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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	北京中医药大学中药学院，北京 100029 温州医科大学中医药学院，浙江温州 325035	School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing100029, China School of Chinese Medicine, Wenzhou Medical University, Wenzhou325035, China
伍一炜	WU Yi-wei	北京中医药大学中药学院，北京 100029 温州医科大学中医药学院，浙江温州 325035	School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing100029, China School of Chinese Medicine, Wenzhou Medical University, Wenzhou325035, China
张韵寒	ZHANG Yun-han	北京中医药大学中药学院，北京 100029 温州医科大学中医药学院，浙江温州 325035	School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing100029, China School of Chinese Medicine, Wenzhou Medical University, Wenzhou325035, China
范佳萍	FAN Jia-ping	温州医科大学中医药学院，浙江温州 325035	School of Chinese Medicine, Wenzhou Medical University, Wenzhou325035, China
杨慧珍	YANG Hui-zhen	北京中医药大学中药学院，北京 100029	School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing100029, China
孙文	SUN Wen	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	Centre for Translational Medicine, Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen518100, China
徐暾海*	XU Tun-hai	北京中医药大学中药学院，北京 100029	School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing100029, China
朱寅荻*	ZHU Yin-di	温州医科大学中医药学院，浙江温州 325035	School of Chinese Medicine, Wenzhou Medical University, Wenzhou325035, China

中文摘要: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（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25~100 μg·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。

中文关键词: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

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

Abstract: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 activities on podocytes. Compounds 4 and 5 showed significant protective activities on mouse glomerular podocytes, and the activities were positively correlated with the compound concentration within the range of 25-100 μg·mL^–1.Conclusion Compound 1 may exert the protective effect on the glomerular podocytes exposed to high glucose by acting on target genes such as EGFR, PTGS2, MAPK1, PARP1, and NR3C1 and modulating HIF-1, JAK-STAT, and FoXO signaling pathways.

keywords:Curcumae Rhizoma chemical components 7R-11-hydroxy-4,9-gemadiene-1,8-dione sesquiterpenoid podocytes

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