温莪术中一个新的倍半萜及其对高糖所致肾小球足细胞保护活性
投稿时间:2024-05-03  修订日期:2024-05-15   点此下载全文
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作者中文名作者英文名单位中文名单位英文名E-Mail
徐玉岩 XU Yu-yan 北京中医药大学 Beijing University of Chinese Medicine 2673060310@qq.com 
伍一炜 WU Yi-wei 北京中医药大学 Beijing University of Chinese Medicine 1715910148@qq.com 
张韵寒 ZHANG Yun-han 北京中医药大学 Beijing University of Chinese Medicine 1244061945@qq.com 
范佳萍 FAN Jia-ping 温州医科大学 Wenzhou Medical University fjp18772409203@163.com 
杨慧珍 YANG Hui-zhen 北京中医药大学 Beijing University of Chinese Medicine 2078123386@qq.com 
徐暾海* XU Tun-hai 北京中医药大学 Beijing University of Chinese Medicine thxu@163.com 
朱寅荻 ZHU Yin-di 温州医科大学 Wenzhou Medical University zhuyindi314@sina.com 
中文摘要:目的:温莪术是来源于温郁金的莪术的习称,本文对温莪术的倍半萜类成分及其对肾小球足细胞的保护活性进行研究。方法:综合运用硅胶、Sephadex LH-20凝胶柱色谱及半制备性高效液相色谱等方法,对温莪术乙酸乙酯溶性部位进行分离纯化。通过理化性质和谱学方法(如1D和2D-NMR、MS、IR、CD、UV)对单体化合物进行结构鉴定。运用网络药理学方法及分子对接初步预测新化合物(化合物1)对治疗糖尿病肾病的主要靶点,采用高糖诱导的小鼠肾小球足细胞模型研究化合物1~5对足细胞保护活性。结果:从温莪术乙酸乙酯溶性部位分离得到5个化合物,分别鉴定为7R-11-羟基-4,9-吉玛二烯-1,8二酮(7R-11-hydroxy-4,9-gemadiene-1,8-dione,1)、多穗金粟兰内酯B(multistalactone B,2)、2β-羟基莪术二酮(2β-hydroxycurdione,3)、海尼姜黄酮B(heyneanone B,4)、1α,4β-二羟基桉叶-7(11)-烯-8-酮[1α,4β-dihydroxyeudesm-7(11)-en-8-one,5]。通过网络药理学方法对化合物1进行靶点预测得到99个靶点,化合物1对糖尿病肾病共同靶点59个,其中关键靶点为EGFR、PTGS2、MAPK1、PARP1、NR3C1,KEGG富集程度较高的为HIF-1、PI3K-Akt和FoXO信号通路,分子对接显示结合能良好。体外实验中,与模型组相比,化合物1高剂量组及化合物3中、高剂量组对高糖诱导的足细胞有保护活性,化合物4、5保护活性显著,且在25~100 μg·mL–1范围内与浓度呈正相关。结论:化合物1是未见报道的新化合物,化合物对高糖诱导的肾小球足细胞的保护作用可能是通过作用于STAT3、HIF1-α、HSP90AB1、NR3C1、MTOR、HDAC2等靶点基因,调控胰岛素抵抗、HIF-1、AGE-RAGE等信号通路实现的。
中文关键词:温莪术  化学成分  倍半萜  足细胞
 
A new sesquiterpenoid from Curcumae Rhizoma and its protective activity against high glucose-induced glomerular podocytes
Abstract:Objective: Curcumae Rhizoma is the idiomatic name for Curcuma zedoaria, which is derived from Curcuma wenyujin. This paper investigates the sesquiterpene constituents of Curcumae Rhizoma and their protective activity on glomerular podocytes. Methods: The chemical constituents of the ethyl acetate extract of Curcumae Rhizoma were isolated and purified by column chromatography with silica gel, Sephadex LH-20, and semi-preparative high performance liquid chromatography. The monomer compounds were structurally characterized by physicochemical properties and spectroscopic methods (e.g., 1D and 2D-NMR, MS, IR, CD, UV). The main target of new compound (compound 1) in the treatment of diabetic nephropathy was predicted by network pharmacology and molecular docking. High glucose-induced mouse glomerular podocyte model was used to study the podocytoprotective activity of compounds 1–5. Results: Five compounds were isolated from the ethyl acetate extraction site of Curcumae Rhizoma, which were identified as 7R-11-hydroxy-4,9-Gemadiene-1,8-dione (1), multistalactone B (2), 2β-hydroxycurcumene-dione (3), heyneanone B (4), 1α,4β-dihydroxyeudesm-7(11)-en-8-one (5). Ninety-nine targets of compound 1 and fifty-nine common targets of compound 1-diabetic nephropathy were obtained by network pharmacological methods, and the key targets were EGFR, PTGS2, MAPK1, PARP1, NR3C1. KEGG was highly enriched in HIF-1, PI3K-Akt and FoXO signalling pathways. Molecular docking showed good binding energy. In the in vitro experiments, compared with the survival rate of the model group, the high dose groups of compound 1, the medium and high dose groups of compound 3 showed podocytesprotective activity, compounds 4 and 5 showed significant protective activity against mouse glomerular podocytes and were positively correlated with concentration in the range of 25–100 μg·mL–1. Conclusions: Compound 1 is new and not reported. The protective effect of the compounds on high glucose-induced glomerular podocytes may be achieved by acting on target genes such as STAT3, HIF1-α, HSP90AB1, NR3C1, MTOR, HDAC2 and modulating signalling pathways such as insulin resistance, HIF-1, and AGE-RAGE.
keywords:Curcumae Rhizoma  chemical components  sesquiterpenoid  podocytes
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