和山奈酚被鉴定为LQWDD的潜在活性成分。这些成分抑制胃癌细胞和患者源性类器官的生长，同时增加细胞内ATP和NAD+水平。值得注意的是，槲皮素通过激活AMPK信号通路，在线粒体氧化呼吸中发挥了优先调节作用。结论我们的研究首次提供了线粒体OXPHOS功能障碍在胃癌发生中起关键作用的系统证据。LQWDD及其潜在活性成分槲皮素通过减轻氧化磷酸化损伤而抑制胃癌发生，是治疗胃癌前病变的有前景的治疗方。

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Lian Qiao Wen Dan Decoction attenuates gastric carcinogenesis by alleviating oxidative phosphorylation dysfunction

Background

Wen Dan Decoction (WDD) is primarily utilized as an “expectorant” in clinical practice. The combination of WDD and Lian Qiao (LQWDD) exhibits synergistic effects on phlegm resolution, qi regulation, and detoxification. In preliminary clinical practice, we observed that LQWDD effectively alleviates the severity of gastric precancerous lesions. Nevertheless, the underlying mechanism remains elusive.

Purpose

This study was designed to explore the efficacy and potential mechanisms of LQWDD against gastric carcinogenesis.

Methods

Retrospective analyses of patients with gastric precancerous lesions and an N-methyl-N9-nitro-N-nitrosoguanidine (MNNG)-induced rat gastric cancer model were conducted to evaluate the efficacy of LQWDD against gastric carcinogenesis. Proteomic analyses were employed to investigate the underlying mechanisms of LQWDD. Moreover, energy metabolites were quantified using metabolomics. Network pharmacology and high-performance liquid chromatography-mass spectrometry were integrated to elucidate the potential active components of LQWDD. Additionally, seahorse analysis and RNA sequencing were used to explore the effects and underlying mechanisms of compound quercetin on oxidative phosphorylation.

Results

LQWDD effectively impeded gastric carcinogenesis in an MNNG-induced rat gastric cancer model and patients. Proteomic analyses revealed that LQWDD protected the integrity of the oxidative phosphorylation pathway during gastric carcinogenesis, which was significantly suppressed in human gastric intraepithelial neoplasia and MNNG-induced gastric carcinoma. Moreover, LQWDD administration significantly reversed MNNG-induced reductions in the expression of mitochondrial complex I-related proteins (ALDH3A1 and NDUFS4), as well as in ATP, NAD⁺, and metabolite levels, indicating its protective role against oxidative phosphorylation dysfunction through the modulation of mitochondrial complex I-associated proteins. Furthermore, quercetin and kaempferol were identified as potential active components of LQWDD. These components suppressed the growth of gastric cancer cells and patient-derived organoids while simultaneously increasing intracellular ATP and NAD⁺ levels. Notably, quercetin exerted its preferential regulatory role in mitochondrial oxidative respiration by activating the AMPK signaling pathway.

Conclusions

Our study provides the first systematic evidence that mitochondrial OXPHOS dysfunction plays a pivotal role in gastric carcinogenesis. LQWDD and its potential active ingredient quercetin inhibit gastric carcinogenesis by mitigating oxidative phosphorylation impairment, highlighting on a promising therapeutic prescription for treating with gastric precancerous lesions.

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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.