Network Pharmacology-based Investigation of the Underlying Mechanism of Panax notoginseng Treatment of Diabetic Retinopathy

Author(s): Chunli Piao*, Zheyu Sun, De Jin, Han Wang, Xuemin Wu, Naiwen Zhang, Fengmei Lian*, Xiaolin Tong*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 23 , Issue 4 , 2020

Become EABM
Become Reviewer

Abstract:

Background: Panax notoginseng, a Chinese herbal medicine, has been widely used to treat vascular diseases. Diabetic retinopathy (DR) is one of the complications of diabetic microangiopathy. According to recent studies, the application of Panax notoginseng extract and related Chinese patent medicine preparations can significantly improve DR. However, the pharmacological mechanisms remain unclear. Therefore, the purpose of this study was to decipher the potential mechanism of Panax notoginseng treatment of DR using network pharmacology.

Methods: We evaluated and screened the active compounds of Panax notoginseng using the Traditional Chinese Medicine Systems Pharmacology database and collected potential targets of the compounds by target fishing. A multi-source database was also used to organize targets of DR. The potential targets as the treatment of DR with Panax notoginseng were then obtained by matching the compound targets with the DR targets. Using protein-protein interaction networks and topological analysis, interactions between potential targets were identified. In addition, we also performed gene ontology-biological process and pathway enrichment analysis for the potential targets by using the Biological Information Annotation Database.

Results: Eight active ingredients of Panax notoginseng and 31 potential targets for the treatment of DR were identified. The screening and enrichment analysis revealed that the treatment of DR using Panax notoginseng primarily involved 28 biological processes and 10 related pathways. Further analyses indicated that angiogenesis, inflammatory reactions, and apoptosis may be the main processes involved in the treatment of DR with Panax notoginseng. In addition, we determined that the mechanism of intervention of Panax notoginseng in treating DR may involve five core targets, VEGFA, MMP-9, MMP-2, FGF2, and COX-2.

Conclusion: Panax notoginseng may treat diabetic retinopathy through the mechanism of network pharmacological analysis. The underlying molecular mechanisms were closely related to the intervention of angiogenesis, inflammation, and apoptosis with VEGFA, MMP-9, MMP-2, FGF2, and COX-2 being possible targets.

Keywords: Panax notoginseng, molecular mechanism, network pharmacology, diabetic retinopathy, treatment, vascular disease.

