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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Exploration of the Potential Mechanisms of Lingqihuangban Granule for Treating Diabetic Retinopathy Based on Network Pharmacology

Author(s): Shuai He*, Chufeng Gu*, Tong Su*, Chuandi Zhou, Thashi Lhamo, Deji Draga, Lili Yin and Qinghua Qiu

Volume 26, Issue 1, 2023

Published on: 01 July, 2022

Page: [14 - 29] Pages: 16

DOI: 10.2174/1386207325666220407112018

Price: $65

Abstract

Background: The Lingqihuangban Granule (LQHBG), a remarkable Chinese herbal compound, has been used for decades to treat diabetic retinopathy (DR) in the Department of Ophthalmology, Shanghai General Hospital (National Clinical Research Center for Eye Diseases) with obvious effects. Through the method of network pharmacology, the present study constructed bioactive component-relative targets and protein-protein interaction network of the LQHBG and implemented gene function analysis and pathway enrichment of targets, discussing the mechanisms of traditional Chinese medicine LQHBG in treating DR.

Materials and Methods: The bioactive ingredients of LQHBG were screened and obtained using TCMSP and ETCM databases, while the potential targets of bioactive ingredients were predicted by SwissTargetPrediction and ETCM databases. Compared with the disease target databases of TTD, Drugbank, OMIM and DisGeNET, the therapeutic targets of LQHBG for DR were extracted. Based on the DAVID platform, GO annotation and KEGG pathway analyses of key targets were explored, combined with the screening of core pathways on the Omicshare database and pathway annotation on the Reactome database.

Results: A total of 357 bioactive components were screened from LQHBG, involving 86 possible targets of LQHBG treating DR. In the PPI network, INS and ALB were identified as key genes. The effective targets were enriched in multiple signaling pathways, such as PI3K/Akt and MAPK pathways.

Conclusion: This study revealed the possible targets and pathways of LQHBG treating DR, reflecting the characteristics of multicomponent, multitarget and multipathway treatment of a Chinese herbal compound, and provided new ideas for further discussion.

Keywords: Lingqihuangban Granule, diabetic retinopathy, network pharmacology, Chinese herbal compound

