Network pharmacology and molecular docking analysis on molecular targets and mechanisms of <em>Gastrodia elata </em>Blume in the treatment of ischemic stroke

Luo,Yuan; Luo,Yuan; Chen,Pu; Chen,Pu; Yang,Liping; Yang,Liping; Duan,Xiaohua; Duan,Xiaohua

doi:10.3892/etm.2022.11678

Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Gastrodia elata Blume in the treatment of ischemic stroke

Authors:
- Yuan Luo
- Pu Chen
- Liping Yang
- Xiaohua Duan
View Affiliations

Affiliations: Yunnan Key Laboratory of Dai and Yi Medicines, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, P.R. China, Yunnan Key Laboratory of Dai and Yi Medicines, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, P.R. China
Published online on: November 3, 2022 https://doi.org/10.3892/etm.2022.11678
Article Number: 742
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gastrodia elata Blume (GEB) is widely used to treat cardio-cerebrovascular disease in China and in traditional Chinese medicine it is considered to be a dispelling wind and dredging collateral. However, the mechanism and active components of the plant in treating ischemic stroke (IS) remain unclear. The present study aimed to identify the active components and mechanism of GEB in treating IS using network pharmacology and molecular docking technology. Network analysis predicted 752 potential targets from 14 compounds in GEB, sharing 32 key targets with IS-associated targets. Gene Ontology analysis of key targets showed that ‘oxidative stress’, ‘immune response’ and ‘regulation of blood circulation’ were significantly enriched. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the key targets regulated 11 representative pathways including ‘arachidonic acid metabolism’, ‘lipid and galactose metabolism’. In the protein-protein interaction network, five core targets, including toll-like receptor agonist, STAT3, myeloperoxidase (MPO), prostaglandin-endoperoxide synthase and matrix metalloproteinase (MMP)9, were identified and successfully docked with four active components: Palmitic acid, alexandrin, para-hydroxybenzaldehyde and gastrodin. Alexandrin, para-hydroxybenzaldehyde, and gastrodin are closely related to brain ischemia/reperfusion damage and repair. Therefore, to further verify the mechanism of action of three active components in the second part, we established the HT22 oxygen-glucose deprivation-reperfusion (OGD/R) model. Cell Counting Kit-8 assay and western blot analysis demonstrated that these three active components of GEB regulated core targets of molecular docking, such as STAT3, MPO and MMP9. In vitro experiments showed that OGD/R decreased cell survival, while this effect was reversed by the three active components of GEB. In addition, western blot analysis indicated that alexandrin upregulated expression of phosphorylated-STAT3, para-hydroxybenzaldehyde downregulated MPO and gastrodin downregulated MMP9. Therefore, the present study showed that GEB may prevent and treat IS via interaction between the active components and the main targets, which is key for investigating the efficacy of traditional Chinese medicine.

