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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Network Pharmacology and Molecular Docking to Unveil the Mechanism of Shudihuang against Amyotrophic Lateral Sclerosis

Author(s): Xiaojing Li, Yueqin Tian, Haidong Wu* and Tong Wang*

Volume 29, Issue 19, 2023

Published on: 03 July, 2023

Page: [1535 - 1545] Pages: 11

DOI: 10.2174/1381612829666230621105552

Price: $65

Abstract

Background: Shudihuang has been clinically proven to be an effective Chinese medicine compatible with the treatment of amyotrophic lateral sclerosis. However, the underlying mechanism of Shudihuang against amyotrophic lateral sclerosis remains unclear.

Objectives: The present study aims to elucidate the possible mechanism of Shudihuang in treating ALS using network pharmacology and molecular docking.

Methods: The primary active components of Shudihuang and their relevant targets were identified by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Swiss Target Prediction database, respectively. The ALS-related targets were obtained from the Disgenet and OMIM databases. The shared targets were derived by the intersection of disease-associated and component-associated targets and then introduced into the Cytoscape software to construct a network of drug-component-target. In addition, protein interaction relationships among the shared targets were analyzed by the STRING and Cytoscape software. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis were conducted by the Metascape platform. The binding activities between the hub targets and the active components were assessed with molecular docking.

Results: Stigmasterol and sitosterol were identified as the core components of Shudihuang, and the hub targets of ALS are PTGS2, PPARG, ESR1, IGF-1R, and MAPK3, with the highest degrees in the PPI network. The finding that stigmasterol and sitosterol had a good affinity with PTGS2, PPARG, ESR1, IGF-1R, and MAPK3 also supported this. Finally, it was revealed that Shudihuang treatment of ALS predominantly involves estrogen- related pathways such as nuclear receptor activity and steroid binding.

Conclusion: In summary, this study suggested that the main active components of Shudihuang (stigmasterol and sitosterol) may exert a critical effect in ALS treatment by binding to hub targets (PTGS2, PPARG, ESR1, IGF-1R, and MAPK3) and then modulating estrogen receptor-related pathways to attenuate glutamate excitotoxicity, inhibit oxidative stress and antagonize inflammation.

Keywords: Shudihuang, molecular docking, network pharmacology, amyotrophic lateral sclerosis, mechanism, ALS treatment.