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[1]
Piao, C.L.; Luo, J.L.; Jin, D.; Tang, C.; Wang, L.; Lian, F.M.; Tong, X.L. Utilizing network pharmacology to explore the underlying mechanism of Radix Salviae in diabetic retinopa-thy. Chin. Med., 2019, 14(1), 58.
[http://dx.doi.org/10.1186/s13020-019-0280-7] [PMID: 31892939]
[2]
Lee, R.; Wong, T.Y.; Sabanayagam, C. Epidemiology of dia-betic retinopathy, diabetic macular edema and related vision loss. Eye Vis. (Lond.), 2015, 2(1), 17.
[http://dx.doi.org/10.1186/s40662-015-0026-2] [PMID: 26605370]
[3]
Zhao, Y.; Singh, R.P. The role of anti-vascular endothelial growth factor (anti-VEGF) in the management of proliferative diabetic retinopathy. Drugs Context, 2018, 7, 212532.
[http://dx.doi.org/10.7573/dic.212532] [PMID: 30181760]
[4]
Whitcup, S.M.; Cidlowski, J.A.; Csaky, K.G.; Ambati, J. Pharmacology of corticosteroids for diabetic macular edema. Invest. Ophthalmol. Vis. Sci., 2018, 59(1), 1-12.
[http://dx.doi.org/10.1167/iovs.17-22259] [PMID: 29297055]
[5]
Pang, B.; Li, Q.W.; Qin, Y.L.; Dong, G.T.; Feng, S.; Wang, J.; Tong, X.L.; Ni, Q. Traditional chinese medicine for diabetic retinopathy: A systematic review and meta-analysis. Medicine (Baltimore), 2020, 99(7), e19102.
[http://dx.doi.org/10.1097/MD.0000000000019102] [PMID: 32049817]
[6]
Song, W.; Zhu, Y.W. Chinese medicines in diabetic retinopa-thy therapies. Chin. J. Integr. Med., 2019, 25(4), 316-320.
[http://dx.doi.org/10.1007/s11655-017-2911-0] [PMID: 30264267]
[7]
Li, S.; Xutian, S. New development in traditional chinese medicine: Symbolism-digit therapy as a special naturopathic treatment. Am. J. Chin. Med., 2016, 44(7), 1311-1323.
[http://dx.doi.org/10.1142/S0192415X16500737] [PMID: 27785941]
[8]
Li, S.; Zhang, B.; Zhang, N. Network target for screening synergistic drug combinations with application to traditional Chinese medicine. BMC Syst. Biol., 2011, 5(Suppl. 1), S10.
[http://dx.doi.org/10.1186/1752-0509-5-S1-S10]
[9]
Xu, Z.H.; Gao, Y.Y.; Zhang, H.T.; Ruan, K.F.; Feng, Y. Pro-gress in experimental and clinical research of the diabetic ret-inopathy treatment using traditional Chinese medicine. Am. J. Chin. Med., 2018, 46(7), 1-27.
[http://dx.doi.org/10.1142/S0192415X1850074X] [PMID: 30284463]
[10]
Zhang, L.; Dai, S.Z.; Nie, X.D.; Zhu, L.; Xing, F.; Wang, L.Y. Effect of Salvia miltiorrhiza on retinopathy. Asian Pac. J. Trop. Med., 2013, 6(2), 145-149.
[http://dx.doi.org/10.1016/S1995-7645(13)60011-5] [PMID: 23339918]
[11]
Manthey, A.L.; Chiu, K.; So, K.F. Effects of Lycium barba-rum on the visual system. Int. Rev. Neurobiol., 2017, 135, 1-27.
[http://dx.doi.org/10.1016/bs.irn.2017.02.002] [PMID: 28807155]
[12]
Song, M.K.; Salam, N.K.; Roufogalis, B.D.; Huang, T.H. Lyci-um barbarum (Goji Berry) extracts and its taurine component inhibit PPAR-γ-dependent gene transcription in human retinal pigment epithelial cells: Possible implications for diabetic ret-inopathy treatment. Biochem. Pharmacol., 2011, 82(9), 1209-1218.
[http://dx.doi.org/10.1016/j.bcp.2011.07.089] [PMID: 21820420]
[13]
Yao, Q.; Yang, Y.; Lu, X.; Zhang, Q.; Luo, M.; Li, P.A.; Pan, Y. Lycium barbarum polysaccharides improve retinopathy in diabetic sprague-dawley rats. Evid. Based Complement. Alternat. Med., 2018, 2018, 7943212.
[http://dx.doi.org/10.1155/2018/7943212] [PMID: 30581486]
[14]
Tsuneki, H.; Ma, E.L.; Kobayashi, S.; Sekizaki, N.; Maekawa, K.; Sasaoka, T.; Wang, M.W.; Kimura, I. Antiangiogenic ac-tivity of beta-eudesmol in vitro and in vivo. Eur. J. Pharmacol., 2005, 512(2-3), 105-115.
[http://dx.doi.org/10.1016/j.ejphar.2005.02.035] [PMID: 15840394]
[15]
Kimura, I. Medical benefits of using natural compounds and their derivatives having multiple pharmacological actions. Yakugaku Zasshi, 2006, 126(3), 133-143.
[http://dx.doi.org/10.1248/yakushi.126.133] [PMID: 16508237]
