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  

A New Sesquiterpenoid from Curcumae Rhizoma and Its Protective Activity on Glomerular Podocytes Exposed to High Glucose

作　　者：徐玉岩 伍一炜 张韵寒 范佳萍 杨慧珍 孙文 徐暾海[1] 朱寅荻[2] XU Yu-yan;WU Yi-wei;ZHANG Yun-han;FAN Jia-ping;YANG Hui-zhen;SUN Wen;XU Tun-hai;ZHU Yin-di(School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China;School of Chinese Medicine,Wenzhou Medical University,Wenzhou 325035,China;Centre for Translational Medicine,Shenzhen Bao'an Chinese Medicine Hospital,Guangzhou University of Chinese Medicine,Shenzhen 518100,China)

机构地区：[1]北京中医药大学中药学院,北京100029 [2]温州医科大学中医药学院,浙江温州325035 [3]广州中医药大学附属宝安中医院转化医学中心,广东深圳518100

出　　处：《中国现代中药》2024年第11期1909-1918,共10页Modern Chinese Medicine

摘　　要：目的:研究温莪术的倍半萜类成分及其对肾小球足细胞的保护活性。方法:综合运用硅胶、Sephadex LH-20凝胶柱色谱及半制备高效液相色谱等方法,对温莪术乙酸乙酯部位进行分离纯化。通过理化性质和谱学方法,如一维核磁共振图谱(1D-NMR)、2D-NMR、质谱(MS)、红外光谱(IR)、圆二色谱(CD)、紫外光谱(UV)等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)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对足细胞的保护活性。结果:从温莪术乙酸乙酯部位分离得到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(multistalactoneB,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,其中关键靶点为表皮生长因子受体(EGFR)、前列腺素过氧化物合酶2(PTGS2)、丝裂原活化蛋白激酶1(MAPK1)、多聚ADP核糖聚合酶1(PARP1)、核受体亚家族3C组成员1(NR3C1),京都基因与基因组百科全书(KEGG)富集程度较高的为缺氧诱导因子-1(HIF-1)、Janus激酶信号转导和转录激活因子(JAK-STAT)和叉头状转录因子(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、化合物5保护活性显著,且在25~100μg·mL–1范围内与质量浓度呈正相关。结论:化合物1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EGFR、PTGS2、MAPK1、PARP1、NR3C1等靶点基因,调控HIF-1、JAK-STAT、FoXO等信号通路实现的。Objective:To investigate the sesquiterpenoids of Curcumae Rhizoma(this study focused on that derived from Curcuma wenyujin Y.H.Chen et C.Ling)and their protective activities on glomerular podocytes.Methods:The ethyl acetate extract of Curcumae Rhizoma was purified by column chromatography with silica gel and Sephadex LH-20 and semi-preparative high performance liquid chromatography.The compounds in the extract were structurally characterized based on physicochemical properties and data from one-and two-dimensional nuclear magnetic resonance(1D and 2D-NMR),mass spectrometry(MS),infrared spectroscopy(IR),circular dichroism(CD)spectroscopy,and ultraviolet-visible(UV)spectroscopy.The main targets of the new compound(compound 1)in the treatment of diabetic nephropathy were predicted by network pharmacology and molecular docking.High glucose-induced mouse glomerular podocyte model was established to study the protective activities of compounds 1-5.Results:Five compounds were isolated from the ethyl acetate extract of Curcumae Rhizoma and identified as 7R-11-hydroxy-4,9-gemadiene-1,8-dione(1),multistalactone B(2),2β-hydroxycurdione(3),heyneanone B(4),and 1α,4β-dihydroxyeudesm-7(11)-en-8-one(5).Ninety-nine targets of compound 1 were predicted,including 59 common targets shared with diabetic nephropathy.The key targets were epidermal growth factor receptor(EGFR),prostaglandin G/H synthase 2(PTGS2),mitogen-activated protein kinase 1(MAPK1),poly-ADP-ribose polymerase 1(PARP1),and nuclear receptor subfamily 3 group C member 1(NR3C1).The Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis showed that the targets were mainly enriched in the hypoxia-inducible factor-1(HIF-1),Janus kinase(JAK)-signal transducer and activator of transcription(STAT),and forkhead box O(FoXO)signaling pathways.Molecular docking showed strong binding affinity between the compounds and targets.In the cell experiments,compared with the model group,high-dose compound 1 and medium-and high-dose compound 3 showed protective activit

关 键 词：温莪术 化学成分 7R-11-羟基-4 9-吉玛二烯-1 8二酮 倍半萜 足细胞 

分 类 号：R284[医药卫生—中药学] R285[医药卫生—中医学]