Network Pharmacology and Molecular Docking Analysis on Mechanisms of Scutellariae Radix in the Treatment of Cerebral Ischemia-reperfusion Injury


Cite item

Full Text

Abstract

Background:Multiple brain disorders are treated by Scutellaria Radix (SR), including cerebral ischemia-reperfusion (CI/R). However, more studies are needed to clarify the molecular mechanism of SR for CI/R.

Methods:The active substances and potential targets of SR and CI/R-related genes were obtained through public databases. Overlapping targets of SR and CI/R were analyzed using proteinprotein interaction (PPI) networks. GO and KEGG enrichment analyses were performed to predict the pathways of SR against CI/R, and the key components and targets were screened for molecular docking. The results of network pharmacology analysis were verified using in vitro experiments.

Results:15 components and 64 overlapping targets related to SR and CI/R were obtained. The top targets were AKT1, IL-6, CAS3, TNF, and TP53. These targets have been studied by GO and KEGG to be connected to a number of signaling pathways, including MAPK, PI3K-Akt pathway, and apoptosis. Molecular docking and cell experiments helped to further substantiate the network pharmacology results.

Conclusion:The active compound of SR was able to significantly decrease the apoptosis of HT22 cells induced by OGD/R. This finding suggests that SR is a potentially effective treatment for CI/R by modulating the MAPK and PI3K-Akt pathways.

About the authors

Yang Yang

Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University

Email: info@benthamscience.net

Mengrong Xu

Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University

Email: info@benthamscience.net

Wenting Yuan

Department of College of Life Sciences, Northwest University

Email: info@benthamscience.net

Yue Feng

Department of College of Life Sciences, Northwest University

Email: info@benthamscience.net

Yongqiang Hou

Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University

Email: info@benthamscience.net

Fei Fang

Deparment of Central Lab, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University