[16]
Lin, T.H.; Hsieh, C.L. Pharmacological effects of Salvia milti-orrhiza (Danshen) on cerebral infarction. Chin. Med., 2010, 5(1), 22.
[http://dx.doi.org/10.1186/1749-8546-5-22] [PMID: 20565944]
[17]
Hu, C.K.; Lee, Y.J.; Colitz, C.M.; Chang, C.J.; Lin, C.T. The protective effects of Lycium barbarum and Chrysanthemum morifolum on diabetic retinopathies in rats. Vet. Ophthalmol., 2012(Suppl. 2), 65-71.
[18]
Liu, L.; Lao, W.; Ji, Q.S.; Yang, Z.H.; Yu, G.C.; Zhong, J.X. Lycium barbarum polysaccharides protected human retinal pigment epithelial cells against oxidative stress-induced apop-tosis. Int. J. Ophthalmol., 2015, 8(1), 11-16.
[19]
Song, M.K. Roufogalis Bd Fau - Huang, T.H.W.; Huang, T.H. Reversal of the caspase-dependent apoptotic cytotoxicity pathway by taurine from Lycium barbarum (Goji Berry) in human retinal pigment epithelial cells: Potential benefit in dia-betic retinopathy. Evid. Based Complement. Alternat. Med., 2012, 2012, 323784.
[20]
Zhang, R.; Zhu, X.; Bai, H.; Ning, K. Network pharmacology databases for traditional Chinese medicine: Review and as-sessment. Front. Pharmacol., 2019, 10, 123.
[http://dx.doi.org/10.3389/fphar.2019.00123] [PMID: 30846939]
[21]
Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[22]
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(1), 13.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[23]
Xu, H.Y.; Zhang, Y.Q.; Liu, Z.M.; Chen, T.; Lv, C.Y.; Tang, S.H.; Zhang, X.B.; Zhang, W.; Li, Z.Y.; Zhou, R.R.; Yang, H.J.; Wang, X.J.; Huang, L.Q. ETCM: An encyclopaedia of traditional Chinese medicine. Nucleic Acids Res., 2019, 47(D1), D976-D982.
[http://dx.doi.org/10.1093/nar/gky987] [PMID: 30365030]
[24]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2019 update: Improved ac-cess to chemical data. Nucleic Acids Res., 2019, 47(D1), D1102-D1109.
[http://dx.doi.org/10.1093/nar/gky1033] [PMID: 30371825]
[25]
Gfeller, D.; Michielin, O.; Zoete, V. Shaping the interaction landscape of bioactive molecules. Bioinformatics, 2013, 29(23), 3073-3079.
[http://dx.doi.org/10.1093/bioinformatics/btt540] [PMID: 24048355]
[26]
Wang, Y.; Zhang, S.; Li, F.; Zhou, Y.; Zhang, Y.; Wang, Z.; Zhang, R.; Zhu, J.; Ren, Y.; Tan, Y.; Qin, C.; Li, Y.; Li, X.; Chen, Y.; Zhu, F. Therapeutic target database 2020: Enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res., 2020, 48(D1), D1031-D1041.
[PMID: 31691823]
[27]
Wishart, D.S.; Feunang, Y.D.; Guo, A.C.; Lo, E.J.; Marcu, A.; Grant, J.R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; Assempour, N.; Iynkkaran, I.; Liu, Y.; Maciejewski, A.; Gale, N.; Wilson, A.; Chin, L.; Cummings, R.; Le, D.; Pon, A.; Knox, C.; Wilson, M. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res., 2018, 46(D1), D1074-D1082.
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[28]
Amberger, J.S.; Bocchini, C.A.; Schiettecatte, F.; Scott, A.F.; Hamosh, A. OMIM.org: Online mendelian inheritance in man (OMIM®), an online catalog of human genes and genetic dis-orders. Nucleic Acids Res., 2015, 43(Database issue), D789-D798.
[http://dx.doi.org/10.1093/nar/gku1205] [PMID: 25428349]
[29]
Piñero, J.; Bravo, À.; Queralt-Rosinach, N.; Gutiérrez-Sacristán, A.; Deu-Pons, J.; Centeno, E.; García-García, J.; Sanz, F.; Furlong, L.I. DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res., 2017, 45(D1), D833-D839.
[http://dx.doi.org/10.1093/nar/gkw943] [PMID: 27924018]
[30]
Otasek, D.; Morris, J.H.; Bouças, J.; Pico, A.R.; Demchak, B. Cytoscape automation: Empowering workflow-based network analysis. Genome Biol., 2019, 20(1), 185.
[http://dx.doi.org/10.1186/s13059-019-1758-4] [PMID: 31477170]
[31]
Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C.V. STRING v11: Pro-tein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res., 2019, 47(D1), D607-D613.
