PMID- 33945919 OWN - NLM STAT- MEDLINE DCOM- 20210601 LR - 20220422 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 86 DP - 2021 Jun TI - Higenamine alleviates allergic rhinitis by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. PG - 153565 LID - S0944-7113(21)00107-0 [pii] LID - 10.1016/j.phymed.2021.153565 [doi] AB - BACKGROUND: 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. METHODS: 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). RESULTS: 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-kappaB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine. CONCLUSION: 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. CI - Copyright (c) 2021. Published by Elsevier GmbH. FAU - Wei, Xiaohan AU - Wei X AD - 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. FAU - Zhang, Baoping AU - Zhang B AD - 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. FAU - Liang, Xiao AU - Liang X AD - School of Pharmaceutical Sciences, Guilin Medical University. Guilin, China. 541199. FAU - Liu, Changshun AU - Liu C AD - 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. FAU - Xia, Ting AU - Xia T AD - 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. FAU - Xie, Yingjie AU - Xie Y AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Deng, Xue AU - Deng X AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. FAU - Tan, Xiaomei AU - Tan X AD - 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. Electronic address: tanxm_smu@163.com. LA - eng PT - Journal Article DEP - 20210420 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Alkaloids) RN - 0 (Proto-Oncogene Proteins c-jun) RN - 0 (Tetrahydroisoquinolines) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.2 (JAK2 protein, human) RN - EC 2.7.10.2 (Janus Kinase 2) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - TBV5O16GAP (higenamine) SB - IM MH - Alkaloids/*pharmacology/therapeutic use MH - Animals MH - ErbB Receptors/metabolism MH - Humans MH - Janus Kinase 2/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Molecular Docking Simulation MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Proto-Oncogene Proteins c-jun/*metabolism MH - Rhinitis, Allergic/*drug therapy MH - Tetrahydroisoquinolines/*pharmacology/therapeutic use OTO - NOTNLM OT - Allergic rhinitis OT - Higenamine OT - Multiple targets OT - Network pharmacology EDAT- 2021/05/05 06:00 MHDA- 2021/06/02 06:00 CRDT- 2021/05/04 20:14 PHST- 2021/01/16 00:00 [received] PHST- 2021/03/29 00:00 [revised] PHST- 2021/04/02 00:00 [accepted] PHST- 2021/05/05 06:00 [pubmed] PHST- 2021/06/02 06:00 [medline] PHST- 2021/05/04 20:14 [entrez] AID - S0944-7113(21)00107-0 [pii] AID - 10.1016/j.phymed.2021.153565 [doi] PST - ppublish SO - Phytomedicine. 2021 Jun;86:153565. doi: 10.1016/j.phymed.2021.153565. Epub 2021 Apr 20.