基于疏肝解郁功效的逍遥散寒苦肝和温辛肝性效关系研究

doi:10.3976/j.issn.1002-4026.2022.01.006

摘要/Abstract

摘要：

为探讨逍遥散中疏肝解郁中药的寒温差异与其功效的内在联系,通过数据库检索获取寒苦肝和温辛肝药性的主要有效成分及作用靶点,基于STRING平台构建蛋白质-蛋白质相互作用网络,采用Metascape对识别出的药性组合蛋白质-蛋白质相互作用网络进行京都基因与基因组百科全书通路注释和统计分析。结果表明:逍遥散中归肝经药性主要通过HTR2B等靶点参与神经递质、信号通路、内分泌发挥疏肝解郁的功效特点;逍遥散中寒苦药性主要通过CREBRF等靶点参与能量代谢、炎症反应发挥疏肝解郁的功效特点;逍遥散中温辛组合药性主要通过ADCY5等靶点参与炎症反应神经营养、氨基酸代谢发挥疏肝解郁的功效特点。该研究从分子网络水平阐释了逍遥散中归肝经药性的共性特征和寒苦药性、温辛药性的特异性特征,为逍遥散的药性与功效的内在联系研究提供了新思路和新方法。

关键词: 药性组合, 蛋白质-蛋白质相互作用网络, 功能模块, 疏肝解郁, 逍遥散

Abstract:

The purpose of this study was to explore the internal relationship between temperature differences and efficacy of Traditional Chinese Medicine Xiaoyaosan,used for soothing liver and relieving depression. The main active ingredients and targets of the combination of cold bitter and warm pungent medicinal properties were obtained by database retrieval. The protein-protein interaction network was constructed based on STRING platform, and Kyoto encyclopedia of genes and genomes pathway and statistical analysis of the identified medicinal properties' combination protein-protein interaction network were carried out using metascape. The results show that the liver meridian properties of Xiaoyaosan were mainly involved in neurotransmitter, signal pathway, and endocrine pathway through HTR2B and other targets, and the cold bitter medicinal properties of Xiaoyaosan were mainly involved in energy metabolism and inflammatory reaction through CREBRF and other targets. The warm pungent medicinal properties of Xiaoyaosan was mainly involved in inflammatory reaction, neuronutrition, and amino acid metabolism through ADCY5 and other targets, thereby soothing the liver and relieving depression. The study explained the common characteristics of the liver meridian medicinal properties and specific characteristics of cold bitter medicinal properties and warm pungent medicinal properties from the molecular network level in Xiaoyaosan, and provided new ideas and new methods for the study of the internal relationship between the medicinal properties and efficacy of Xiaoyaosan.

Key words: drug combination, protein-protein interaction, network functional module, soothing the liver and relieving depression, Xiaoyaosan

中图分类号:

R285

师建茹,高耀,赵慧亮,田俊生,武嫣斐. 基于疏肝解郁功效的逍遥散寒苦肝和温辛肝性效关系研究[J]. 山东科学, 2022, 35(1): 37-44.

SHI Jian-ru,GAO Yao,ZHAO Hui-liang,TIAN Jun-sheng,WU Yan-fei. Nature-effect relationship research of cold bitter and warm pungent medicinal properties of Xiaoyaosan for soothing the liver and relieving depression based on nature combination[J]. Shandong Science, 2022, 35(1): 37-44.

