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Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study
J Ethnopharmacol. 2023 Dec 6:117550. doi: 10.1016/j.jep.2023.117550.
Jiajia Liao 1, Lingyun Fu 2, Shidie Tai 3, Yini Xu 4, Shengquan Wang 5, Lingling Guo 6, Die Guo 7, Youqi Du 8, Jinggang He 9, Hong Yang 10, Xiaoxia Hu 11, Ling Tao 12, Xiangchun Shen 13
Affiliations
Affiliations
1 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 948087580@qq.com.
2 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 605606875@qq.com.
3 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 1937354359@qq.com.
4 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 605446623@qq.com.
5 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 963078224@qq.com.
6 The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 2992833889@qq.com.
7 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 2387703699@qq.com.
8 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 2196699044@qq.com.
9 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China. Electronic address: 1715083695@qq.com.
10 Department of Pharmacy, Guiyang Maternal and Child Health Care Hospital, Guiyang, 550003, Guizhou, China. Electronic address: 1329070275@qq.com.
11 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education, Guizhou Medical University, 550004, Guiyang, China. Electronic address: 251982143@qq.com.
12 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education, Guizhou Medical University, 550004, Guiyang, China. Electronic address: taoling@gmc.edu.cn.
13 The State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, 550025, Guiyang, China; The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education, Guizhou Medical University, 550004, Guiyang, China. Electronic address: shenxiangchun@126.com.
Ethnopharmacological relevance: Vascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear.
Aim of the study: To investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes.
Materials and methods: A diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cell (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, β-galactosidase staining, cell cycle, Reactive Oxygen Species (ROS), cell migration, and Enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against endothelial cell senescence. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats endothelial cell senescence.
Results: EOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the Peroxisome Proliferator-activated Receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blot and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA.
Conclusions: EOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.
