Network pharmacology prediction and molecular docking-based study on the mechanism of Erigeron breviscapus in the treatment of age-related macular degeneratio

doi:10.5246/jcps.2023.11.074

Abstract

Abstract:

In the present study, we utilized network pharmacology and molecular docking to investigate the potential mechanism of Erigeron breviscapus (ErB) in treating age-related macular degeneration (AMD). By analyzing databases, we identified 12 active ingredients and 195 targets of Erigeron breviscapus, as well as 1490 related targets of AMD. Through further analysis, we selected 9 active components and 103 overlapping target genes of ErB. These genes were found to be involved in various biological processes and pathways related to apoptosis, oxidative stress, and inflammatory response based on GO and KEGG enrichment analyses. To identify critical active ingredients and key targets, we used the Cytohubba plugin or Degree value screening in Cytoscape software. The analysis revealed that quercetin, luteolin, and kaempferol were identified as critical active ingredients, while VEGFA, CASP3, TNF, TP53, AKT1, MMP9, IL-6, EGF, PTGS2, and IL-1B were identified as key targets. We obtained crystal conformations of these core proteins from the RCSB PDB database and performed molecular docking using AutoDock Vina and Pymol software. The results showed that luteolin, quercetin, and baicalein could form stable interactions with their corresponding key targets (CASP3, IL-6, and VEGFA). Based on these findings, we predicted that ErB might exert its therapeutic effects on AMD through multiple components, targets, and pathways. This study provided a theoretical basis and reference for the potential use of traditional Chinese medicine (TCM) in the treatment of AMD.

Key words: Age-related macular degeneration, Erigeron breviscapus, Network pharmacology, Molecular docking, Mechanism research

Supporting:

Daiying Zhou, Jing Chen, Zhigang Lv. Network pharmacology prediction and molecular docking-based study on the mechanism of Erigeron breviscapus in the treatment of age-related macular degeneratio[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(11): 923-934.

Figures/Tables 9

Table 1. Active ingredients of ErB.

Table 2. Binding affinity (kcal/mol).