Email: info@benthamscience.net

Shiwan Duan

Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University

Email: info@benthamscience.net

Lu Bai

Department of Pharmacy, Xi'an No.1 Hospital, The First Affiliated Hospital of Northwest University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Higashida, R.T.; Furlan, A.J.; Roberts, H.; Tomsick, T.; Connors, B.; Barr, J.; Dillon, W.; Warach, S.; Broderick, J.; Tilley, B.; Sacks, D. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke, 2003, 34(8), e109-e137. doi: 10.1161/01.STR.0000082721.62796.09 PMID: 12869717
  2. Lo, E.H.; Dalkara, T.; Moskowitz, M.A. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci., 2003, 4(5), 399-414. doi: 10.1038/nrn1106 PMID: 12728267
  3. Pekna, M.; Pekny, M Fau - Nilsson, M.; Nilsson, M. Modulation of neural plasticity as a basis for stroke rehabilitation. Stroke, 2012, 43(1524-4628), 2819-2828.
  4. Khalil, A.A.; Aziz, F.A.; Hall, J.C. Reperfusion Injury. Plast. Reconstr. Surg., 2006, 117(3), 1024-1033. doi: 10.1097/01.prs.0000204766.17127.54 PMID: 16525303
  5. Rosenberg, G. A. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke, 1998, 29(0039-2499), 2189-2195.
  6. Ahn, J.H.; Song, M.; Kim, H.; Lee, T.K.; Park, C.W.; Park, Y.E.; Lee, J.C.; Cho, J.H.; Kim, Y.M.; Hwang, I.K.; Won, M.A.O.; Park, J.H. Differential regional infarction, neuronal loss and gliosis in the gerbil cerebral hemisphere following 30 min of unilateral common carotid artery occlusion. Metab. Brain Dis., 2019, 34, 223-233. doi: 10.1007/s11011-018-0345-9
  7. Ghavami, S.; Shojaei, S.; Yeganeh, B.; Ande, S.R.; Jangamreddy, J.R.; Mehrpour, M.; Christoffersson, J.; Chaabane, W.; Moghadam, A.R.; Kashani, H.H.; Hashemi, M.; Owji, A.A.; Łos, M.J. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog. Neurobiol., 2014, 12, 24-49. doi: 10.1016/j.pneurobio.2013.10.004
  8. Zhao, T.A.O.X.; Tang, H.A.O.; Xie, L.; Zheng, Y.; Ma, Z.; Sun, Q.; Li, X. Scutellaria baicalensis Georgi. (Lamiaceae): A review of its traditional uses, botany, phytochemistry, pharmacology and toxicology. J Pharm Pharmacol, 2019, 71(2042-7158), 1353-1369.
  9. Huang, T.; Liu, Y.; Zhang, C. Pharmacokinetics and Bioavailability Enhancement of Baicalin: A Review. Eur. J. Drug Metab. Pharmacokinet., 2019, 44(2), 159-168. doi: 10.1007/s13318-018-0509-3 PMID: 30209794
  10. Cheng, O.; Li, Z.; Han, Y.; Jiang, Q.; Yan, Y.; Cheng, K. Baicalin improved the spatial learning ability of global ischemia/reperfusion rats by reducing hippocampal apoptosis. Brain Res., 2012, 1470, 111-118. doi: 10.1016/j.brainres.2012.06.026 PMID: 22796597
  11. Wang, P.; Cao, Y.; Yu, J.; Liu, R.; Bai, B.; Qi, H.; Zhang, Q.; Guo, W.; Zhu, H.; Qu, L. Baicalin alleviates ischemia-induced memory impairment by inhibiting the phosphorylation of CaMKII in hippocampus. Brain Res., 2016, 1642, 95-103. doi: 10.1016/j.brainres.2016.03.019 PMID: 27016057
  12. Liang, W.; Huang, X.; Chen, W. The Effects of Baicalin and Baicalein on Cerebral Ischemia: A Review. Aging Dis., 2017, 8(6), 850-867. doi: 10.14336/AD.2017.0829 PMID: 29344420
  13. Zhang, R.; Zhu, X.; Bai, H.; Ning, K. Network pharmacology databases for traditional chinese medicine: Review and assessment. Front. Pharmacol., 2019, 10, 123.
  14. Westerhoff, H.V. Network-based pharmacology through systems biology. Drug Discov. Today. Technol., 2015, 15, 15-16. doi: 10.1016/j.ddtec.2015.05.001 PMID: 26464085
  15. Nogales, C.; Mamdouh, Z.M.; List, M.; Kiel, C.; Casas, A.I.; Schmidt, H.H.H.W. Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol. Sci., 2022, 43(2), 136-150. doi: 10.1016/j.tips.2021.11.004 PMID: 34895945
  16. Ferreira, L.; dos Santos, R.; Oliva, G.; Andricopulo, A. Molecular docking and structure-based drug design strategies. Molecules, 2015, 20(7), 13384-13421. doi: 10.3390/molecules200713384 PMID: 26205061
  17. Pinzi, L.; Rastelli, G. Molecular docking: Shifting paradigms in drug discovery. Int. J. Mol. Sci., 2019, 20(18), 4331. doi: 10.3390/ijms20184331 PMID: 31487867
