School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570100, China.
Phytomedicine. 2022 Sep;104:154285. doi: 10.1016/j.phymed.2022.154285. Epub 2022 Jun 18.
5-Demethylnobiletin (5DN) is a polymethoxyflavone (PMF) primarily found in citrus fruits. It has various health-promoting properties and hence has attracted significant attention from scholars worldwide.
This review is the first to systematically summarize the recent research progress of 5DN, including its pharmacological activity, mechanism of action, pharmacokinetics, and toxicological effects. In addition, the pharmacological mechanism of action of 5DN has been discussed from a molecular biological perspective, and data from in vivo and in vitro animal studies have been compiled to provide a more thorough understanding of 5DN as a potential lead drug.
Data were extracted from SciFinder, PubMed, ScienceDirect and China National Knowledge Infrastructure (CNKI) from database inception to January 2022.
5DN has broad pharmacological activities. It exerts anti-inflammatory effects, promotes apoptosis and autophagy, and induces melanogenesis mainly by regulating the JAK2/STAT3, caspase-dependent apoptosis, ROS-AKT/mTOR, MAPK and PKA-CREB signaling pathways. 5DN can be used for treating diseases such as cancer, inflammation-related diseases, rheumatoid arthritis, and neurodegenerative diseases. To date, there have been only a few toxicological studies on 5DN, and both in vitro and in vivo on 5DN have not revealed significant toxic side effects. Pharmacokinetic studies have revealed that the metabolites of 5DN are mainly 5,3'-didemethylnobiletin (M1); 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), in either, glucuronide-conjugated or monomeric form. The pharmacokinetic products of 5DN, especially M1, possess better activity than 5DN for the treatment of cancer.
The anticancer effects of 5DN and its metabolites warrant further investigation as potential drug candidates, especially through in vivo studies. In addition, the therapeutic effects of 5DN in neurodegenerative diseases should be examined in more experimental models, and the absorption and metabolism of 5DN should be further investigated in vivo.
5-去甲氧基诺必灵（5DN）是一种主要存在于柑橘类水果中的多甲氧基黄酮（PMF）。它具有多种促进健康的特性，因此引起了全球学者的极大关注。
这是第一篇系统性总结 5DN 近期研究进展的综述，包括其药理学活性、作用机制、药代动力学和毒理学效应。此外，还从分子生物学角度探讨了 5DN 的药理作用机制，并编译了来自体内和体外动物研究的数据，以更全面地了解 5DN 作为一种潜在的先导药物。
从 SciFinder、PubMed、ScienceDirect 和中国知网（CNKI）中提取了从数据库建立到 2022 年 1 月的数据。
5DN 具有广泛的药理活性。它主要通过调节 JAK2/STAT3、半胱天冬酶依赖性凋亡、ROS-AKT/mTOR、MAPK 和 PKA-CREB 信号通路，发挥抗炎作用、促进细胞凋亡和自噬、诱导黑色素生成。5DN 可用于治疗癌症、炎症相关疾病、类风湿关节炎和神经退行性疾病等疾病。迄今为止，仅有少数关于 5DN 的毒理学研究，5DN 的体外和体内研究均未显示出明显的毒性副作用。药代动力学研究表明，5DN 的代谢物主要为 5,3'-二甲氧基诺必灵（M1）；5,4'-二甲氧基诺必灵（M2）和 5,3',4'-三甲氧基诺必灵（M3），或以葡萄糖醛酸结合物或单体形式存在。5DN 的代谢产物，特别是 M1，在治疗癌症方面比 5DN 具有更好的活性。
5DN 及其代谢物的抗癌作用值得进一步研究，作为潜在的药物候选物，特别是通过体内研究。此外，应在更多的实验模型中研究 5DN 在神经退行性疾病中的治疗效果，并进一步在体内研究 5DN 的吸收和代谢。