图/表 7

图1

表1

图2

图3

图4

表2

图5

参考文献 28

[1]	MOKDAD A H, FOROUZANFAR M H, DAOUD F, et al. Global burden of diseases, injuries, and risk factors for young People's health during 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013[J]. The Lancet, 2016, 387(10036):2383-2401. DOI: 10.1016/S0140-6736(16)00648-6. doi: 10.1016/S0140-6736(16)00648-6
[2]	FERRARI A J, STOCKINGS E, KHOO J P, et al. The prevalence and burden of bipolar disorder:Findings from the Global Burden of Disease Study 2013[J]. Bipolar Disorders, 2016, 18(5):440-450. DOI: 10.1111/bdi.12423. doi: 10.1111/bdi.12423
[3]	KESSLER R C, ANGERMEYER M, ANTHONY J C, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization's World Mental Health Survey Initiative[J]. World Psychiatry, 2007, 6(3):168-176.
[4]	曾霖, 李惠林, 赵恒侠, 等. 张学文国医大师从肝论治抑郁症经验[J]. 陕西中医药大学学报, 2019, 42(1):9-10.DOI: 10.13424/j.cnki.jsctcm.2019.01.003. doi: 10.13424/j.cnki.jsctcm.2019.01.003
[5]	TIAN J S, PENG G J, WU Y F, et al. A GC-MS urinary quantitative metabolomics analysis in depressed patients treated with TCM formula ofXiaoyaosan[J]. Journal of Chromatography B, 2016, 1026:227-235. DOI: 10.1016/j.jchromb.2015.12.026. doi: 10.1016/j.jchromb.2015.12.026
[6]	LIU CC, WU Y F, FENG G M, et al. Plasma-metabolite-biomarkers for the therapeutic response in depressed patients by the traditional Chinese medicine formula Xiaoyaosan: A (1)H NMR-based metabolomics approach[J]. Journal of Affective Disorders, 2015, 185:156-163. DOI: 10.1016/j.jad.2015.05.005. doi: 10.1016/j.jad.2015.05.005
[7]	YAN Z Y, JIAO H Y, DING X F, et al. Xiaoyaosan improves depressive-like behaviors in mice through regulating apelin-APJ system in hypothalamus[J]. Molecules, 2018, 23(5):1073. DOI: 10.3390/molecules23051073. doi: 10.3390/molecules23051073
[8]	GAOX X, ZHENG X Y, LI Z Y, et al. Metabonomic study on chronic unpredictable mild stress and intervention effects of Xiaoyaosan in rats using gas chromatography coupled with mass spectrometry[J]. Journal of Ethnopharmacology, 2011, 137(1):690-699. DOI: 10.1016/j.jep.2011.06.024. doi: 10.1016/j.jep.2011.06.024
[9]	吴丹, 高耀, 向欢, 等. 基于网络药理学的柴胡抗抑郁作用机制研究[J]. 药学学报, 2018, 53(2):210-219. DOI: 10.16438/j.0513-4870.2017-0914. doi: 10.16438/j.0513-4870.2017-0914
[10]	宫文霞, 周玉枝, 李肖, 等. 当归抗抑郁化学成分及药理作用研究进展[J]. 中草药, 2016, 47(21):3905-3911. DOI: 10.7501/j.issn.0253-2670.2016.21.026. doi: 10.7501/j.issn.0253-2670.2016.21.026
[11]	邵继红, 韩珍, 杨艳, 等. 白芍抗抑郁作用的实验研究[J]. 宁夏医学杂志, 2008, 30(6):490-491. DOI: 10.3969/j.issn.1001-5949.2008.06.004. doi: 10.3969/j.issn.1001-5949.2008.06.004
[12]	薛劲松, 李鸿雁, 傅强, 等. 左旋薄荷酮抗抑郁作用及机制研究[J]. 药学与临床研究, 2015, 23(3):238-241. DOI: 10.13664/j.cnki.pcr.2015.03.008. doi: 10.13664/j.cnki.pcr.2015.03.008
[13]	施学丽, 陈贵海, 赵晓芳, 等. 基于数据挖掘技术的中药专利复方治疗抑郁症用药规律分析[J]. 时珍国医国药, 2013, 24(11):2822-2824. DOI: 10.3969/j.issn.1008-0805.2013.11.108. doi: 10.3969/j.issn.1008-0805.2013.11.108