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[32]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioin-formatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[33]
Kleinwort, K.J.H.; Amann, B.; Hauck, S.M.; Hirmer, S.; Blu-tke, A.; Renner, S.; Uhl, P.B.; Lutterberg, K.; Sekundo, W.; Wolf, E.; Deeg, C.A. Retinopathy with central oedema in an INS C94Y transgenic pig model of long-term diabetes. Diabetologia, 2017, 60(8), 1541-1549.
[http://dx.doi.org/10.1007/s00125-017-4290-7] [PMID: 28480495]
[34]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[35]
Jassal, B.; Matthews, L.; Viteri, G.; Gong, C.; Lorente, P.; Fabregat, A.; Sidiropoulos, K.; Cook, J.; Gillespie, M.; Haw, R.; Loney, F.; May, B.; Milacic, M.; Rothfels, K.; Sevilla, C.; Shamovsky, V.; Shorser, S.; Varusai, T.; Weiser, J.; Wu, G.; Stein, L.; Hermjakob, H.; D’Eustachio, P. The reactome pathway knowledgebase. Nucleic Acids Res., 2020, 48(D1), D498-D503.
[PMID: 31691815]
[36]
Treins, C.; Giorgetti-Peraldi, S.; Murdaca, J.; Van Obberghen, E. Regulation of vascular endothelial growth factor expres-sion by advanced glycation end products. J. Biol. Chem., 2001, 276(47), 43836-43841.
[http://dx.doi.org/10.1074/jbc.M106534200] [PMID: 11571295]
[37]
Moore, T.C.; Moore, J.E.; Kaji, Y.; Frizzell, N.; Usui, T.; Poulaki, V.; Campbell, I.L.; Stitt, A.W.; Gardiner, T.A.; Arch-er, D.B.; Adamis, A.P. The role of advanced glycation end products in retinal microvascular leukostasis. Invest. Ophthalmol. Vis. Sci., 2003, 44(10), 4457-4464.
[http://dx.doi.org/10.1167/iovs.02-1063] [PMID: 14507893]
[38]
Wang, X.L.; Yu, T.; Yan, Q.C.; Wang, W.; Meng, N.; Li, X.J.; Luo, Y.H. AGEs Promote oxidative stress and induce apop-tosis in retinal pigmented epithelium cells RAGE-dependently. J. Mol. Neurosci., 2015, 56(2), 449-460.
[http://dx.doi.org/10.1007/s12031-015-0496-7] [PMID: 25682235]
[39]
Czabotar, P.E.; Lessene, G.; Strasser, A.; Adams, J.M. Con-trol of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat. Rev. Mol. Cell Biol., 2014, 15(1), 49-63.
[http://dx.doi.org/10.1038/nrm3722] [PMID: 24355989]
[40]
Zong, H.; Ward, M.; Stitt, A.W. AGEs, RAGE, and diabetic retinopathy. Curr. Diab. Rep., 2011, 11(4), 244-252.
[http://dx.doi.org/10.1007/s11892-011-0198-7] [PMID: 21590515]
[41]
Zong, H.; Ward, M.; Madden, A.; Yong, P.H.; Limb, G.A.; Curtis, T.M.; Stitt, A.W. Hyperglycaemia-induced pro-inflammatory responses by retinal Müller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia, 2010, 53(12), 2656-2666.
[http://dx.doi.org/10.1007/s00125-010-1900-z] [PMID: 20835858]
[42]
Goda, N.; Kanai, M. Hypoxia-inducible factors and their roles in energy metabolism. Int. J. Hematol., 2012, 95(5), 457-463.
[http://dx.doi.org/10.1007/s12185-012-1069-y] [PMID: 22535382]
[43]
Fu, Z.; Chen, D.; Cheng, H.; Wang, F. Hypoxia-inducible factor-1α protects cervical carcinoma cells from apoptosis in-duced by radiation via modulation of vascular endothelial growth factor and p53 under hypoxia. Med. Sci. Monit., 2015, 21, 318-325.
[http://dx.doi.org/10.12659/MSM.893265] [PMID: 25623525]
[44]
Zhang, D.; Lv, F.L.; Wang, G.H. Effects of HIF-1α on diabet-ic retinopathy angiogenesis and VEGF expression. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(16), 5071-5076.
[PMID: 30178824]
[45]
Muilwijk, M.; Goorden, S.M.I.; Celis-Morales, C.; Hof, M.H.; Ghauharali-van der Vlugt, K.; Beers-Stet, F.S.; Gill, J.M.R.; Vaz, F.M.; van Valkengoed, I.G.M. Contributions of amino acid, acylcarnitine and sphingolipid profiles to type 2 diabetes risk among South-Asian Surinamese and Dutch adults. BMJ Open Diabetes Res. Care, 2020, 8(1), e001003.
[http://dx.doi.org/10.1136/bmjdrc-2019-001003] [PMID: 32376636]
[46]
Mondal, K.; Mandal, N. Role of bioactive sphingolipids in inflammation and eye diseases. Adv. Exp. Med. Biol., 2019, 1161, 149-167.
