基于网络药理学的猫爪草治疗结核病作用机制研究

doi:10.3976/j.issn.1002-4026.2021.06.007

Abstract

Abstract:

This study aimed to investigate the mechanism of Ranunculi Ternati Radix in the treatment of tuberculosis based on network pharmacology. The active ingredients and related targets of Ranunculi Ternati Radix were screened using the Traditional Chinese Medicine System Pharmacology database and analysis platform. With the help of the GeneCards database to search disease targets, the intersections of active ingredient targets and disease targets are used as the predicted targets of Ranunculi Ternati Radix for tuberculosis treatment. A protein-protein interaction network diagram was constructed using the STRING database, and gene ontoeogy and Kyoto encyclopedia of gene and genomes(KEGG) enrichment analyses were performed for the overlapping genes. Finally, molecular docking verification between active ingredients and potential targets was performed using the AutoDock software. In total, 12 active compounds were selected from Ranunculi Ternati Radix. These active ingredients mainly act on the key targets of tuberculosis, including CASP3, CASP8, CASP9, BCL2, and BAX. KEGG results indicate that Ranunculi Ternati Radix may interfere with tuberculosis by regulating the apoptosis signaling pathway. The main components of Ranunculi Ternati Radix identified using molecular docking include stigmasta-4,6,8, vittadinoside, stigmasterol, stigmasterol glucoside, sitosterol acetate, and beta-sitosterol. These components were known to have obvious effects on BAX, CASP3, and CASP9. This study explored the active ingredients of Ranunculi Ternati Radix and corresponding potential targets when treating tuberculosis at the molecular level based on network pharmacology. Furthermore, the mechanism of action of Ranunculi Ternati Radix was verified.

Key words: network pharmacology, Ranunculi Ternati Radix, tuberculosis, signaling pathway, molecular docking

CLC Number:

R285

LIU Yuan, CHEN Jie, SUN Hui, XU Yuan-nan, MA Zhi-qiang, LIU Xiang-fang, LIU Meng-xing, LIU Xing. Study on the mechanism of Ranunculi Ternati Radix in the treatment of tuberculosis based on network pharmacology[J].Shandong Science, 2021, 34(6): 51-61.