[14]	李晶, 吴东雪, 候宁, 等. 基于活血化瘀功效的温苦肝、寒苦肝性效关系研究[J]. 中国中药杂志, 2019, 44(2):212-217. DOI: 10.19540/j.cnki.cjcmm.20180903.001. doi: 10.19540/j.cnki.cjcmm.20180903.001
[15]	王耘, 张燕玲, 史新元, 等. 基于药性组合的中药性效规律研究框架[J]. 世界科学技术-中医药现代化, 2012, 14(4):1798-1802. DOI: 10.3969/j.issn.1674-3849.2012.04.009. doi: 10.3969/j.issn.1674-3849.2012.04.009
[16]	吴东雪, 霍梦琪, 候宁, 等. 基于药性组合的活血化瘀中药性效关系研究[J]. 中国中药杂志, 2019, 44(2):205-211. DOI: 10.19540/j.cnki.cjcmm.20180913.001. doi: 10.19540/j.cnki.cjcmm.20180913.001
[17]	候宁, 吴东雪, 刘敏, 等. 基于药性组合的丹参和红花的性效关系研究[J]. 中国中药杂志, 2019, 44(2):224-228. DOI: 10.19540/j.cnki.cjcmm.20180903.002. doi: 10.19540/j.cnki.cjcmm.20180903.002
[18]	朱艳玲. 《中华本草》归肝经药物性效规律文献研究[D]. 济南: 山东中医药大学, 2011.
[19]	国家药典委员会. 中华人民共和国药典2020年版一部[M]. 北京: 中国医药科技出版社, 2020.
[20]	DAVIS A P, GRONDIN C J, JOHNSON R J, et al. The comparativetoxicogenomics database: Update 2017[J]. Nucleic Acids Research, 2017, 45(D1):D972-D978. DOI: 10.1093/nar/gkw838. doi: 10.1093/nar/gkw838
[21]	ZHU F, SHI Z, QIN C, et al. Therapeutic target database update 2012:A resource for facilitating target-oriented drug discovery[J]. Nucleic Acids Research, 2012, 40(D1):D1128-D1136. DOI: 10.1093/nar/gkr797. doi: 10.1093/nar/gkr797
[22]	WHIRL-CARRILLO M, MCDONAGH E M, HEBERT J M, et al. Pharmacogenomics knowledge for personalized medicine[J]. Clinical Pharmacology & Therapeutics, 2012, 92(4):414-417. DOI: 10.1038/clpt.2012.96. doi: 10.1038/clpt.2012.96
[23]	ASSENOV Y, RAMÍREZ F, SCHELHORN S E, et al. Computing topological parameters of biological networks[J]. Bioinformatics, 2008, 24(2):282-284. DOI: 10.1093/bioinformatics/btm554. doi: 10.1093/bioinformatics/btm554
[24]	ZHOU Y Y, ZHOU B, PACHE L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets[J]. Nature Communications, 2019, 10:1523. DOI: 10.1038/s41467-019-09234-6. doi: 10.1038/s41467-019-09234-6
[25]	HAMATI R, MANSARI M E, BLIER P. Serotonin-2B receptor antagonism increases the activity of dopamine and glutamate neurons in the presence of selective serotonin reuptake inhibition[J]. Neuropsychopharmacology, 2020, 45(12):2098-2105. DOI: 10.1038/s41386-020-0723-y. doi: 10.1038/s41386-020-0723-y
[26]	白娟, 杨铁柱, 史占江, 等. 逍遥散对抑郁症小鼠前额皮质BDNF和NGF蛋白表达水平的影响[J]. 时珍国医国药, 2019, 30(7):1572-1575. DOI: 10.3969/j.issn.1008-0805.2019.07.012. doi: 10.3969/j.issn.1008-0805.2019.07.012
[27]	贺欣雨, 王学, 石博宇, 等. 基于CUMS大鼠逍遥散拆方药队抗抑郁作用的BDNF通路分子机制研究[J]. 中药与临床, 2019, 10(1):18-22.
[28]	VIJIARATNAM N, NEWBY R, KEMPSTER P A. Depression and psychosis in ADCY₅-related dyskinesia:part of the phenotypic spectrum?[J]. Journal of Clinical Neuroscience, 2018, 57:167-168. DOI: 10.1016/j.jocn.2018.08.049. doi: 10.1016/j.jocn.2018.08.049

药性组合	基因名	药性组合	基因名
逍遥散中寒苦肝药性	AR	逍遥散中温辛肝药性	SCN5A
	ADORA1		SCN10A
	PGR		IL1B
	SCN5A		ADORA1
	ESR1		KCNA5
	KCNA5		ADH1C
	SCN10A		RAPGEF2
	KCNQ1		KCNK4
	CACNAD1		FADD
	···		···
	NPPA		NPPA

药性组合	通路数目	通路
温辛药性和寒苦药性	1	胰导素抵抗
		神经活性配体-受体相互作用
温辛药性和归肝经药性	3	cAMP信号通路
		胆碱能突触
寒苦药性和归肝经药性	2	MAPK信号通路
		心肌细胞肾上腺素能信号