10-Methoxy-leonurine accelerated wound healing through ErbB4/PI3K-AKT pathway

IF 5.4 2区医学 Q1 CHEMISTRY, MEDICINAL Journal of ethnopharmacology Pub Date : 2025-03-19 DOI:10.1016/j.jep.2025.119641

Yue Zhang , Bang-Yin Tan , Hui-Zhen Peng , Yu Duan , Xi Wen , Xin-Yao Li , Xian-Run Wu , Yun-Li Zhao , Xiao-Dong Luo

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Abstract

Ethnopharmacological relevance

Leonurus japonicus Houtt., commonly known as motherwort, has been used in traditional Chinese medicine to treat trauma and wound infections historically. However, the main compounds responsible for promoting wound healing need to be identified and explained fully.

Aim of the study

To investigate the wound healing effect of 10-methoxy-leonurine (MN) and explore its mechanism.

Materials and methods

Following the UHPLC/Q-TOF-MS analysis of L. japonicus, the phytochemical isolation was carried out, and then the effect of isolated compounds in promoting the proliferation of human skin fibroblasts (HSF) was screened. Additionally, scratch and 5-ethynyl-2′-deoxyuridine assay in HSF were further adopted to support the effects of MN in vitro. A rat model with full-thickness skin wounds was used to verify in vivo by hematoxylin and eosin staining, Masson's trichrome and immunohistochemistry. Furthermore, network pharmacology and molecular docking were performed to predict the potential pathway, which were subsequently validated by cell cycle and RT-qPCR.

Results

A total 11 compounds were isolated, in which MN exhibited the most significant bioactivity in promoting HSF proliferation and migration. Moreover, the wound healing rates in low (10 μg/mL) and high dose (50 μg/mL) of MN groups reached 93.9 % and 94.5 %, respectively, which was better than basic fibroblast growth factor (bFGF) 89.4 %. Additionally, the epithelial thickness, collagen Ⅰ deposition and α-smooth muscle actin expression were enhanced and the proportion of HSF cells in the S phase of the cell cycle was increased. Network pharmacological and molecular docking analysis suggested ErbB pathway was involved in the regulation of wound healing by MN, which was further supported by the up-regulation of Erbb4, Stat5, Pi3k, Akt and mTOR mRNA levels.

Conclusion

MN showed potent effect on wound healing by regulating ErbB4/PI3K-AKT pathway, even better than bFGF.

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10-甲氧基亮氨酸通过 ErbB4/PI3K-AKT 通路加速伤口愈合

民族药理学相关性：益母草。益母草，俗称益母草，历来用于治疗创伤和伤口感染。然而，负责促进伤口愈合的主要化合物需要被识别和充分解释。目的：观察10-甲氧基-leonurine （MN）的创面愈合作用并探讨其作用机制。材料与方法：通过UHPLC/Q-TOF-MS分析，对枇杷进行植物化学分离，筛选分离化合物对人皮肤成纤维细胞（HSF）增殖的促进作用。此外，我们进一步采用刮痕法和5-乙基-2'-脱氧尿苷法来支持MN在体外的作用。采用苏木精染色、伊红染色、马松三色染色和免疫组织化学方法对大鼠全层皮肤损伤模型进行体内验证。此外，通过网络药理学和分子对接预测潜在通路，随后通过细胞周期和RT-qPCR验证。结果：共分离到11个化合物，其中MN在促进HSF增殖和迁移方面表现出最显著的生物活性。低剂量组（10 μg/mL）和高剂量组（50 μg/mL）创面愈合率分别达到93.9%和94.5%，优于碱性成纤维细胞生长因子（bFGF）的89.4%。上皮细胞厚度、胶原Ⅰ沉积、α-平滑肌肌动蛋白表达增加，细胞周期S期HSF细胞比例增加。网络药理与分子对接分析表明，ErbB通路参与了MN对创面愈合的调控，Erbb4、Stat5、Pi3k、Akt和mTOR mRNA水平上调也进一步支持了这一观点。结论：MN通过调控ErbB4/PI3K-AKT通路对创面愈合有明显的促进作用，其作用优于bFGF。

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来源期刊

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.