View Figures

View References

1	Kuklina EV, Tong X, George MG and Bansil P: Epidemiology and prevention of stroke: A worldwide perspective. Expert Rev Neurother. 12:199–208. 2012.PubMed/NCBI View Article : Google Scholar
2	GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol. 18:459–480. 2019.PubMed/NCBI View Article : Google Scholar
3	Mendelson SJ and Prabhakaran S: Diagnosis and management of transient ischemic attack and acute ischemic stroke: A review. JAMA. 325:1088–1098. 2021.PubMed/NCBI View Article : Google Scholar
4	Paul S and Candelario-Jalil E: Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Exp Neurol. 335(113518)2021.PubMed/NCBI View Article : Google Scholar
5	Zhang C, Liao Y, Liu L, Sun Y, Lin S, Lan J, Mao H, Chen H and Zhao Y: A network pharmacology approach to investigate the active compounds and mechanisms of musk for ischemic stroke. Evid Based Complement Alternat Med. 2020(4063180)2020.PubMed/NCBI View Article : Google Scholar
6	Chavez LM, Huang SS, MacDonald I, Lin JG, Lee YC and Chen YH: Mechanisms of acupuncture therapy in ischemic stroke rehabilitation: A literature review of basic studies. Int J Mol Sci. 18(2270)2017.PubMed/NCBI View Article : Google Scholar
7	Venketasubramanian N: Complementary and alternative interventions for stroke recovery-a narrative overview of the published evidence. J Complement Integr Med. 18:553–559. 2021.PubMed/NCBI View Article : Google Scholar
8	Han SY, Hong ZY, Xie YH, Zhao Y and Xu X: Therapeutic effect of Chinese herbal medicines for post stroke recovery: A traditional and network meta-analysis. Medicine (Baltimore). 96(e8830)2017.PubMed/NCBI View Article : Google Scholar
9	Hsieh CL, Chiang SY, Cheng KS, Lin YH, Tang NY, Lee CJ, Pon CZ and Hsieh CT: Anticonvulsive and free radical scavenging activities of Gastrodia elata Bl. in kainic acid-treated rats. Am J Chin Med. 29:331–341. 2001.PubMed/NCBI View Article : Google Scholar
10	Zhu H, Liu C, Hou J, Long H, Wang B, Guo D, Lei M and Wu W: Gastrodia elata Blume polysaccharides: A review of their acquisition, analysis, modification, and pharmacological activities. Molecules. 24(2436)2019.PubMed/NCBI View Article : Google Scholar
11	Wang ZH, Chen BH, Lin YY, Xing J, Wei ZL and Ren L: Herbal decoction of Gastrodia, Uncaria, and Curcuma confers neuroprotection against cerebral ischemia in vitro and in vivo. J Integr Neurosci. 19:513–519. 2020.PubMed/NCBI View Article : Google Scholar
12	Xu N, Li M, Wang P, Wang S and Shi H: Spectrum-effect relationship between antioxidant and anti-inflammatory effects of banxia baizhu tianma decoction: An identification method of active substances with endothelial cell protective effect. Front Pharmacol. 13(823341)2022.PubMed/NCBI View Article : Google Scholar
13	He KL, Zhang P and Liu XL: Tianma injection in the treatment of vertebral basilar artery insufficiency randomized parallel group study. J Pract Tradit Chin Intern Med. 28:44–46. 2014.
14	Tang X, Lu J, Chen H, Zhai L, Zhang Y, Lou H, Wang Y, Sun L and Song B: Underlying mechanism and active ingredients of tianma gouteng acting on cerebral infarction as determined via network pharmacology analysis combined with experimental validation. Front Pharmacol. 12(760503)2021.PubMed/NCBI View Article : Google Scholar
15	Duan X, Wang W, Liu X, Yan H, Dai R and Lin Q: Neuroprotective effect of ethyl acetate extract from Gastrodia elata against transient focal cerebral ischemia in rats induced by middle cerebral artery occlusion. J Tradit Chin Med. 35:671–678. 2015.PubMed/NCBI View Article : Google Scholar
16	He F, Duan X, Dai R, Wang W, Yang C and Lin Q: Protective effects of Ethyl acetate extraction from Gastrodia elata Blume on blood-brain barrier in focal cerebral ischemia reperfusion. Afr J Tradit Complement Altern Med. 13:199–209. 2016.PubMed/NCBI View Article : Google Scholar
17	Wang T, Chen H, Xia S, Chen X, Sun H and Xu Z: Ameliorative effect of parishin C against cerebral ischemia-induced brain tissue injury by reducing oxidative stress and inflammatory responses in rat model. Neuropsychiatr Dis Treat. 17:1811–1823. 2021.PubMed/NCBI View Article : Google Scholar
18	Ruan Y, Yao L, Zhang B, Zhang S and Guo J: Nanoparticle-mediated delivery of neurotoxin-II to the brain with intranasal administration: An effective strategy to improve antinociceptive activity of neurotoxin. Drug Dev Ind Pharm. 38:123–128. 2012.PubMed/NCBI View Article : Google Scholar
19	Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI and Schmidt HHHW: Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci. 43:136–150. 2022.PubMed/NCBI View Article : Google Scholar