« Previous
[1]
Strohm L, Behrends C. Glia-specific autophagy dysfunction in ALS. Semin Cell Dev Biol 2020; 99: 172-82.
[http://dx.doi.org/10.1016/j.semcdb.2019.05.024] [PMID: 31132469]
[2]
van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet 2017; 390(10107): 2084-98.
[http://dx.doi.org/10.1016/S0140-6736(17)31287-4] [PMID: 28552366]
[3]
Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules 2019; 24(8): 1583.
[http://dx.doi.org/10.3390/molecules24081583] [PMID: 31013638]
[4]
Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology 2019; 161: 107559.
[http://dx.doi.org/10.1016/j.neuropharm.2019.03.002] [PMID: 30851309]
[5]
Weil C, Zach N, Rishoni S, Shalev V, Chodick G. Epidemiology of amyotrophic lateral sclerosis: A population-based study in Israel. Neuroepidemiology 2016; 47(2): 76-81.
[http://dx.doi.org/10.1159/000448921] [PMID: 27617889]
[6]
Marin B, Boumédiene F, Logroscino G, et al. Variation in worldwide incidence of amyotrophic lateral sclerosis: A meta-analysis. Int J Epidemiol 2017; 46(1): 57-74.
[PMID: 27185810]
[7]
Mehta P, Kaye W, Raymond J, et al. Prevalence of amyotrophic lateral sclerosis — United States, 2014. MMWR Morb Mortal Wkly Rep 2018; 67(7): 216-8.
[http://dx.doi.org/10.15585/mmwr.mm6707a3] [PMID: 29470458]
[8]
Manjaly ZR, Scott KM, Abhinav K, et al. The sex ratio in amyotrophic lateral sclerosis: A population based study. Amyotroph Lateral Scler 2010; 11(5): 439-42.
[http://dx.doi.org/10.3109/17482961003610853] [PMID: 20225930]
[9]
Arend RC, Londoño AI, Montgomery AM, et al. Molecular response to neoadjuvant chemotherapy in high-grade serous ovarian carcinoma. Mol Cancer Res 2018; 16(5): 813-24.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0594] [PMID: 29523763]
[10]
Jaiswal MK. Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs. Med Res Rev 2019; 39(2): 733-48.
[http://dx.doi.org/10.1002/med.21528] [PMID: 30101496]
[11]
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Libr 2012; 2012(3): CD001447.
[http://dx.doi.org/10.1002/14651858.CD001447.pub3] [PMID: 22419278]
[12]
Inoue-Shibui A, Kato M, Suzuki N, et al. Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: A retrospective observational study. BMC Neurol 2019; 19(1): 72.
[http://dx.doi.org/10.1186/s12883-019-1299-1] [PMID: 31029113]
[13]
Cho H, Shukla S. Role of edaravone as a treatment option for patients with amyotrophic lateral sclerosis. Pharmaceuticals 2020; 14(1): 29.
[http://dx.doi.org/10.3390/ph14010029] [PMID: 33396271]
[14]
Cruz MP. Edaravone (Radicava): A novel neuroprotective agent for the treatment of amyotrophic lateral sclerosis. P&T 2018; 43(1): 25-8.
[PMID: 29290672]
[15]
Lao Y. Traditional Chinese medicine treatment of kidney yin deficiency. World Latest Med Inform 2014; 14(4): 175-80.
[16]
Li Z, Wang X. Exploration of primordial qi in TCM. J Beijing Univ Tradit Chinese Med 2019; 42(9): 709-12.
[17]
He Y, Ma Y, Xu J, Wu W. Analysis of pathogenesis change of age-related debility from perspective of “kidney-mingmen-triple jiao qi transformation”. J Beijing Univ Tradit Chinese Med 2022; 45(9): 929-33.
[18]
Zhou W, Cheng X, Zhang Y. Effect of Liuwei Dihuang decoction, a traditional Chinese medicinal prescription, on the neuroendocrine immunomodulation network. Pharmacol Ther 2016; 162: 170-8.
[http://dx.doi.org/10.1016/j.pharmthera.2016.02.004] [PMID: 26896567]
[19]
Li G. Experience of treating motor neuron disease. Guangming J Chin Med 2011; 26(9): 1812-3.
[20]
Liu L, Zhang H, Niu Y. Experience of traditional Chinese medicine in treating motor neuron disease. Guangming J Chin Med 2016; 31(20): 3008-9.
[21]
Li M, Song Y, Jia Q, Liu J, Kazuo S, Gao Y. Prescription and medication rules of professor Gao Ying in treatment of amyotrophic lateral sclerosis based on data mining. Acta Chinese Medicine 2022; 37(5): 1114-9.
[22]
Qiu H, Li J, Yin S, Ke J, Qiu C, Zheng G. Yinzi D. A classical chinese herbal prescription, for amyotrophic lateral sclerosis. Medicine 2016; 95(14): e3324.
[http://dx.doi.org/10.1097/MD.0000000000003324] [PMID: 27057909]
[23]
Lee B, Shim I, Lee H, Hahm DH. Rehmannia glutinosa ameliorates scopolamine-induced learning and memory impairment in rats. J Microbiol Biotechnol 2011; 21(8): 874-83.