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References 24

[1]	国家药典委员会. 中华人民共和国药典2015年版一部[M]. 北京: 中国医药科技出版社, 2015: 319-320.
	Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China 2015 Volume 1[M]. Beijing: China Medical Science and Technology Press, 2015: 319-320.
[2]	杨堃, 邓可众, 李汉兴, 等. 猫爪草体外抗结核作用研究[J]. 安徽农业科学, 2015, 43(19):76-77. DOI: 10.13989/j.cnki.0517-6611.2015.19.029. doi: 10.13989/j.cnki.0517-6611.2015.19.029
	YANG K, DENG K Z, LI H X, et al. Study on effects of Ranunculusternatus against Mycobacterium tuberculosis in vitro[J]. Journal of Anhui Agricultural Sciences, 2015, 43(19):76-77. DOI: 10.13989/j.cnki.0517-6611.2015.19.029. doi: 10.13989/j.cnki.0517-6611.2015.19.029
[3]	ZHANG L, LI R, LI M, et al. In vitro and in vivo study of anti-tuberculosis effect of extracts isolated from Ranunculi Ternati Radix[J]. Sarcoidosis,Vasculitis, and Diffuse Lung Diseases, 2015, 31(4):336-342.
[4]	FLOYD K. Global tuberculosis report 2019[R]. Geneva: World Health Organization, 2019.
[5]	LOHIYA A, SULIANKATCHI ABDULKADER R, RATH R S, et al. Prevalence and patterns of drug resistant pulmonary tuberculosis in India-A systematic review and meta-analysis[J]. Journal of Global Antimicrobial Resistance, 2020, 22:308-316. DOI: 10.1016/j.jgar.2020.03.008. doi: 10.1016/j.jgar.2020.03.008
[6]	FENG Z M, ZHAN Z L, YANG Y N, et al. New heterocyclic compounds from Ranunculus ternatus Thunb.[J]. Bioorganic Chemistry, 2017, 74:10-14. DOI: 10.1016/j.bioorg.2017.07.004. doi: 10.1016/j.bioorg.2017.07.004
[7]	周勇, 程芳. 猫爪草对肺结核患者外周血淋巴细胞颗粒裂解肽表达及其T淋巴细胞杀菌能力的影响[J]. 中国药学杂志, 2017, 52(18):1629-1632. DOI: 10.11669/cpj.2017.18.015. doi: 10.11669/cpj.2017.18.015
	ZHOU Y, CHENG F. The effect of Radix Ranuncoli Ternati on the expression of granule lytic peptide and bactericidal ability of T lymphocyte in peripheral blood lymphocytes of patients with pulmonary tuberculosis[J]. Chinese Pharmaceutical Journal, 2017, 52(18):1629-1632. DOI: 10.11669/cpj.2017.18.015. doi: 10.11669/cpj.2017.18.015
[8]	杨牧之, 王国萍, 王斌. 猫爪草多糖对小鼠腹腔巨噬细胞活力的调节作用[J]. 基因组学与应用生物学, 2019, 38(5):1997-2003. DOI: 10.13417/j.gab.038.001997. doi: 10.13417/j.gab.038.001997
	YANG M Z, WANG G P, WANG B. Regulating effects of polysaccharide from Radix Ranunculi Ternati on the cell vitality of murine peritoneal macrophages[J]. Genomics and Applied Biology, 2019, 38(5):1997-2003. DOI: 10.13417/j.gab.038.001997. doi: 10.13417/j.gab.038.001997
[9]	RU J L, LI P, WANG J N, et al. TCMSP: a database of systems pharmacology for drug discovery from herbalmedicines[J]. Journal of Cheminformatics, 2014, 6:13. DOI: 10.1186/1758-2946-6-13. doi: 10.1186/1758-2946-6-13
[10]	刘淇, 纪雅菲, 周洪莉, 等. 基于网络药理学探索荆芥-防风药对抗过敏作用的研究[J]. 中药药理与临床, 2020, 36(5):136-143. DOI: 10.13412/j.cnki.zyyl.20200825.002. doi: 10.13412/j.cnki.zyyl.20200825.002
	LIU Q, JI Y F, ZHOU H L, et al. Study on the anti-allergic effect of Jingjie-Fangfeng drug pair based on network pharmacology[J]. Pharmacology and Clinics of Chinese Materia Medica, 2020, 36(5):136-143. DOI: 10.13412/j.cnki.zyyl.20200825.002. doi: 10.13412/j.cnki.zyyl.20200825.002
[11]	ZHANG R Z, ZHU X, BAI H, et al. Network pharmacology databases for traditional Chinese medicine: Review and assessment[J]. Frontiers in Pharmacology, 2019, 10:123. DOI: 10.3389/fphar.2019.00123. doi: 10.3389/fphar.2019.00123
[12]	但文超, 何庆勇, 曲艺, 等. 基于网络药理学的枳术丸调治血脂异常的分子机制研究[J]. 世界科学技术-中医药现代化, 2019, 21(11):2396-2405. DOI: 10.11842/wst.20190723008. doi: 10.11842/wst.20190723008
	DAN W C, HE Q Y, QU Y, et al. Molecular mechanism of Zhizhu Pill in treatment of dyslipidemia based on network pharmacology[J]. Modernization of Traditional Chinese Medicine-World Science and Technology, 2019, 21(11):2396-2405. DOI: 10.11842/wst.20190723008. doi: 10.11842/wst.20190723008
[13]	SZKLARCZYK D, GABLE A L, LYON D, et al. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Research, 2019, 47(D1):D607-D613. DOI: 10.1093/nar/gky1131. doi: 10.1093/nar/gky1131
[14]	袁岸, 刘淇, 饶志粒, 等. 基于网络药理学的荆芥挥发油主要成分抗炎机制研究[J]. 中国药理学通报, 2020, 36(1):97-103. DOI: 10.3969/j.issn.1001-1978.2020.01.020. doi: 10.3969/j.issn.1001-1978.2020.01.020
	YUAN A, LIU Q, RAO Z L, et al. Anti-inflammatory mechanism of main constituents in essential oil from Schizonepeta tenuifolia Briq. based on network pharmacology[J]. Chinese Pharmacological Bulletin, 2020, 36(1):97-103. DOI: 10.3969/j.issn.1001-1978.2020.01.020. doi: 10.3969/j.issn.1001-1978.2020.01.020
[15]	ABDALLA A E, EJAZ H, MAHJOOB M O, et al. Intelligent mechanisms of macrophage apoptosis subversion by Mycobacterium[J]. Pathogens, 2020, 9(3):218. DOI: 10.3390/pathogens9030218. doi: 10.3390/pathogens9030218
[16]	VILCHÈZE C, JACOBS W R. The isoniazid paradigm of killing, resistance, and persistence in Mycobacterium tuberculosis[J]. Journal of Molecular Biology, 2019, 431(18):3450-3461. DOI: 10.1016/j.jmb.2019.02.016. doi: 10.1016/j.jmb.2019.02.016
[17]	师清博, 赵明明, 王春凤, 等. 结核分枝杆菌感染与巨噬细胞凋亡的免疫机制研究进展[J]. 中国兽医学报, 2017, 37(9):1811-1816. DOI: 10.16303/j.cnki.1005-4545.2017.09.32. doi: 10.16303/j.cnki.1005-4545.2017.09.32
	SHI Q B, ZHAO M M, WANG C F, et al. Immune mechanisms of Mycobacterium tuberculosis-induced macro phage apoptosis[J]. Chinese Journal of Veterinary Medicine, 2017, 37(9):1811-1816. DOI: 10.16303/j.cnki.1005-4545.2017.09.32. doi: 10.16303/j.cnki.1005-4545.2017.09.32
[18]	罗红, 郑碧英, 徐军发. 巨噬细胞凋亡抗结核分枝杆菌感染的研究进展[J]. 细胞与分子免疫学杂志, 2019, 35(7):665-670. DOI: 10.13423/j.cnki.cjcmi.008849. doi: 10.13423/j.cnki.cjcmi.008849
	LUO H, ZHENG B Y, XU J F. Research progress of macrophage apoptosis against Mycobacterium tuberculosis infection[J]. Journal of Cellular and Molecular Immunology, 2019, 35(7):665-670. DOI: 10.13423/j.cnki.cjcmi.008849. doi: 10.13423/j.cnki.cjcmi.008849
[19]	王旭东, 吴利先. 结核分枝杆菌与巨噬细胞相互作用的研究进展[J]. 中国病原生物学杂志, 2015, 10(6):571-573. DOI: 10.13350/j.cjpb.150622. doi: 10.13350/j.cjpb.150622
	WANG X D, WU L X. Advances in study of the interaction of Mycobacterium tuberculosis and macrophages[J]. Journal of Pathogen Biology, 2015, 10(6):571-573. DOI: 10.13350/j.cjpb.150622. doi: 10.13350/j.cjpb.150622
[20]	王健宏, 徐兆坤, 李武. 结核分枝杆菌CFP10和ESAT6对巨噬细胞RAW264.7凋亡及AIM2/ASC/Caspase-8通路的影响[J]. 微生物学通报, 2020, 47(12):113-4121. DOI: 10.13344/j.microbiol.china.200056. doi: 10.13344/j.microbiol.china.200056
	WANG J H, XU Z K, LI W. Effects of CFP10 and ESAT6 on cell apoptosis and AIM2/ASC/Caspase-8 pathway in RAW264.7 macrophages[J]. Microbiology China, 2020, 47(12):4113-4121. DOI: 10.13344/j.microbiol.china.200056. doi: 10.13344/j.microbiol.china.200056
[21]	ZHAO X, KHAN N, GAN H, et al. Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages[J]. Mucosal Immunology, 2017, 10(6):1553-1568. DOI: 10.1038/mi.2017.12. doi: 10.1038/mi.2017.12
[22]	ZHANG W, LU Q, DONG Y S, et al. Rv3033, as an emerging anti-apoptosis factor, facilitates Mycobacteria survival via inhibiting macrophage intrinsic apoptosis[J]. Frontiers in Immunology, 2018, 9:2136. DOI: 10.3389/fimmu.2018.02136. doi: 10.3389/fimmu.2018.02136
[23]	FANG M, SHINOMIYA T, NAGAHARA Y. Cell death induction by Ranunculusternatus extract is independent of mitochondria and dependent on Caspase-7[J]. 3 Biotech, 2020, 10(3):1-11. DOI: 10.1007/s13205-020-2111-z. doi: 10.1007/s13205-020-2111-z
[24]	周玲玉. β-谷甾醇对人肺癌细胞增殖、凋亡影响的初步研究[D]. 重庆:重庆医科大学, 2016.
	ZHOU L Y. Effect of β-sitosterol on the proliferation and apoptosis of lung cancer cell line[D]. Chongqing: Chongqing Medical University, 2016.

编号	活性成分	OB/%	DL
MOL000242	7-O-methyleridictyol(7-O-甲基圣草酚)	56.56	0.27
MOL011328	stigmasta-4,6,8(豆甾-4,6,8)	48.02	0.77
MOL011330	vittadinoside_qt(维太菊苷)	43.83	0.76
MOL000449	stigmasterol(豆甾醇)	43.83	0.76
MOL006772	poriferasterolmonoglucoside_qt(豆甾醇葡萄糖苷)	43.83	0.76
MOL011319	truflex OBP(邻苯二甲酸正丁异辛酯)	43.74	0.24
MOL001494	mandenol(亚油酸乙酯)	42.00	0.19
MOL001973	sitosteryl acetate(谷甾醇乙酸酯)	40.39	0.85
MOL000593	cholesterol(胆固醇)	37.87	0.68
MOL005438	cmpesterol(菜油甾醇)	37.58	0.71
MOL000358	bate-sitosterol(β-谷甾醇)	36.91	0.75
MOL011312	(3R,8S,9S,10S,13R,17R)-17-((2S,5R)-5-ethyl-6-methylheptan-2-yl)-3,10,13-trimethyl- 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenthrene	30.10	0.74

序号	靶点	Uniprot ID	序号	靶点	Uniprot ID	序号	靶点	Uniprot ID
1	ADH1C	P00326	15	CHRM3	P20309	29	OPRM1	P35372
2	ADRA1A	P35348	16	CHRM4	P08173	30	PGR	P06401
3	ADRA1B	P35368	17	CHRNA2	Q15822	31	PLAU	P00749
4	ADRA2A	P08913	18	CTRB1	P17538	32	PON1	P27169
5	ADRB1	P08588	19	GABRA1	P14867	33	PRKCA	P17612
6	ADRB2	P07550	20	JUN	P05412	34	PTGS1	P23219
7	AKR1B1	P15121	21	KCNH2	Q12809	35	PTGS2	P35354
8	BAX	Q07812	22	LTA4H	P09960	36	RXRA	P19793
9	BCL2	P10415	23	MAOA	P21397	37	SCN5A	Q14524
10	CASP3	P42574	24	MAP2	P11137	38	SLC6A2	P23975
11	CASP8	Q14790	25	NCOA1	Q15788	39	SLC6A3	Q01959
12	CASP9	P55211	26	NCOA2	Q15596	40	SLC6A4	P31645
13	CHRM1	P11229	27	NR3C2	P08235
14	CHRM2	P08172	28	MAOB	P27338

关键靶点	全称	Uniprot ID	度值
CASP3	Caspase-3	P42574	5
CASP8	Caspase-8	Q14790	5
CASP9	Caspase-9	P55211	5
BCL2	Apoptosis regulator Bcl-2	P10415	4
BAX	Apoptosis regulator BAX	Q07812	5
JUN	Transcription factor AP-1	P05412	4

信号通路	基因数	靶点	P值
乙肝	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	2.57×10^-7
凋亡	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	4.30×10^-7
癌症通路	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	3.57×10^-5
EB病毒感染	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	3.96×10^-5
麻疹	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	4.18×10^-5
TB	5	BAX、BCL2、CASP3、CASP8、CASP9	4.76×10^-5
HIV-1病毒感染	6	JUN、BAX、BCL2、CASP3、CASP8、CASP9	5.13×10^-5
p53信号通路	5	BAX、BCL2、CASP3、CASP8、CASP9	6.79×10^-5
单纯疱疹病毒感染	5	BAX、BCL2、CASP3、CASP8、CASP9	2.63×10^-2
沙门氏菌感染	5	JUN、BAX、BCL2、CASP3、CASP8	2.94×10^-2

活性成分	靶点
活性成分	CASP3	CASP8	CASP9	BCL2	BAX
7-O-Methyleridictyol	-7.5	-6.4	-6.3	-6.7	-7.0
Stigmasta-4,6,8	-7.6	-6.8	-8.4	-7.8	-9.0
vittadinoside_qt	-7.5	-7.1	-7.9	-7.0	-8.5
Stigmasterol	-7.7	-7.6	-8.5	-7.2	-8.7
poriferasterol monoglucoside_qt	-8.5	-7.2	-7.9	-8.2	-8.0
Truflex OBP	-5.3	-4.8	-4.5	-5.4	-5.8
Mandenol	-5.1	-4.4	-4.4	-5.6	-5.0
Sitosteryl acetate	-8.2	-6.8	-8.2	-7.6	-8.2
CLR	-7.3	-6.8	-8.0	-6.9	-8.5
cmpesterol	-6.9	-6.9	-8.4	-7.6	-8.8
bate-sitosterol	-6.9	-7.3	-8.4	-7.7	-8.3
(3R,8S,9S,10S,13R,17R)-17-((2S,5R)-5-ethyl-6- methylheptan-2-yl)-3,10,13-trimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenthrene	-7.1	-6.2	-7.1	-7.8	-8.2

Study on the mechanism of Ranunculi Ternati Radix in the treatment of tuberculosis based on network pharmacology

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