柚皮素靶向并抑制单胺氧化酶A/B双向调节肠道蠕动。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions Pub Date : 2025-09-11 DOI:10.1016/j.cbi.2025.111742

Qi Li , Yi Chen , Yige Zhang , Canwei Xu , Ting Tang , Yunzhi Qian , Ong Shun seng , Yujuan Wang , Ling Fang , Tianshu Xu

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引用次数: 0

摘要

背景：单胺氧化酶（MAO）是单胺类神经递质分解代谢的主要酶促因子，在调节肠道运动动力学中起关键作用。在结肠组织中，MAO-A主要在单胺降解过程中表达，而MAO-B的表达水平相对较低。这种MAO亚型的差异表达赋予柚皮素（NAR），一种黄酮类化合物，可以竞争性地结合MAO- a和MAO- b的活性位点，具有不同的剂量反应阈值来抑制这两种酶亚型。因此，本研究旨在系统阐明NAR通过选择性抑制两种MAO亚型调控肠道运动的分子机制，并综合分析相关的量效关系。最终，本研究旨在为其优化剂量和减轻毒副作用提供理论依据。方法：本研究建立洛哌丁胺（loperamide， LOP）诱导的C57BL/6雄性小鼠慢传性便秘模型，系统研究不同浓度NAR对肠道蠕动、MAO活性及神经递质代谢的影响。结果：本研究表明，25-300 mg/kg剂量的NAR选择性靶向肠道MAO-A，抑制酶活性，降低5-羟色胺（5-HT）分解代谢。这种5-羟色胺的积累增强了肠道蠕动。但当NAR浓度≥150mg/kg时，还可引起MAO-B抑制，导致多巴胺代谢明显受阻，导致多巴胺含量异常升高。最终，它通过激活多巴胺信号通路抑制结肠蠕动。结论：NAR可通过阈值依赖性调节MAO-A/B活性，实现肠道运动的双向调节。

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Naringenin targets and inhibits Monoamine Oxidase A/B to bidirectionally regulate intestinal motility.

Background

Monoamine oxidase (MAO), the principal enzymatic regulator of monoamine neurotransmitter catabolism, plays a critical role in modulating intestinal motility dynamics. In colonic tissues, MAO-A is predominantly expressed during monoamine degradation, whereas MAO-B exhibits a relatively lower expression level. This differential expression of MAO subtypes endows naringenin (NAR), a flavonoid compound that can competitively bind to the active sites of both MAO-A and MAO-B, with distinct dose-response thresholds for inhibiting these two enzyme isoforms. Consequently, this study aims to systematically elucidate the molecular mechanisms underlying NAR's regulation of intestinal motility through its selective inhibition of the two MAO subtypes, and to comprehensively analyze the associated dose-effect relationships. Ultimately, the research seeks to provide a theoretical basis for its dose optimization and the mitigation of toxicity and side effects.

Methods

In this study, we constructed a slow-transmission constipation model in male C57BL/6 mice induced by loperamide (LOP), and systematically investigated the effects of NAR at different concentrations on intestinal motility, MAO activity and neurotransmitter metabolism.

Results

This research showed that NAR at a dose of 25–300 mg/kg selectively targeted intestinal MAO-A, suppressing enzymatic activity and reducing 5-hydroxytryptamine (5-HT) catabolism. This accumulation of 5-HT enhanced intestinal motility. However, when the NAR concentration is ≥ 150 mg/kg, it can additionally cause MAO-B inhibition, which resulted in significant blockage of dopamine metabolism and caused an abnormal increase in dopamine content. Ultimately, it inhibited colonic peristalsis through the activation of the dopamine signaling pathway.

Conclusion

The results confirmed that NAR can regulate the activities of MAO-A/B in a threshold-dependent manner to achieve bidirectional regulation of intestinal motility.

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来源期刊

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.