References 38

[1]	Armento, A.; Ueffing, M.; Clark, S.J. The complement system in age-related macular degeneration. Cell Mol. Life Sci. 2021, 78, 4487–4505.
[2]	Chakravarthy, U.; Peto, T. Current perspective on age-related macular degeneration. JAMA. 2020, 324, 794.
[3]	Wong, W.L.; Su, X.Y.; Li, X.; Cheung, C.M.G.; Klein, R.; Cheng, C.Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health. 2014, 2, e106–e116.
[4]	Keenan, T.D.L.; Cukras, C.A.; Chew, E.Y. Age-related macular degeneration: epidemiology and clinical aspects. Adv. Exp. Med. Biol. 2021, 1256, 1–31.
[5]	Campagne, M.V.; LeCouter, J.; Yaspan, B.L.; Ye, W.L. Mechanisms of age-related macular degeneration and therapeutic opportunities. J. Pathol. 2014, 232, 151–164.
[6]	Mitchell, P.; Liew, G.; Gopinath, B.; Wong, T.Y. Age-related macular degeneration. Lancet. 2018, 392, 1147–1159.
[7]	Wu, R.X.; Liang, Y.; Xu, M.; Fu, K.; Zhang, Y.L.; Wu, L.; Wang, Z. Advances in chemical constituents, clinical applications, pharmacology, pharmacokinetics and toxicology of erigeron breviscapus. Front Pharmacol. 2021, 12, 656335.
[8]	Fan, H.; Lin, P.; Kang, Q.; Zhao, Z.L.; Wang, J.; Cheng, J.Y. Metabolism and pharmacological mechanisms of active ingredients in Erigeron breviscapus. Curr. Drug Metab. 2021, 22, 24–39.
[9]	Zhu, J.Y.; Chen, L.; Qi, Y.; Feng, J.; Zhu, L.; Bai, Y.J.; Wu, H.J. Protective effects of Erigeron breviscapus Hand.–Mazz. (EBHM) extract in retinal neurodegeneration models. Mol. Vis. 2018, 24, 315–325.
[10]	Ru, J.L.; Li, P.; Wang, J.N.; Zhou, W.; Li, B.H.; Huang, C.; Li, P.D.; Guo, Z.H.; Tao, W.Y.; Yang, Y.F.; Xu, X.; Li, Y.; Wang, Y.H.; Yang, L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform. 2014, 6, 13.
[11]	The UniProt Consortium. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2017, 45, D158–D169.
[12]	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: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019, 47, D607–D613.
[13]	Zhou, Y.Y.; Zhou, B.; Pache, L.; Chang, M.; Khodabakhshi, A.H.; Tanaseichuk, O.; Benner, C.; Chanda, S.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 2019, 10, 1523.
[14]	Yang, X.H.; Liu, H.H.; Liu, J.N.; Li, F.; Li, X.H.; Shi, L.L.; Chen, J.W. Rational selection of the 3D structure of biomacromolecules for molecular docking studies on the mechanism of endocrine disruptor action. Chem. Res. Toxicol. 2016, 29, 1565–1570.
[15]	Rosenfeld, P.J.; Brown, D.M.; Heier, J.S.; Boyer, D.S.; Kaiser, P.K.; Chung, C.Y.; Kim, R.Y.; Study Group, M.A.R.I.A.A. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2006, 355, 1419–1431.
[16]	Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin, D.F.; Maguire, M.G.; Fine, S.L.; Ying, G.S.; Jaffe, G.J.; Grunwald, J.E.; Toth, C.; Redford, M.; Ferris, F.L. 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012, 119, 1388–1398.
[17]	Boyer, D.S.; Schmidt-Erfurth, U.; van Lookeren Campagne, M.; Henry, E.C.; Brittain, C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017, 37, 819–835.
[18]	MacLaren, R.E.; Bennett, J.; Schwartz, S.D. Gene therapy and stem cell transplantation in retinal disease: the new frontier. Ophthalmology. 2016, 123, S98–S106.
[19]	Wu, D.Y.; Wang, X.D.; Cai, J.M.; Li, Y.; Bi, M.; Gui, W.W.; Cao, H.M. Study on the mechanism of Danggui Buxue Decoction in the treatment of diabetic retinopathy based on network pharmacology and experiment. J. Chin. Pharm. Sci. 2023, 32, 527.
[20]	Dong, X.Y.; Qu, S.T. Erigeron breviscapus (vant.) hand-mazz.: a promising natural neuroprotective agent for Alzheimer’s disease. Front. Pharmacol. 2022, 13, 877872.
[21]	Yang, L.; Tao, Y.W.; Luo, L.L.; Zhang, Y.; Wang, X.B.; Meng, X.L. Dengzhan Xixin injection derived from a traditional Chinese herb Erigeron breviscapus ameliorates cerebral ischemia/reperfusion injury in rats via modulation of mitophagy and mitochondrial apoptosis. J. Ethnopharmacol. 2022, 288, 114988.
[22]	Gao, J.L.; Chen, G.; He, H.Q.; Liu, C.; Xiong, X.J.; Li, J.; Wang, J. Therapeutic effects of breviscapine in cardiovascular diseases: a review. Front. Pharmacol. 2017, 8, 289.
[23]	Zhong, Y.S.; Xiang, M.H.; Ye, W.; Cheng, Y.; Jiang, Y.Q. Visual field protective effect of Erigeron breviscapus (vant.) hand. mazz. extract on glaucoma with controlled intraocular pressure. Drugs R D. 2010, 10, 75–82.
[24]	Yin, S.; Wang, Z.F.; Duan, J.G.; Ji, L.; Lu, X.J. Extraction (DSX) from Erigeron breviscapus modulates outward potassium currents in rat retinal ganglion cells. Int. J. Ophthalmol. 2015, 8, 1101–1106.
[25]	Xi, J.X.; Rong, Y.Z.; Zhao, Z.F.; Huang, Y.H.; Wang, P.; Luan, H.L.; Xing, Y.; Li, S.Y.; Liao, J.; Dai, Y.; Liang, J.Y.; Wu, F.H. Scutellarin ameliorates high glucose-induced vascular endothelial cells injury by activating PINK1/Parkin-mediated mitophagy. J. Ethnopharmacol. 2021, 271, 113855.
[26]	Ye, J.Z.; Zeng, B.; Zhong, M.Y.; Li, H.C.; Xu, L.H.; Shu, J.X.; Wang, Y.F.; Yang, F.; Zhong, C.S.; Ye, X.J.; He, X.H.; Ouyang, D.Y. Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling. Acta Pharm. Sin. B. 2021, 11, 112–126.
[27]	Kaarniranta, K.; Blasiak, J.; Liton, P.; Boulton, M.; Klionsky, D.J.; Sinha, D. Autophagy in age-related macular degeneration. Autophagy. 2023, 19, 388–400.
[28]	Kauppinen, A.; Paterno, J.J.; Blasiak, J.; Salminen, A.; Kaarniranta, K. Inflammation and its role in age-related macular degeneration. Cell Mol. Life Sci. 2016, 73, 1765–1786.
[29]	Celkova, L.; Doyle, S.L.; Campbell, M. NLRP3 inflammasome and pathobiology in AMD. J. Clin. Med. 2015, 4, 172–192.
[30]	Ildefonso, C.J.; Biswal, M.R.; Ahmed, C.M.; Lewin, A.S. The NLRP3 inflammasome and its role in age-related macular degeneration. Retinal. Degenerat. Dis. 2016, 854, 59–65.
[31]	Dowling, J.K.; O’Neill, L.A.J. Biochemical regulation of the inflammasome. Crit. Rev. Biochem. Mol. Biol. 2012, 47, 424–443.
[32]	Bauernfeind, F.G.; Horvath, G.; Stutz, A.; Alnemri, E.S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.H.; Monks, B.G.; Fitzgerald, K.A.; Hornung, V.; Latz, E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 2009, 183, 787–791.
[33]	Tseng, W.A.; Thein, T.; Kinnunen, K.; Lashkari, K.; Gregory, M.S.; D'Amore, P.A.; Ksander, B.R. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013, 54, 110–120.
[34]	Marneros, A.G. NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration. Cell Rep. 2013, 4, 945–958.
[35]	Liu, R.T.; Gao, J.Y.; Cao, S.J.; Sandhu, N.; Cui, J.Z.; Chou, C.L.; Fang, E.; Matsubara, J.A. Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013, 54, 2225.
[36]	Ruan, Y.; Jiang, S.B.; Musayeva, A.; Gericke, A. Oxidative stress and vascular dysfunction in the retina: therapeutic strategies. Antioxidants. 2020, 9, 761.
[37]	Wang, Z.; Yu, J.G.; Wu, J.B.; Qi, F.; Wang, H.L.; Wang, Z.G.; Xu, Z.J. Scutellarin protects cardiomyocyte ischemia-reperfusion injury by reducing apoptosis and oxidative stress. Life Sci. 2016, 157, 200–207.
[38]	Wang, Z.H.; Zhang, P.F.; Zhao, Y.P.; Yu, F.R.; Wang, S.Y.; Liu, K.W.; Cheng, X.; Shi, J.; He, Q.T.; Xia, Y.N.; Cheng, L. Scutellarin protects against mitochondrial reactive oxygen species-dependent NLRP3 inflammasome activation to attenuate intervertebral disc degeneration. Front. Bioeng. Biotechnol. 2022, 10, 883118.