[1]
Yau, J.W.; Rogers, S.L.; Kawasaki, R.; Lamoureux, E.L.; Kowalski, J.W.; Bek, T.; Chen, S.J.; Dekker, J.M.; Fletcher, A.; Grauslund, J.; Haffner, S.; Hamman, R.F.; Ikram, M.K.; Kayama, T.; Klein, B.E.; Klein, R.; Krishnaiah, S.; Mayurasakorn, K.; O’Hare, J.P.; Orchard, T.J.; Porta, M.; Rema, M.; Roy, M.S.; Sharma, T.; Shaw, J.; Taylor, H.; Tielsch, J.M.; Varma, R.; Wang, J.J.; Wang, N.; West, S.; Xu, L.; Yasuda, M.; Zhang, X.; Mitchell, P.; Wong, T.Y. Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 2012, 35(3), 556-564.
[http://dx.doi.org/10.2337/dc11-1909] [PMID: 22301125]
[2]
Leasher, J.L.; Bourne, R.R.; Flaxman, S.R.; Jonas, J.B.; Keeffe, J.; Naidoo, K.; Pesudovs, K.; Price, H.; White, R.A.; Wong, T.Y.; Resnikoff, S.; Taylor, H.R. Vision Loss Expert Group of the Global Burden of Disease Study. Diabetes Care, 2016, 39(9), 1643-1649.
[http://dx.doi.org/10.2337/dc16-er11] [PMID: 27926893]
[3]
Das, A. Diabetic retinopathy: battling the global epidemic. Invest. Ophthalmol. Vis. Sci., 2016, 57(15), 6669-6682.
[http://dx.doi.org/10.1167/iovs.16-21031] [PMID: 27936469]
[4]
Global Report on Diabetes; World Health Organization: Geneva, 2016.
[5]
Wong, T.Y.; Klein, R.; Islam, F.M.; Cotch, M.F.; Folsom, A.R.; Klein, B.E.; Sharrett, A.R.; Shea, S. Diabetic retinopathy in a multi-ethnic cohort in the United States. Am. J. Ophthalmol., 2006, 141(3), 446-455.
[http://dx.doi.org/10.1016/j.ajo.2005.08.063] [PMID: 16490489]
[6]
Klein, B.E. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiol., 2007, 14(4), 179-183.
[http://dx.doi.org/10.1080/09286580701396720] [PMID: 17896294]
[7]
Klein, R.; Klein, B.E.; Moss, S.E.; Davis, M.D.; DeMets, D.L. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch. Ophthalmol., 1989, 107(2), 237-243.
[http://dx.doi.org/10.1001/archopht.1989.01070010243030] [PMID: 2916977]
[8]
Klein, R.; Klein, B.E.; Moss, S.E.; Davis, M.D.; DeMets, D.L. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch. Ophthalmol., 1984, 102(4), 527-532.
[http://dx.doi.org/10.1001/archopht.1984.01040030405011] [PMID: 6367725]
[9]
Fan, C.; Qiao, Y.; Tang, M. Notoginsenoside R1 attenuates high glucose-induced endothelial damage in rat retinal capillary endothelial cells by modulating the intracellular redox state. Drug Des. Devel. Ther., 2017, 11, 3343-3354.
[http://dx.doi.org/10.2147/DDDT.S149700] [PMID: 29200830]
[10]
Fan, Y.; Qiao, Y.; Huang, J.; Tang, M. Protective effects of Panax notoginseng saponins against high glucose-induced oxidative injury in rat retinal capillary endothelial cells. Evid. Based Complement. Alternat. Med., 2016., 5326382
[11]
Wang, D.D.; Zhu, H.Z.; Li, S.W.; Yang, J.M.; Xiao, Y.; Kang, Q.R.; Li, C.Y.; Zhao, Y.S.; Zeng, Y.; Li, Y.; Zhang, J.; He, Z.D.; Ying, Y. Crude saponins of Panax notoginseng have neuroprotective effects to inhibit palmitate-triggered endoplasmic reticulum stress-associated apoptosis and loss of postsynaptic proteins in staurosporine differentiated RGC-5 retinal ganglion cells. J. Agric. Food Chem., 2016, 64(7), 1528-1539.
[http://dx.doi.org/10.1021/acs.jafc.5b05864] [PMID: 26832452]
[12]
Zhou, P.; Xie, W.; Meng, X.; Zhai, Y.; Dong, X.; Zhang, X.; Sun, G.; Sun, X. Notoginsenoside R1 ameliorates diabetic retinopathy through PINK1-dependent activation of mitophagy. Cells, 2019, 8(3), 213.
[http://dx.doi.org/10.3390/cells8030213] [PMID: 30832367]
[13]
Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6, 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[14]
Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for the prediction of human oral bioavailability. Int. J. Mol. Sci., 2012, 13(6), 6964-6982.
[http://dx.doi.org/10.3390/ijms13066964] [PMID: 22837674]
[15]
Missiuro, P.V.; Liu, K.; Zou, L.; Ross, B.C.; Zhao, G.; Liu, J.S.; Ge, H. Information flow analysis of interactome networks. PLOS Comput. Biol., 2009, 5(4), e1000350