[http://dx.doi.org/10.1007/978-3-030-21735-8_14] [PMID: 31562629]
[47]
Yaribeygi, H.; Bo, S.; Ruscica, M.; Sahebkar, A. Ceramides and diabetes mellitus: An update on the potential molecular relationships. Diabet. Med., 2020, 37(1), 11-19.
[http://dx.doi.org/10.1111/dme.13943] [PMID: 30803019]
[48]
Arai, T.; Bhunia, A.K.; Chatterjee, S.; Bulkley, G.B. Lacto-sylceramide stimulates human neutrophils to upregulate Mac-1, adhere to endothelium, and generate reactive oxygen me-tabolites in vitro. Circ. Res., 1998, 82(5), 540-547.
[http://dx.doi.org/10.1161/01.RES.82.5.540] [PMID: 9529158]
[49]
Baeyens, A.; Fang, V.; Chen, C.; Schwab, S.R. Exit strategies: S1P signaling and T cell migration. Trends Immunol., 2015, 36(12), 778-787.
[http://dx.doi.org/10.1016/j.it.2015.10.005] [PMID: 26596799]
[50]
Lu, J.M.; Zhang, Z.Z.; Ma, X.; Fang, S.F.; Qin, X.H. Repres-sion of microRNA-21 inhibits retinal vascular endothelial cell growth and angiogenesis via PTEN dependent-PI3K/Akt/VEGF signaling pathway in diabetic retinopathy. Exp. Eye Res., 2020, 190, 107886.
[http://dx.doi.org/10.1016/j.exer.2019.107886] [PMID: 31759996]
[51]
Zhang, G.; Cai, X.; He, L.; Qin, D.; Li, H.; Fan, X. Skimmin improves insulin resistance via regulating the metabolism of glucose: In vitro and in vivo models. Front. Pharmacol., 2020, 11, 540.
[http://dx.doi.org/10.3389/fphar.2020.00540] [PMID: 32425786]
[52]
Yang, M.; Ren, Y.; Lin, Z.; Tang, C.; Jia, Y.; Lai, Y.; Zhou, T.; Wu, S.; Liu, H.; Yang, G.; Li, L. Krüppel-like factor 14 in-creases insulin sensitivity through activation of PI3K/Akt sig-nal pathway. Cell. Signal., 2015, 27(11), 2201-2208.
[http://dx.doi.org/10.1016/j.cellsig.2015.07.019] [PMID: 26226221]
[53]
Ren, Z.; Xie, Z.; Cao, D.; Gong, M.; Yang, L.; Zhou, Z.; Ou, Y. C-Phycocyanin inhibits hepatic gluconeogenesis and in-creases glycogen synthesis via activating Akt and AMPK in insulin resistance hepatocytes. Food Funct., 2018, 9(5), 2829-2839.
[http://dx.doi.org/10.1039/C8FO00257F] [PMID: 29693104]
[54]
Akrami, H.; Mahmoodi, F.; Havasi, S.; Sharifi, A. PlGF knockdown inhibited tumor survival and migration in gastric cancer cell via PI3K/Akt and p38MAPK pathways. Cell Biochem. Funct., 2016, 34(3), 173-180.
[http://dx.doi.org/10.1002/cbf.3176] [PMID: 26968576]
[55]
Nadeem, A.; Ahmad, S.F.; Al-Harbi, N.O.; Fardan, A.S.; El-Sherbeeny, A.M.; Ibrahim, K.E.; Attia, S.M. IL-17A causes depression-like symptoms via NFκB and p38MAPK signaling pathways in mice: Implications for psoriasis associated de-pression. Cytokine, 2017, 97, 14-24.
[http://dx.doi.org/10.1016/j.cyto.2017.05.018] [PMID: 28570931]
[56]
Feng, D.; Ling, W.H.; Duan, R.D. Lycopene suppresses LPS-induced NO and IL-6 production by inhibiting the activation of ERK, p38MAPK, and NF-kappaB in macrophages. Inflamm. Res., 2010, 59(2), 115-121.
[http://dx.doi.org/10.1007/s00011-009-0077-8] [PMID: 19693648]
[57]
Yin, Y.; Chen, F.; Wang, W.; Wang, H.; Zhang, X. Resolvin D1 inhibits inflammatory response in STZ-induced diabetic retinopathy rats: Possible involvement of NLRP3 inflam-masome and NF-κB signaling pathway. Mol. Vis., 2017, 23, 242-250.
[PMID: 28465656]
[58]
Lim, R.R.; Wieser, M.E.; Ganga, R.R.; Barathi, V.A.; Laksh-minarayanan, R.; Mohan, R.R.; Hainsworth, D.P.; Chaurasia, S.S. NOD-like receptors in the eye: Uncovering its role in di-abetic retinopathy. Int. J. Mol. Sci., 2020, 21(3), E899.
[http://dx.doi.org/10.3390/ijms21030899] [PMID: 32019187]
[59]
Shuai, H.; Chufeng, G.; Tong, S.; Chuandi, Z.; Thashi, L.; Deji, D.; Lili, Y.; Qinghua, Q. Exploration of the potential mechanisms of lingqihuangban granule for treating diabetic retinopathy based on network pharmacology. Res. Square, 2022, 22(1), 141.
[http://dx.doi.org/10.21203/rs.3.rs-90763/v1]

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