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
Abstract
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.
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.