[http://dx.doi.org/10.1371/journal.pcbi.1000350] [PMID: 19503817]
[16]
Raman, K.; Damaraju, N.; Joshi, G.K. The organisational structure of protein networks: revisiting the centrality-lethality hypothesis. Syst. Synth. Biol., 2014, 8(1), 73-81.
[http://dx.doi.org/10.1007/s11693-013-9123-5] [PMID: 24592293]
[17]
Watanabe, D.; Suzuma, K.; Matsui, S.; Kurimoto, M.; Kiryu, J.; Kita, M.; Suzuma, I.; Ohashi, H.; Ojima, T.; Murakami, T.; Kobayashi, T.; Masuda, S.; Nagao, M.; Yoshimura, N.; Takagi, H. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med., 2005, 353(8), 782-792.
[http://dx.doi.org/10.1056/NEJMoa041773] [PMID: 16120858]
[18]
Shen, J.; Choy, D.F.; Yoshida, T.; Iwase, T.; Hafiz, G.; Xie, B.; Hackett, S.F.; Arron, J.R.; Campochiaro, P.A. Interleukin-18 has antipermeablity and antiangiogenic activities in the eye: reciprocal suppression with VEGF. J. Cell. Physiol., 2014, 229(8), 974-983.
[http://dx.doi.org/10.1002/jcp.24575] [PMID: 24515951]
[19]
Chan, Y.C.; Khanna, S.; Roy, S.; Sen, C.K. miR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells. J. Biol. Chem., 2011, 286(3), 2047-2056.
[http://dx.doi.org/10.1074/jbc.M110.158790] [PMID: 21081489]
[20]
Wirostko, B.; Wong, T.Y.; Simó, R. Vascular endothelial growth factor and diabetic complications. Prog. Retin. Eye Res., 2008, 27(6), 608-621.
[http://dx.doi.org/10.1016/j.preteyeres.2008.09.002] [PMID: 18929676]
[21]
Ruan, G.X.; Kazlauskas, A. Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J., 2012, 31(7), 1692-1703.
[http://dx.doi.org/10.1038/emboj.2012.21] [PMID: 22327215]
[22]
Im, E.; Kazlauskas, A. Regulating angiogenesis at the level of PtdIns-4,5-P2. EMBO J., 2006, 25(10), 2075-2082.
[http://dx.doi.org/10.1038/sj.emboj.7601100] [PMID: 16628216]
[23]
Katsura, Y.; Okano, T.; Matsuno, K.; Osako, M.; Kure, M.; Watanabe, T.; Iwaki, Y.; Noritake, M.; Kosano, H.; Nishigori, H.; Matsuoka, T. Erythropoietin is highly elevated in vitreous fluid of patients with proliferative diabetic retinopathy. Diabetes Care, 2005, 28(9), 2252-2254.
[http://dx.doi.org/10.2337/diacare.28.9.2252] [PMID: 16123502]
[24]
Cunningham, E.T., Jr; Adamis, A.P.; Altaweel, M.; Aiello, L.P.; Bressler, N.M.; D’Amico, D.J.; Goldbaum, M.; Guyer, D.R.; Katz, B.; Patel, M.; Schwartz, S.D. Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology, 2005, 112(10), 1747-1757.
[http://dx.doi.org/10.1016/j.ophtha.2005.06.007] [PMID: 16154196]
[25]
Kerbel, R.S. Tumor angiogenesis. N. Engl. J. Med., 2008, 358(19), 2039-2049.
[http://dx.doi.org/10.1056/NEJMra0706596] [PMID: 18463380]
[26]
Brown, D.M.; Kaiser, P.K.; Michels, M.; Soubrane, G.; Heier, J.S.; Kim, R.Y.; Sy, J.P.; Schneider, S. ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med., 2006, 355(14), 1432-1444.
[http://dx.doi.org/10.1056/NEJMoa062655] [PMID: 17021319]
[27]
Rosenfeld, P.J.; Brown, D.M.; Heier, J.S.; Boyer, D.S.; Kaiser, P.K.; Chung, C.Y.; Kim, R.Y. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med., 2006, 355(14), 1419-1431.
[http://dx.doi.org/10.1056/NEJMoa054481] [PMID: 17021318]
[28]
Singh, K.; Goyal, P.; Singh, M.; Deshmukh, S.; Upadhyay, D.; Kant, S.; Agrawal, N.K.; Gupta, S.K.; Singh, K. Association of functional SNP-1562C>T in MMP9 promoter with proliferative diabetic retinopathy in north Indian type 2 diabetes mellitus patients. J. Diabetes Complications, 2017, 31(12), 1648-1651.
[http://dx.doi.org/10.1016/j.jdiacomp.2017.08.010] [PMID: 28964682]
[29]
Kowluru, R.A.; Zhong, Q.; Santos, J.M. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9. Expert Opin. Investig. Drugs, 2012, 21(6), 797-805.
[http://dx.doi.org/10.1517/13543784.2012.681043] [PMID: 22519597]
[30]
Mohammad, G.; Kowluru, R.A. Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction. Lab. Invest., 2010, 90(9), 1365-1372.