  18. 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. doi: 10.1186/1758-2946-6-13 PMID: 24735618
  19. Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623. doi: 10.1021/jm020017n PMID: 12036371
  20. Jia, C.Y.; Li, J.Y.; Hao, G.F.; Yang, G.F. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov. Today, 2020, 25(1), 248-258. doi: 10.1016/j.drudis.2019.10.014 PMID: 31705979
  21. UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res, 2019, 47(1362-4962), D506-D515.
  22. Stelzer, G.; Rosen, N.; Plaschkes, I.; Zimmerman, S.; Twik, M.; Fishilevich, S.; Stein, T. I.; Nudel, R.; Lieder, I.; Mazor, Y.; Kaplan, S.; Dahary, D.; Warshawsky, D.; Guan-Golan, Y.; Kohn, A.; Rappaport, N.; Safran, M.; Lancet, D. GeneCards suite: From gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinform., 2016, 54(1), 1.30.1-1.30.33.
  23. Amberger, J. S.; Hamosh, A. Mendelian inheritance in man (OMIM): A knowledgebase of human genes and genetic phenotypes. Curr. Protoc. Bioinform., 2017, 58(1), 1.2.1-1.2.12.
  24. von Mering, C. STRING: Known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res, 2005, 33(1362-4962), D433-D437.
  25. Shannon, P.; Markiel, A Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res, 2003, 13(1088-9051), 2498-504.
  26. Kanehisa, M.; Sato, Y.; Furumichi, M.; Morishima, K.; Tanabe, M. New approach for understanding genome variations in KEGG. Nucleic Acids Res., 2019, 47(D1), D590-D595. doi: 10.1093/nar/gky962 PMID: 30321428
  27. Li, Z.; Xiao, G.; Wang, H.; He, S.; Zhu, Y. A preparation of Ginkgo biloba L. leaves extract inhibits the apoptosis of hippocampal neurons in post-stroke mice via regulating the expression of Bax/Bcl-2 and Caspase-3. J. Ethnopharmacol., 2021, 280, 114481. doi: 10.1016/j.jep.2021.114481 PMID: 34343651
  28. Pei, X.; Li, Y.; Zhu, L.; Zhou, Z. Astrocyte-derived exosomes transfer miR-190b to inhibit oxygen and glucose deprivation-induced autophagy and neuronal apoptosis. Cell Cycle, 2020, 19(8), 906-917. doi: 10.1080/15384101.2020.1731649 PMID: 32150490
  29. Li, C.; Lin, G.; Zuo, Z. Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones. Biopharm. Drug Dispos., 2011, 32(8), 427-445. doi: 10.1002/bdd.771 PMID: 21928297
  30. Liu, Q.; Zuo, R.; Wang, K.; Nong, F.; Fu, Y.; Huang, S.; Pan, Z.; Zhang, Y.; Luo, X.; Deng, X.; Zhang, X.; Zhou, L.; Chen, Y. Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway. Acta Pharmacol. Sin., 2020, 41(6), 771-781. doi: 10.1038/s41401-019-0335-4 PMID: 31937929
  31. Lee, S.; Rauch, J.; Kolch, W. Targeting MAPK signaling in Cancer: Mechanisms of drug resistance and sensitivity. Int. J. Mol. Sci., 2020, 21(3), 1102.
  32. Fluri, F.; Schuhmann, M.K.; Kleinschnitz, C. Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther, 2015, 9(1177-8881), 3445-3454.
  33. Chamorro, Á.; Dirnagl, U.; Urra, X.; Planas, A.M. Neuroprotection in acute stroke: Targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol., 2016, 15(8), 869-881. doi: 10.1016/S1474-4422(16)00114-9 PMID: 27180033
  34. Xu, M.; Chen, X.; Gu, Y.; Peng, T.; Yang, D.; Chang, R.C.C.; So, K.F.; Liu, K.; Shen, J. Baicalin can scavenge peroxynitrite and ameliorate endogenous peroxynitrite-mediated neurotoxicity in cerebral ischemia-reperfusion injury. J. Ethnopharmacol., 2013, 150(1), 116-124. doi: 10.1016/j.jep.2013.08.020 PMID: 23973788
  35. Zhao, J.; Jiang, P Molecular networks for the study of TCM pharmacology. Brief Bioinform, 2010, 11(1477-4054), 417.(430).
  36. Ge, Q.; Hu, X.; Ma, Z.; Liu, J.; Zhang, W.; Chen, Z.; Wei, E. Baicalin attenuates oxygen–glucose deprivation-induced injury via inhibiting NMDA receptor-mediated 5-lipoxygenase activation in rat cortical neurons. Pharmacol. Res., 2007, 55(2), 148-157. doi: 10.1016/j.phrs.2006.11.007 PMID: 17187986
  37. Wu, J.; Wang, B.; Li, M.; Shi, Y.H.; Wang, C.; Kang, Y.G. Network pharmacology identification of mechanisms of cerebral ischemia injury amelioration by Baicalin and Geniposide. Eur. J. Pharmacol., 2019, 859, 172484. doi: 10.1016/j.ejphar.2019.172484 PMID: 31229537
