School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Guangzhou Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou 510515, China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology, Guangzhou 510515, China.
School of Pharmaceutical Sciences, Guilin Medical University. Guilin, China. 541199.
Phytomedicine. 2021 Jun;86:153565. doi: 10.1016/j.phymed.2021.153565. Epub 2021 Apr 20.
Allergic rhinitis (AR) is an inflammatory, immunoglobulin E (IgE)-mediated disease characterized by the typical symptoms of sneezing, rhinorrhea, nasal itching, and congestion. Higenamine (HG) is a plant-based alkaloid, possesses a wide range of activities, including vascular and tracheal relaxation, antioxidative, antiapoptotic, anti-inflammatory, and immunomodulatory activities. So far, the effect and the underlying mechanism of HG on AR have not been studied.
HYPOTHESIS/PURPOSE: The purpose of this study was to evaluate the effects of HG on AR and investigate its underlying mechanism.
The effects of HG on AR were evaluated in an ovalbumin-induced AR mouse model. Network pharmacology-based methods such as target prediction, protein-protein interaction (PPI) network analysis, pathway analysis, and molecular docking were used to identify the likely HG targets. Finally, we validated the mechanism of action of HG through its effects on these targets in human nasal epithelial cells (HNEpCs).
Oral administration of 30, 60, and 120 mg/kg HG significantly alleviated rubbing and sneezing in AR mice and attenuated histopathological changes in the lung and nasal tissues. Additionally, HG reduced the levels of IgE, histamine, and IL-4 in the serum of AR mice, and regulated imbalance in Th1/Th2 cells. Using network pharmacology-based methods, we identified 29 HG targets related to AR. These targets are mainly involved in the PD-L1, relaxin, estrogen, HIF-1, Th1 and Th2 cell differentiation, T cell receptor, and the Th17 cell differentiation signaling pathways. Molecular docking showed that HG may well be suited to the receptor binding pockets of key target AKT1, EGFR, c-Jun, NOS2, and JAK2. In HNEpCs, HG inhibited the histamine-induced mRNA expression and secretion of interleukin (IL)-6, and IL-8, as well as the expression of MUC5AC and the phosphorylation of NF-κB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine.
Overall, our results suggest that HG may alleviate AR by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. HG, therefore, has great potential as a therapeutic agent for the treatment of AR.
变应性鼻炎（AR）是一种炎症性、免疫球蛋白 E（IgE）介导的疾病，其特征是打喷嚏、流涕、鼻痒和鼻塞等典型症状。盐酸育亨宾（HG）是一种植物源性生物碱，具有广泛的活性，包括血管和气管松弛、抗氧化、抗凋亡、抗炎和免疫调节活性。迄今为止，HG 对 AR 的作用及其潜在机制尚未得到研究。
假设/目的：本研究旨在评估 HG 对 AR 的影响，并探讨其潜在机制。
在卵清蛋白诱导的 AR 小鼠模型中评价 HG 对 AR 的影响。采用网络药理学方法，如靶标预测、蛋白质-蛋白质相互作用（PPI）网络分析、通路分析和分子对接，鉴定可能的 HG 靶标。最后，我们通过其对人鼻上皮细胞（HNEpCs）中这些靶标的作用来验证 HG 的作用机制。
口服 30、60 和 120mg/kg HG 可显著缓解 AR 小鼠的搔抓和打喷嚏，并减轻肺和鼻组织的组织病理学变化。此外，HG 降低了 AR 小鼠血清中 IgE、组胺和 IL-4 的水平，并调节了 Th1/Th2 细胞失衡。采用网络药理学方法，我们鉴定出 29 个与 AR 相关的 HG 靶标。这些靶标主要涉及 PD-L1、松弛素、雌激素、HIF-1、Th1 和 Th2 细胞分化、T 细胞受体和 Th17 细胞分化信号通路。分子对接显示，HG 可能与关键靶标 AKT1、EGFR、c-Jun、NOS2 和 JAK2 的受体结合口袋很好地适配。在 HNEpCs 中，HG 抑制组胺诱导的白细胞介素（IL）-6 和 IL-8 的 mRNA 表达和分泌，以及 MUC5AC 的表达和 NF-κB 的磷酸化。此外，HG 影响组胺诱导的 AKT1、EGFR、c-Jun、iNOS 和 JAK2 的变化。
总的来说，我们的结果表明，HG 通过激活 AKT1 和抑制 EGFR/JAK2/c-JUN 信号通路可能缓解 AR。因此，HG 作为治疗 AR 的治疗剂具有很大的潜力。