[http://dx.doi.org/10.1038/labinvest.2010.89] [PMID: 20479714]
[31]
Mohammad, G.; Kowluru, R.A. Diabetic retinopathy and signaling mechanism for activation of matrix metalloproteinase-9. J. Cell. Physiol., 2012, 227(3), 1052-1061.
[http://dx.doi.org/10.1002/jcp.22822] [PMID: 21567393]
[32]
Kosano, H.; Okano, T.; Katsura, Y.; Noritake, M.; Kado, S.; Matsuoka, T.; Nishigori, H. ProMMP-9 (92 kDa gelatinase) in vitreous fluid of patients with proliferative diabetic retinopathy. Life Sci., 1999, 64(25), 2307-2315.
[http://dx.doi.org/10.1016/S0024-3205(99)00184-8] [PMID: 10374894]
[33]
Kowluru, R.A.; Mishra, M. Regulation of matrix metalloproteinase in the pathogenesis of diabetic retinopathy. Prog. Mol. Biol. Transl. Sci., 2017, 148, 67-85.
[http://dx.doi.org/10.1016/bs.pmbts.2017.02.004] [PMID: 28662829]
[34]
Ronca, R.; Giacomini, A.; Rusnati, M.; Presta, M. The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis. Expert Opin. Ther. Targets, 2015, 19(10), 1361-1377.
[http://dx.doi.org/10.1517/14728222.2015.1062475] [PMID: 26125971]
[35]
Qazi, Y.; Maddula, S.; Ambati, B.K. Mediators of ocular angiogenesis. J. Genet., 2009, 88(4), 495-515.
[http://dx.doi.org/10.1007/s12041-009-0068-0] [PMID: 20090210]
[36]
Mathew, J.G.; Clyne, A.M. Fibroblast growth factor-2 did not restore plasminogen system activity in endothelial cells on glycated collagen. Biochem. Biophys. Rep., 2015, 4, 104-110.
[http://dx.doi.org/10.1016/j.bbrep.2015.09.001] [PMID: 29124193]
[37]
Boulton, M.; Gregor, Z.; McLeod, D.; Charteris, D.; Jarvis-Evans, J.; Moriarty, P.; Khaliq, A.; Foreman, D.; Allamby, D.; Bardsley, B. Intravitreal growth factors in proliferative diabetic retinopathy: correlation with neovascular activity and glycaemic management. Br. J. Ophthalmol., 1997, 81(3), 228-233.
[http://dx.doi.org/10.1136/bjo.81.3.228] [PMID: 9135388]
[38]
Beranek, M.; Kolar, P.; Tschoplova, S.; Kankova, K.; Vasku, A. Genetic variation and plasma level of the basic fibroblast growth factor in proliferative diabetic retinopathy. Diabetes Res. Clin. Pract., 2008, 79(2), 362-367.
[http://dx.doi.org/10.1016/j.diabres.2007.09.012] [PMID: 17997184]
[39]
Zheng, L.; Howell, S.J.; Hatala, D.A.; Huang, K.; Kern, T.S. Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes, 2007, 56(2), 337-345.
[http://dx.doi.org/10.2337/db06-0789] [PMID: 17259377]
[40]
Joussen, A.M.; Poulaki, V.; Mitsiades, N.; Kirchhof, B.; Koizumi, K.; Döhmen, S.; Adamis, A.P. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J., 2002, 16(3), 438-440.
[http://dx.doi.org/10.1096/fj.01-0707fje] [PMID: 11821258]
[41]
Han, S.Y.; Li, H.X.; Bai, C.C.; Wang, L.; Tu, P.F. Component analysis and free radical-scavenging potential of Panax notoginseng and Carthamus tinctorius extracts. Chem. Biodivers., 2010, 7(2), 383-391.
[http://dx.doi.org/10.1002/cbdv.200800313] [PMID: 20151384]
[42]
Ola, M.S.; Ahmed, M.M.; Shams, S.; Al-Rejaie, S.S. Neuroprotective effects of quercetin in diabetic rat retina. Saudi J. Biol. Sci., 2017, 24(6), 1186-1194.
[http://dx.doi.org/10.1016/j.sjbs.2016.11.017] [PMID: 28855811]
[43]
Lee, M.; Yun, S.; Lee, H.; Yang, J. Quercetin mitigates inflammatory responses induced by vascular endothelial growth factor in mouse retinal photoreceptor cells through suppression of nuclear factor kappa B. Int. J. Mol. Sci., 2017, 18(11)
[http://dx.doi.org/10.3390/ijms18112497] [PMID: 29165402]
[44]
Chen, B.; He, T.; Xing, Y.; Cao, T. Effects of quercetin on the expression of MCP-1, MMP-9 and VEGF in rats with diabetic retinopathy. Exp. Ther. Med., 2017, 14(6), 6022-6026.
[http://dx.doi.org/10.3892/etm.2017.5275] [PMID: 29285153]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 23
ISSUE: 4
Year: 2020
Page: [334 - 344]
Pages: 11
DOI: 10.2174/1386207323666200305093709

Article Metrics

PDF: 36
HTML: 3
EPUB: 1
PRC: 4