[http://dx.doi.org/10.4014/jmb.1104.04012] [PMID: 21876380]
[24]
Tseng YT, Jong YJ, Liang WF, Chang FR, Lo YC. The water extract of Liuwei dihuang possesses multi-protective properties on neurons and muscle tissue against deficiency of survival motor neuron protein. Phytomedicine 2017; 34: 97-105.
[http://dx.doi.org/10.1016/j.phymed.2017.08.018] [PMID: 28899515]
[25]
Yuan HX, Ni XQ, Wu ZZ, et al. Regulatory effect of Shudihuang on expressions of BDNF/TrkB and NRG-3 in prefrontal cortex and striatum of ADHD model rats. Zhongguo Zhongyao Zazhi 2018; 43(17): 3539-44.
[PMID: 30347924]
[26]
Hopkins AL. Network pharmacology. Nat Biotechnol 2007; 25(10): 1110-1.
[http://dx.doi.org/10.1038/nbt1007-1110] [PMID: 17921993]
[27]
Yıldırım MA, Goh KI, Cusick ME, Barabási AL, Vidal M. Drug—target network. Nat Biotechnol 2007; 25(10): 1119-26.
[http://dx.doi.org/10.1038/nbt1338] [PMID: 17921997]
[28]
Ferreira L, dos Santos R, Oliva G, Andricopulo A. Molecular docking and structure-based drug design strategies. Molecules 2015; 20(7): 13384-421.
[http://dx.doi.org/10.3390/molecules200713384] [PMID: 26205061]
[29]
Ru J, Li P, Wang J, et al. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6(1): 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[30]
Liang J, Wu M, Bai C, et al. Network pharmacology approach to explore the potential mechanisms of jieduan-niwan formula treating acute-on-chronic liver failure. Evid Based Complement Alternat Med 2020; 2020: 1-16.
[http://dx.doi.org/10.1155/2020/1041307] [PMID: 33456481]
[31]
Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V. A web server for target prediction of bioactive small molecules. Nucleic Acids Res 2014; 42: W32-8.
[http://dx.doi.org/10.1093/nar/gku293]
[32]
Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res 2015; 43(D1): D789-98.
[http://dx.doi.org/10.1093/nar/gku1205] [PMID: 25428349]
[33]
Piñero J, Saüch J, Sanz F, Furlong LI. The DisGeNET cytoscape app: Exploring and visualizing disease genomics data. Comput Struct Biotechnol J 2021; 19: 2960-7.
[http://dx.doi.org/10.1016/j.csbj.2021.05.015] [PMID: 34136095]
[34]
Jia A, Xu L, Wang Y. Venn diagrams in bioinformatics. Brief Bioinform 2021; 22(5): bbab108.
[http://dx.doi.org/10.1093/bib/bbab108] [PMID: 33839742]
[35]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[36]
Szklarczyk D, Morris JH, Cook H, et al. The STRING database in 2017: Quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res 2017; 45(D1): D362-8.
[http://dx.doi.org/10.1093/nar/gkw937] [PMID: 27924014]
[37]
Ashburner M, Ball CA, Blake JA, et al. Gene Ontology: Tool for the unification of biology. Nat Genet 2000; 25(1): 25-9.
[http://dx.doi.org/10.1038/75556] [PMID: 10802651]
[38]
Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28(1): 27-30.
[http://dx.doi.org/10.1093/nar/28.1.27] [PMID: 10592173]
[39]
Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10(1): 1523.
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[40]
Goodsell DS, Burley SK. RCSB Protein Data Bank tools for 3D structure-guided cancer research: Human papillomavirus (HPV) case study. Oncogene 2020; 39(43): 6623-32.
[http://dx.doi.org/10.1038/s41388-020-01461-2] [PMID: 32939013]
[41]
Seeliger D, de Groot BL. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des 2010; 24(5): 417-22.
[http://dx.doi.org/10.1007/s10822-010-9352-6] [PMID: 20401516]
[42]
Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ. Computational protein–ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc 2016; 11(5): 905-19.
[http://dx.doi.org/10.1038/nprot.2016.051] [PMID: 27077332]
[43]
Liang Q, Yang J, He J, et al. Stigmasterol alleviates cerebral ischemia/reperfusion injury by attenuating inflammation and improving antioxidant defenses in rats. Biosci Rep 2020; 40(4): BSR20192133.
[http://dx.doi.org/10.1042/BSR20192133] [PMID: 32149332]
[44]
Haque MN, Hannan MA, Dash R, Choi SM, Moon IS. The potential LXRβ agonist stigmasterol protects against hypoxia/reoxygenation injury by modulating mitophagy in primary hippocampal neurons. Phytomedicine 2021; 81: 153415.
[http://dx.doi.org/10.1016/j.phymed.2020.153415] [PMID: 33285471]
[45]
Yuan L, Zhang F, Shen M, Jia S, Xie J. Phytosterols suppress phagocytosis and inhibit inflammatory mediators via ERK pathway on LPS-triggered inflammatory responses in RAW264.7 Macrophages and the correlation with their structure. Foods 2019; 8(11): 582.
[http://dx.doi.org/10.3390/foods8110582] [PMID: 31744147]
[46]
Shi C, Wu F, Zhu X, Xu J. Incorporation of β-sitosterol into the membrane increases resistance to oxidative stress and lipid peroxidation via estrogen receptor-mediated PI3K/GSK3β signaling. Biochim Biophys Acta, Gen Subj 2013; 1830(3): 2538-44.
[http://dx.doi.org/10.1016/j.bbagen.2012.12.012] [PMID: 23266618]
[47]
Smith JA, Das A, Butler JT, Ray SK, Banik NL. Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death. Neurochem Res 2011; 36(9): 1587-93.
[http://dx.doi.org/10.1007/s11064-010-0336-7] [PMID: 21127968]
[48]
Xia Q, Hu Q, Wang H, et al. Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia. Cell Death Dis 2015; 6(3): e1702.
[http://dx.doi.org/10.1038/cddis.2015.69] [PMID: 25811799]
[49]
Mizwicki MT, Fiala M, Magpantay L, et al. Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling. Am J Neurodegener Dis 2012; 1(3): 305-15.
[PMID: 23383400]
[50]
Villapol S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol 2018; 38(1): 121-32.
[http://dx.doi.org/10.1007/s10571-017-0554-5] [PMID: 28975471]
[51]
Green PS, Yang SH, Simpkins JW. Neuroprotective effects of phenolic A ring oestrogens. Novartis Found Symp 2008; 230: 202-20.
[http://dx.doi.org/10.1002/0470870818.ch15] [PMID: 10965510]
[52]
Zlotnik A, Gurevich B, Tkachov S, Maoz I, Shapira Y, Teichberg VI. Brain neuroprotection by scavenging blood glutamate. Exp Neurol 2007; 203(1): 213-20.
[http://dx.doi.org/10.1016/j.expneurol.2006.08.021] [PMID: 17014847]
[53]
Arevalo MA, Santos-Galindo M, Bellini MJ, Azcoitia I, Garcia-Segura LM. Actions of estrogens on glial cells: Implications for neuroprotection. Biochim Biophys Acta, Gen Subj 2010; 1800(10): 1106-12.
[http://dx.doi.org/10.1016/j.bbagen.2009.10.002] [PMID: 19818384]
[54]
Das A, Smith JA, Gibson C, Varma AK, Ray SK, Banik NL. Estrogen receptor agonists and estrogen attenuate TNF-α-induced apoptosis in VSC4.1 motoneurons. J Endocrinol 2011; 208(2): 171-82.
[http://dx.doi.org/10.1677/JOE-10-0338] [PMID: 21068071]
[55]
Nagano I, Shiote M, Murakami T, et al. Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Neurol Res 2005; 27(7): 768-72.
[http://dx.doi.org/10.1179/016164105X39860] [PMID: 16197815]
[56]
Prabhu D, Khan SM, Blackburn K, Marshall JP, Ashpole NM. Loss of insulin-like growth factor-1 signaling in astrocytes disrupts glutamate handling. J Neurochem 2019; 151(6): 689-702.
[http://dx.doi.org/10.1111/jnc.14879] [PMID: 31563149]
[57]
Ramaswamy P, Dalavaikodihalli Nanjaiah N, Prasad C, Goswami K. Transcriptional modulation of calcium-permeable AMPA receptor subunits in glioblastoma by MEK–ERK1/2 inhibitors and their role in invasion. Cell Biol Int 2020; 44(3): 830-7.
[http://dx.doi.org/10.1002/cbin.11279] [PMID: 31814223]
[58]
Zhu H, Yang Y, Zhu M, et al. Alteration in the expression of inflammatory cytokines in primary hippocampal astrocytes in response to MK-801 through ERK1/2 and PI3K signals. Cytokine 2021; 138: 155366.
[http://dx.doi.org/10.1016/j.cyto.2020.155366] [PMID: 33187817]
[59]
Heitzer M, Kaiser S, Kanagaratnam M, et al. Administration of 17β-Estradiol improves motoneuron survival and down-regulates inflammasome activation in male SOD1(G93A) ALS mice. Mol Neurobiol 2017; 54(10): 8429-43.
[http://dx.doi.org/10.1007/s12035-016-0322-4] [PMID: 27957680]
[60]
Yazğan Y, Nazıroğlu M. Ovariectomy-induced mitochondrial oxidative stress, apoptosis, and calcium ion influx through TRPA1, TRPM2, and TRPV1 are prevented by 17β-Estradiol, tamoxifen, and raloxifene in the hippocampus and dorsal root ganglion of rats. Mol Neurobiol 2017; 54(10): 7620-38.
[http://dx.doi.org/10.1007/s12035-016-0232-5] [PMID: 27832523]
[61]
Lu Y, Sareddy GR, Wang J, et al. Neuron-derived estrogen is critical for astrocyte activation and neuroprotection of the ischemic brain. J Neurosci 2020; 40(38): 7355-74.
[http://dx.doi.org/10.1523/JNEUROSCI.0115-20.2020] [PMID: 32817249]

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