  38. Shiojima, I.; Walsh, K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res., 2002, 90(12) doi: 10.1161/01.RES.0000022200.71892.9F
  39. Kandel, E.S.; Hay, N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res., 1999, 253(1), 210-229. doi: 10.1006/excr.1999.4690 PMID: 10579924
  40. Jung, K.; Kim, M.; So, J.; Lee, S.H.; Ko, S.; Shin, D.; Farnesoid, X. Farnesoid X receptor activation impairs liver progenitor cell–mediated liver regeneration via the PTEN‐PI3K‐AKT‐mTOR axis in zebrafish. Hepatology., 2021, 74(1), 397-410. doi: 10.1002/hep.31679 PMID: 33314176
  41. Chang, Z.; Xiao, Q.; Feng, Q.; Yang, Z. PKB/Akt signaling in cardiac development and disease. 2010, 2(4), 1485-1491.
  42. Hou, K.; Xu, D.; Li, F.; Chen, S.; Li, Y. The progress of neuronal autophagy in cerebral ischemia stroke: Mechanisms, roles and research methods. J. Neurol. Sci., 2019, 400, 72-82. doi: 10.1016/j.jns.2019.03.015 PMID: 30904689
  43. Valdés, F.; Pásaro, E.; Díaz, I.; Centeno, A.; López, E.; García-Doval, S.; González-Roces, S.; Alba, A.; Laffon, B. Segmental heterogeneity in Bcl-2, Bcl-xL and Bax expression in rat tubular epithelium after ischemia-reperfusion. Nephrology., 2008, 13(4), 294-301. doi: 10.1111/j.1440-1797.2007.00909.x PMID: 18221257
  44. Quadri, S.M.; Segall, L.; Perrot, M.; Han, B.; Edwards, V.; Jones, N.; Waddell, T.K.; Liu, M.; Keshavjee, S. Caspase inhibition improves ischemia-reperfusion injury after lung transplantation. Am. J. Transplant., 2005, 5(2), 292-299. doi: 10.1111/j.1600-6143.2004.00701.x PMID: 15643988
  45. Weiland, U.; Haendeler, J.; Ihling, C.; Albus, U.; Scholz, W.; Ruetten, H.; Zeiher, A.M.; Dimmeler, S. Inhibition of endogenous nitric oxide synthase potentiates ischemia–reperfusion-induced myocardial apoptosis via a caspase-3 dependent pathway. Cardiovasc. Res., 2000, 45(3), 671-678. doi: 10.1016/S0008-6363(99)00347-8 PMID: 10728388
  46. Li, D.; Shinagawa, K.; Pang, L.; Leung, T.K.; Cardin, S.; Wang, Z.; Nattel, S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation, 2001, 104(21), 2608-2614. doi: 10.1161/hc4601.099402 PMID: 11714658
  47. Pan, B.; Sun, J.; Liu, Z.; Wang, L.; Huo, H.; Zhao, Y.; Tu, P.; Xiao, W.; Zheng, J.; Li, J. Longxuetongluo Capsule protects against cerebral ischemia/reperfusion injury through endoplasmic reticulum stress and MAPK-mediated mechanisms. J. Adv. Res., 2021, 33, 215-225. doi: 10.1016/j.jare.2021.01.016 PMID: 34603791
  48. Xie, W.; Zhu, T.; Dong, X.; Nan, F.; Meng, X.; Zhou, P.; Sun, G.; Sun, X. HMGB1-triggered inflammation inhibition of notoginseng leaf triterpenes against cerebral ischemia and reperfusion injury via MAPK and NF-κB signaling pathways. Biomolecules, 2019, 9(10), 512. doi: 10.3390/biom9100512
  49. Oudit, G.; Sun, H.; Kerfant, B-G.; Crackower, M.A.; Penninger, J.M.; Backx, P.H. The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J. Mol. Cell. Cardiol., 2004, 37(2), 449-471. doi: 10.1016/j.yjmcc.2004.05.015 PMID: 15276015
  50. Choudhury, R.; Bonacci, T.; Wang, X.; Truong, A.; Arceci, A.; Zhang, Y.; Mills, C.A.; Kernan, J.L.; Liu, P.; Emanuele, M.J. The E3 ubiquitin ligase SCF(Cyclin F) transmits AKT signaling to the cell-cycle machinery. Cell Rep., 2017, 20(13), 3212-3222. doi: 10.1016/j.celrep.2017.08.099 PMID: 28954236
  51. He, F.; Zhang, N.; Lv, Y.; Sun, W.; Chen, H. Low dose lipopolysaccharide inhibits neuronal apoptosis induced by cerebral ischemia/reperfusion injury via the PI3K/Akt/FoxO1 signaling pathway in rats. Mol. Med. Rep., 2019, 19(3), 1443-1452. doi: 10.3892/mmr.2019.9827 PMID: 30628689
  52. Lv, M.R.; Li, B.; Wang, M.G.; Meng, F.G.; Yu, J.J.; Guo, F.; Li, Y. RETRACTED: Activation of the PI3K-Akt pathway promotes neuroprotection of the δ-opioid receptor agonist against cerebral ischemia-reperfusion injury in rat models. Biomed. Pharmacother., 2017, 93, 230-237. doi: 10.1016/j.biopha.2017.05.121 PMID: 28645007

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers