石菖蒲治疗阿尔茨海默病的作用机制

doi:10.6040/j.issn.1671-9352.0.2023.485

摘要/Abstract

摘要：

基于网络药理学、分子对接和实验验证分析石菖蒲治疗阿尔兹海默病(Alzheimer's disease, AD)的作用机制。利用TCMSP数据库及查阅文献收集石菖蒲活性成分后通过Swisstargetprediction数据库预测活性成分作用靶点; 使用STRING数据库进行蛋白互作分析; 通过DAVID数据库对关键靶点进行GO和KEGG信号通路富集分析; 最后, 采用AutoDock软件对活性成分与重要靶点进行分子对接验证, 并通过酶抑制实验验证石菖蒲对AChE活性的影响。结果表明：石菖蒲中有7个潜在活性成分, 对应靶点254个, AD靶点1 981个, 药物疾病共同靶点120个; GO富集分析得到306个条目, KEGG通路富集分析获得79条信号通路, 主要包括癌症信号通路、雌激素信号通路及VEGF信号通路等; 分子对接结果显示, AChE和AKT1靶点与多数石菖蒲活性成分能够稳定自发结合; 酶抑制实验证明石菖蒲可抑制AChE活性。本研究从网络药理学、分子对接和酶抑制实验等方面预测并验证了石菖蒲治疗AD的作用机制, 为石菖蒲的临床应用及进一步开发提供参考和依据。

关键词: 石菖蒲, 阿尔兹海默病, 网络药理学, 分子对接, 作用机制

Abstract:

We analyzed the mechanism of action of Acorus tatarinowii Schott (ATS) in the treatment of Alzheimer's disease (AD) based on network pharmacology, molecular docking, and experimental verification. After the active components of ATS were collected by TCMSP database and literature review, the targets of active components of ATS were predicted by Swiss target prediction database. Protein-protein interaction analysis was carried out using STRING database. GO and KEGG signal pathway enrichment analysis was carried out by DAVID database for key targets; Finally, AutoDock was used to verify the molecular docking between active ingredients and important targets, and the effect of ATS on AChE activity was verified by enzyme inhibition experiments. 7 active ingredients were screened, corresponding to 254 targets, 1 981 AD targets, 120 drug disease common targets. GO enrichment analysis obtain 306 entries, KEGG pathway enrichment analysis obtained 79 signal pathways, it mainly included cancer, Estrogen and VEGF signaling pathway; Molecular docking results showed that AChE and AKT1 target could spontaneously bind to most active components of ATS stably. Enzyme inhibition experiment showed that ATS can inhibit AChE activity. In this study, the mechanism of action of ATS in the treatment of AD was predicted and verified from the aspects of network pharmacology, molecular docking and enzyme inhibition experiments, so as to provide reference and basis for clinical application and further development of ATS.

Key words: Acotus tatarinowii Schott, Alzheimer's disease, network pharmacology, molecular docking, mechanism of action

中图分类号:

R285.5

陈亮, 方成维, 蒙吉, 麻秀萍, 朱丹, 李嘉欣. 石菖蒲治疗阿尔茨海默病的作用机制[J]. 《山东大学学报(理学版)》, 2024, 59(11): 64-73, 92.

Liang CHEN, Chengwei FANG, Ji MENG, Xiuping MA, Dan ZHU, Jiaxin LI. Mechanism of Acotus tatarinowii Schott in treating Alzheimer's disease[J]. JOURNAL OF SHANDONG UNIVERSITY(NATURAL SCIENCE), 2024, 59(11): 64-73, 92.

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参考文献 22

1	郭敬, 方萌, 雷登良, 等. 六味地黄丸治疗老年痴呆症的研究进展[J]. 基层中医药, 2023, 2 (7): 102- 113.
	GUO Jing , FANG Meng , LEI Dengliang , et al. Liuwei Dihuang pills in the treatment of senile dementia: a review[J]. Basic Traditional Chinese Medicine, 2023, 2 (7): 102- 113.
2	CUMMINGS J L , TONG G , BALLARD C . Treatment combinations for Alzheimer's disease: current and future pharmacotherapy options[J]. Journal of Alzheimer's Disease, 2019, 67 (3): 779- 794. doi: 10.3233/JAD-180766
3	梅婷婷, 闫珺, 陈晶. 石菖蒲化学成分及其药理作用概述[J]. 中医药信息, 2022, 39 (4): 77- 80.
	MEI Tingting , YAN Jun , CHEN Jing . Overview of active ingredients and pharmacological effects of Acorus tatarinowii[J]. Information on Traditional Chinese Medicine, 2022, 39 (4): 77- 80.
4	芦锰, 周雨慧, 李晓宁, 等. 基于数据挖掘中医药治疗阿尔茨海默病用药规律研究[J]. 中国中药杂志, 2021, 46 (6): 1558- 1563.
	LU Meng , ZHOU Yuhui , LI Xiaoning , et al. Research on regularity of traditional Chinese medicine in treatment of Alzheimer's disease based on data mining[J]. China Journal of Chinese Materia Medica, 2021, 46 (6): 1558- 1563.
5	YANG Y X , CHEN Y T , ZHOU X J , et al. Beta-asarone, a major component of Acorus tatarinowii Schott, attenuates focal cerebral ischemia induced by middle cerebral artery occlusion in rats[J]. BMC Complementary and Alternative Medicine, 2013, 13, 236. doi: 10.1186/1472-6882-13-236
6	GAO P , CHANG K , YUAN S , et al. Exploring the mechanism of hepatotoxicity induced by Dictamnus dasycarpus based on network pharmacology, molecular docking and experimental pharmacology[J]. Molecules, 2023, 28 (13): 5045. doi: 10.3390/molecules28135045
7	GUO W , HUANG J H , WANG N , et al. Integrating network pharmacology and pharmacological evaluation for deciphering the action mechanism of herbal formula Zuojin pill in suppressing hepatocellular carcinoma[J]. Frontiers in Pharmacology, 2019, 10, 1185. doi: 10.3389/fphar.2019.01185
8	陶雪芬, 朱江伟, 金银秀, 等. 双分子γ-咔啉衍生物的合成及其对胆碱酯酶的抑制活性研究[J]. 中国现代应用药学, 2023, 40 (19): 2665- 2668.
	TAO Xuefen , ZHU Jiangwei , JIN Yinxiu , et al. Synthesis and acetylcholinesterase inhibition activity of bivalent γ-carboline derivatives[J]. Chinese Journal of Modern Applied Pharmacy, 2023, 40 (19): 2665- 2668.
9	VENKATESAN K . Anti-amnesic and anti-cholinesterase activities of α-asarone against scopolamine-induced memory impairments in rats[J]. European Review for Medical and Pharmacological Sciences, 2022, 26 (17): 6344- 6350.
10	DU X Y , CAO Y S , YANG J , et al. Preclinical evidence and possible mechanisms of β-asarone for rats and mice with Alzheimer's disease: a systematic review and meta-analysis[J]. Frontiers in Pharmacology, 2022, 13, 956746. doi: 10.3389/fphar.2022.956746
11	GARABADU D , SHARMA M . Eugenol attenuates scopolamine-induced hippocampal cholinergic, glutamatergic, and mitochondrial toxicity in experimental rats[J]. Neurotoxicity Research, 2019, 35 (4): 848- 859. doi: 10.1007/s12640-019-0008-6
12	SON M , PARK C , RAMPOGU S , et al. Discovery of novel acetylcholinesterase inhibitors as potential candidates for the treatment of Alzheimer's disease[J]. International Journal of Molecular Sciences, 2019, 20 (4): 1000. doi: 10.3390/ijms20041000
13	卢彦宇, 方梓庄, 范洋溢, 等. 阿尔茨海默病发病机制与药物治疗研究进展[J]. 生理科学进展, 2023, 54 (2): 81- 89.
	LU Yanyu , FANG Zizhuang , FAN Yangyi , et al. Advances in the mechanism and pharmacotherapies of Alzheimer's disease[J]. Progress in Physiological Sciences, 2023, 54 (2): 81- 89.
14	JUNG H A , YOKOZAWA T , KIM B W , et al. Selective inhibition of prenylated flavonoids from Sophora flavescens against BACE1 and cholinesterases[J]. The American Journal of Chinese Medicine, 2010, 38 (2): 415- 429. doi: 10.1142/S0192415X10007944
15	CASTILLO C , BRAVO-ARREPOL G , WENDT A , et al. Neuroprotective properties of eudesmin on a cellular model of amyloid-β peptide toxicity[J]. Journal of Alzheimer's Disease, 2023, 94 (S1): S97- S108. doi: 10.3233/JAD-220935
16	NEJABATI H R , ROSHANGAR L . Kaempferol as a potential neuroprotector in Alzheimer's disease[J]. Journal of Food Biochemistry, 2022, 46 (12): e14375.
17	HAN X , CHENG X L , XU J Y , et al. Activation of TREM2 attenuates neuroinflammation via PI3K/Akt signaling pathway to improve postoperative cognitive dysfunction in mice[J]. Neuropharmacology, 2022, 219, 109231. doi: 10.1016/j.neuropharm.2022.109231
18	LOPEZ-TOLEDO G , SILVA-LUCERO M D C , HERRERA-DÍAZ J , et al. Patient-derived fibroblasts with presenilin-1 mutations, that model aspects of Alzheimer's disease pathology, constitute a potential object for early diagnosis[J]. Frontiers in Aging Neuroscience, 2022, 14, 921573. doi: 10.3389/fnagi.2022.921573
19	LAN G Y , WANG P , CHAN R B , et al. Astrocytic VEGFA: an essential mediator in blood-brain-barrier disruption in Parkinson's disease[J]. Glia, 2022, 70 (2): 337- 353. doi: 10.1002/glia.24109
20	GUO J P , CHENG J , NORTH B J , et al. Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology[J]. Biochimica et Biophysica Acta Reviews on Cancer, 2017, 1868 (2): 341- 358. doi: 10.1016/j.bbcan.2017.07.001
21	CHEN S H , HE C Y , SHEN Y Y , et al. Polysaccharide krestin prevents Alzheimer's disease-type pathology and cognitive deficits by enhancing monocyte amyloid-β processing[J]. Neuroscience Bulletin, 2022, 38 (3): 290- 302. doi: 10.1007/s12264-021-00779-5
22	TECALCO-CRUZ A C , ZEPEDA-CERVANTES J , ORTEGA-DOMINGUEZ B . Estrogenic hormones receptors in Alzheimer's disease[J]. Molecular Biology Reports, 2021, 11, 7517- 7526.

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数据库名称	网址
TCMSP	https://old.tcmsp-e.com/tcmsp.php
PubChem	https://pubchem.ncbi.nlm.nih.gov/
SwissTargetPrediction	http://www.swisstargetprediction.ch/
GeneCards	https://www.genecards.org/
OMIM	https://www.omim.org/
PharmGKB	https://www.pharmgkb.org/
TTD	http://db.idrblab.net/ttd/
DrugBank	https://go.drugbank.com/
Venny 2.1.0	https://bioinfogp.cnb.csic.es/tools/venny/
STRING	https://cn.string-db.org/
DAVID	https://david.ncifcrf.gov/
PCSD PDB	https://www.rcsb.org/search

编号	中文名	英文名	CAS号	分子量	生物利用度/%	类药性
SCP1	8-异戊烯基山奈酚	8-Isopentenyl-kaempferol	28610-31-3	354.38	38.04	0.39
SCP2	桉脂素	Eudesmin	526-06-7	386.48	52.35	0.62
SCP3	环阿屯醇	Cycloartenol	469-38-5	426.80	38.69	0.78
SCP4	山奈酚	Kaempferol	520-18-3	286.25	41.88	0.24
SCP5	α-细辛醚	α-Asarone	2883-98-9	208.28	35.61	0.06
SCP6	β-细辛醚	β-Asarone	5273-86-9	208.28	35.61	0.06
SCP7	丁香酚	Eugenol	97-53-0	164.22	56.24	0.04

编号	通路	基因
hsa05200	Pathways in cancer (癌症信号通路)	HSP90AA1, F2, PTGS2, HIF1A, ESR1, MMP9, EGFR, RELA, VEGFA, AR, CASP3, AKT1, JAK2
hsa05207	Chemical carcinogenesis-receptor activation (化学致癌-受体激活)	AR, HSP90AA1, SRC, AKT1, JAK2, ESR1, RELA, EGFR, VEGFA
hsa05167	Kaposi sarcoma-associated herpesvirus infection (卡波西肉瘤相关疱疹病毒感染)	SRC, CASP3, AKT1, JAK2, PTGS2, HIF1A, RELA, VEGFA
hsa05205	Proteoglycans in cancer (癌症中的蛋白多糖)	SRC, CASP3, AKT1, HIF1A, ESR1, MMP9, EGFR, VEGFA
hsa04926	Relaxin signaling pathway (松弛素信号通路)	SRC, NOS3, AKT1, MMP9, RELA, EGFR, VEGFA
hsa05417	Lipid and atherosclerosis (脂质和动脉粥样硬化)	HSP90AA1, SRC, NOS3, CASP3, AKT1, JAK2, MMP9, RELA
hsa04915	Estrogen signaling pathway (雌激素信号通路)	HSP90AA1, SRC, NOS3, AKT1, ESR1, MMP9, EGFR
hsa05418	Fluid shear stress and atherosclerosis (液体剪切应力和动脉粥样硬化)	HSP90AA1, SRC, NOS3, AKT1, MMP9, RELA, VEGFA
hsa05215	Prostate cancer (前列腺癌)	AR, HSP90AA1, AKT1, MMP9, RELA, EGFR
hsa04933	AGE-RAGE signaling pathway in diabetic complications (糖尿病并发症AGE-RAGE信号通路)	NOS3, CASP3, AKT1, JAK2, RELA, VEGFA
hsa04066	HIF-1 signaling pathway (HIF-1信号通路)	NOS3, AKT1, HIF1A, RELA, EGFR, VEGFA
hsa04370	VEGF signaling pathway (VEGF信号通路)	SRC, NOS3, AKT1, PTGS2, VEGFA
hsa05163	Human cytomegalovirus infection (人巨细胞病毒感染)	SRC, CASP3, AKT1, PTGS2, RELA, EGFR, VEGFA
hsa04917	Prolactin signaling pathway (催乳素信号通路)	SRC, AKT1, JAK2, ESR1, RELA
hsa05010	Alzheimer's disease (阿尔茨海默病)	APP, GRM5, CDK5, CASP3, AKT1, MAPT, PTGS2, RELA

编号	成分	AChE结合能/(kJ·mol^-1)	AKT1结合能/(kJ·mol^-1)
SCP1	8-Isopentenyl-kaempferol(8-异戊烯基山奈酚)	-32.90	-33.49
SCP2	Eudesmin(桉脂素)	-31.48	-35.08
SCP3	Cycloartenol(环阿屯醇)	-37.84	-44.54
SCP4	Kaempferol(山奈酚)	-28.26	-28.46
SCP5	α-Asarone(α-细辛醚)	-21.60	-19.84
SCP6	β-Asarone(β-细辛醚)	-19.84	-22.27
SCP7	Eugenol(丁香酚)	-22.10	-22.06

石菖蒲挥发油质量浓度/(mg·L^-1)	25	50	100	200	400	800	1 600
AChE活性抑制率/%	10.5±0.4	14.4±1.0	24.3±1.8	36.1±0.4	54.6±1.2	82.0±1.8	87.0±1.9