20	Zhang R, Zhu X, Bai H and Ning K: Network pharmacology databases for traditional Chinese medicine: Review and assessment. Front Pharmacol. 10(123)2019.PubMed/NCBI View Article : Google Scholar
21	Daina A, Michielin O and Zoete V: SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 47 (W1):W357–W364. 2019.PubMed/NCBI View Article : Google Scholar
22	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43(e47)2015.PubMed/NCBI View Article : Google Scholar
23	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012.PubMed/NCBI View Article : Google Scholar
24	Otasek D, Morris JH, Bouças J, Pico AR and Demchak B: Cytoscape automation: Empowering workflow-based network analysis. Genome Biol. 20(185)2019.PubMed/NCBI View Article : Google Scholar
25	Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, et al: The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45 (D1):D362–D368. 2017.PubMed/NCBI View Article : Google Scholar
26	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43 (Database Issue):D447–D452. 2015.PubMed/NCBI View Article : Google Scholar
27	Tang Y, Li M, Wang J, Pan Y and Wu FX: CytoNCA: A cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems. 127:67–72. 2015.PubMed/NCBI View Article : Google Scholar
28	Trott O and Olson AJ: AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 31:455–461. 2010.PubMed/NCBI View Article : Google Scholar
29	Seeliger D and de Groot BL: Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des. 24:417–422. 2010.PubMed/NCBI View Article : Google Scholar
30	Liang Y, Liang B, Wu XR, Chen W and Zhao LZ: Network pharmacology-based systematic analysis of molecular mechanisms of dingji fumai decoction for ventricular arrhythmia. Evid Based Complement Alternat Med. 2021(5535480)2021.PubMed/NCBI View Article : Google Scholar
31	Morris GM, Huey R and Olson AJ: Using AutoDock for ligand-receptor docking. Curr Protoc Bioinformatics Chapter 8. Unit 8.14. 2008.PubMed/NCBI View Article : Google Scholar
32	Yang Y, He Y, Wei X, Wan H, Ding Z, Yang J and Zhou H: Network pharmacology and molecular docking-based mechanism study to reveal the protective effect of salvianolic acid C in a rat model of ischemic stroke. Front Pharmacol. 12(799448)2022.PubMed/NCBI View Article : Google Scholar
33	Ito K and Murphy D: Application of ggplot2 to pharmacometric graphics. CPT Pharmacometrics Syst Pharmacol. 2(e79)2013.PubMed/NCBI View Article : Google Scholar
34	Le TT and Moore JH: treeheatr: An R package for interpretable decision tree visualizations. Bioinformatics. 37:282–284. 2021.PubMed/NCBI View Article : Google Scholar
35	Walter W, Sanchez-Cabo F and Ricote M: GOplot: An R package for visually combining expression data with functional analysis. Bioinformatics. 31:2912–2914. 2015.PubMed/NCBI View Article : Google Scholar
36	Jiang LH, Yang NY, Yuan XL, Zou YJ, Zhao FM, Chen JP, Wang MY and Lu DX: Daucosterol promotes the proliferation of neural stem cells. J Steroid Biochem Mol Biol. 140:90–99. 2014.PubMed/NCBI View Article : Google Scholar
37	Jiang T, Cheng H, Su J, Wang X, Wang Q, Chu J and Li Q: Gastrodin protects against glutamate-induced ferroptosis in HT-22 cells through Nrf2/HO-1 signaling pathway. Toxicol In Vitro. 62(104715)2020.PubMed/NCBI View Article : Google Scholar
38	Xiang B, Chun X, Shen T, Jiang S, Lin Q and Li XF: 4-hydroxybenzyl aldehyde can prevent the acute cerebral ischemic injury in rats. Chin Tradit Pat Med. 39:1572–1576. 2017.(In Chinese).
39	Xiong H, Dong Z, Lou G, Gan Q, Wang J and Huang Q: Analysis of the mechanism of Shufeng Jiedu capsule prevention and treatment for COVID-19 by network pharmacology tools. Eur J Integr Med. 40(101241)2020.PubMed/NCBI View Article : Google Scholar
40	Heese K: Gastrodia elata Blume (Tianma): Hope for brain aging and dementia. Evid Based Complement Alternat Med. 2020(8870148)2020.PubMed/NCBI View Article : Google Scholar
41	Xia C, Zhou H, Xu X, Jiang T, Li S, Wang D, Nie Z and Sheng Q: Identification and investigation of miRNAs From Gastrodia elata Blume and their potential function. Front Pharmacol. 11(542405)2020.PubMed/NCBI View Article : Google Scholar
42	Jurcau A and Ardelean IA: Molecular pathophysiological mechanisms of ischemia/reperfusion injuries after recanalization therapy for acute ischemic stroke. J Integr Neurosci. 20:727–744. 2021.PubMed/NCBI View Article : Google Scholar
43	Wang X, Wang ZY, Zheng JH and Li S: TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med. 19:1–11. 2021.PubMed/NCBI View Article : Google Scholar
44	Khatana C, Saini NK, Chakrabarti S, Saini V, Sharma A, Saini RV and Saini AK: Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis. Oxid Med Cell Longev. 2020(5245308)2020.PubMed/NCBI View Article : Google Scholar
45	Chow YL, Teh LK, Chyi LH, Lim LF, Yee CC and Wei LK: Lipid metabolism genes in stroke pathogenesis: The atherosclerosis. Curr Pharm Des. 26:4261–4271. 2020.PubMed/NCBI View Article : Google Scholar
46	Adibhatla RM and Hatcher JF: Altered lipid metabolism in brain injury and disorders. Subcell Biochem. 49:241–268. 2008.PubMed/NCBI View Article : Google Scholar
47	Wang B, Wu L, Chen J, Dong L, Chen C, Wen Z, Hu J, Fleming I and Wang DW: Metabolism pathways of arachidonic acids: Mechanisms and potential therapeutic targets. Signal Transduct Target Ther. 6(94)2021.PubMed/NCBI View Article : Google Scholar
48	Anrather J and Iadecola C: Inflammation and stroke: An overview. Neurotherapeutics. 13:661–670. 2016.PubMed/NCBI View Article : Google Scholar
49	Ai L, Xu A and Xu J: Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol. 1248:33–59. 2020.PubMed/NCBI View Article : Google Scholar
50	Schütz F, Stefanovic S, Mayer L, von Au A, Domschke C and Sohn C: PD-1/PD-L1 pathway in breast cancer. Oncol Res Treat. 40:294–297. 2017.PubMed/NCBI View Article : Google Scholar
51	Jiang LH, Yuan XL, Yang NY, Ren L, Zhao FM, Luo BX, Bian YY, Xu JY, Lu DX, Zheng YY, et al: Daucosterol protects neurons against oxygen-glucose deprivation/reperfusion-mediated injury by activating IGF1 signaling pathway. J Steroid Biochem Mol Biol. 152:45–52. 2015.PubMed/NCBI View Article : Google Scholar
52	Gao GS, Li Y, Zhai H, Bi JW, Zhang FS, Zhang XY and Fan SH: Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway. Exp Ther Med. 14:3926–3934. 2017.PubMed/NCBI View Article : Google Scholar
53	Zhang Z and Yang W: Paeoniflorin protects PC12 cells from oxygen-glucose deprivation/reoxygenation-induced injury via activating JAK2/STAT3 signaling. Exp Ther Med. 21(572)2021.PubMed/NCBI View Article : Google Scholar
54	Lei JR, Tu XK, Wang Y, Tu DW and Shi SS: Resveratrol downregulates the TLR4 signaling pathway to reduce brain damage in a rat model of focal cerebral ischemia. Exp Ther Med. 17:3215–3221. 2019.PubMed/NCBI View Article : Google Scholar
55	Chen S, Chen H, Du Q and Shen J: Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: Potential application of natural compounds. Front Physiol. 11(433)2020.PubMed/NCBI View Article : Google Scholar
56	Zhu YP, Li X, Du Y, Zhang L, Ran L and Zhou NN: Protective effect and mechanism of p-hydroxybenzaldehyde on blood-brain barrier. Zhongguo Zhong Yao Za Zhi. 43:1021–1027. 2018.PubMed/NCBI View Article : Google Scholar : (In Chinese).
57	Chen KY, Chen YJ, Cheng CJ, Jhan KY, Chiu CH and Wang LC: 3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde enhance survival of mouse astrocytes treated with angiostrongylus cantonensis young adults excretory/secretory products. Biomed J. 44 (6 Suppl 2):S258–S266. 2021.PubMed/NCBI View Article : Google Scholar
58	Jang JH, Son Y, Kang SS, Bae CS, Kim JC, Kim SH, Shin T and Moon C: Neuropharmacological potential of Gastrodia elata Blume and its components. Evid Based Complement Alternat Med. 2015(309261)2015.PubMed/NCBI View Article : Google Scholar
59	Tao J, Luo ZY, Msangi CI, Shu XS, Wen L, Liu SP, Zhou CQ, Liu RX and Hu WX: Relationships among genetic makeup, active ingredient content, and place of origin of the medicinal plant Gastrodia tuber. Biochem Genet. 47:8–18. 2009.PubMed/NCBI View Article : Google Scholar
60	Liu Y, Gao J, Peng M, Meng H, Ma H, Cai P, Xu Y, Zhao Q and Si G: A review on central nervous system effects of gastrodin. Front Pharmacol. 9(24)2018.PubMed/NCBI View Article : Google Scholar
61	Li S, Bian L, Fu X, Ai Q, Sui Y, Zhang A, Gao H, Zhong L and Lu D: Gastrodin pretreatment alleviates rat brain injury caused by cerebral ischemic-reperfusion. Brain Res. 1712:207–216. 2019.PubMed/NCBI View Article : Google Scholar
62	Wang J and Wu M: The up-regulation of miR-21 by gastrodin to promote the angiogenesis ability of human umbilical vein endothelial cells by activating the signaling pathway of PI3K/Akt. Bioengineered. 12:5402–5410. 2021.PubMed/NCBI View Article : Google Scholar
63	Zhang ZL, Gao YG, Zang P, Gu PP, Zhao Y, He ZM and Zhu HY: Research progress on mechanism of gastrodin and p-hydroxybenzyl alcohol on central nervous system. Zhongguo Zhong Yao Za Zhi. 45:312–320. 2020.PubMed/NCBI View Article : Google Scholar : (In Chinese).
64	Peng Z, Wang S, Chen G, Cai M, Liu R, Deng J, Liu J, Zhang T, Tan Q and Hai C: Gastrodin alleviates cerebral ischemic damage in mice by improving anti-oxidant and anti-inflammation activities and inhibiting apoptosis pathway. Neurochem Res. 40:661–673. 2015.PubMed/NCBI View Article : Google Scholar
65	Yuan H, Ma Q, Cui H, Liu G, Zhao X, Li W and Piao G: How can synergism of traditional medicines benefit from network pharmacology? Molecules. 22(1135)2017.PubMed/NCBI View Article : Google Scholar